bluuebunny/crossref_metadata_2025 huggingface dataset:
A role for the nasal cycle in respiratory defence
Authors: Eccles R
Published: July 2003

This review describes the phenomenon of the nasal cycle, which consists of periodic congestion and decongestion of the nasal venous sinusoids. The hypothesis is put forward that the nasal venous sinusoids participate in respiratory defence by generation of plasma exudate. This hypothesis is based on recent studies, which have shown that the nasal venous sinusoids have a fenestrated endothelium and that the nasal cycle is increased during periods of nasal infection; and also on a series of older observations in the literature, which link the generation of nasal fluid to the decongestion of nasal venous sinusoids. It is proposed that the periodic congestion and decongestion of nasal venous sinusoids may provide a pump mechanism for the generation of plasma exudate, and that this mechanism is an important component of respiratory defence.
Increased respiratory burst and phosphodiesterase activity in alveolar eosinophils in chronic eosinophilic pneumonia
Authors: Aloui R , Gormand F , Prigent AF , Perrin-Fayolle M , Pacheco Y
Published: July 2003

A 43 year old woman presented with chronic eosinophilic pneumonia characterised by a high alveolar eosinophilic count, which allowed biochemical study of these cells. Alveolar eosinophils spontaneously produced high amounts of oxygen free radicals and exhibited an increased level of cyclic adenosine monophosphate (cAMP) phosphodiesterase (PDE) activity compared to blood eosinophils from control or allergic subjects. This activity was preferentially located in the plasma membrane, whilst the PDE activity of blood eosinophils from asthmatics or controls predominated in the cytosol. Because of the potential role of phosphodiesterase during eosinophil activation and recruitment, phosphodiesterase inhibitors may be useful in the treatment of eosinophilic pneumonia.
Nongranulomatous interstitial lung disease in Crohn's disease
Authors: Hotermans G , Benard A , Guenanen H , Demarcq-Delerue G , Malart T , Wallaert B
Published: July 2003

Crohn's disease is a granulomatous systemic disorder of unknown aetiology. Obvious pulmonary involvement is exceptional. We report the case of a 33 year old woman treated with mesalazine for Crohn's disease and presenting with dyspnoea. Pulmonary function tests showed a restrictive ventilatory pattern with hypoxaemia on exertion. Chest radiography disclosed an interstitial pattern with ground glass on high resolution computer tomography. Clinical and radiological abnormalities progressed after withdrawal of mesalazine. Corticosteroids led to a partial regression but were stopped because of severe side-effects. Because of worsening of the clinical situation, open lung biopsy was performed and showed a histopathological aspect of nongranulomatous interstitial diffuse lung disease with an inflammatory lymphoid infiltration associated to some mild interstitial collagen fibrosis. Addition of cyclophosphamide to high-dose pulse steroid therapy induced a significant and sustained improvement.
Kaposi's disease and sarcoidosis
Authors: Corda L , Benerecetti D , Ungari M , Facchetti F , Radaeli E
Published: July 2003

A human immunodeficiency virus (HIV) antibody-negative 65 year old woman was treated with corticosteroids for 7 yrs because of bilateral uveitis. One year after the beginning of corticosteroid treatment, erythematous skin lesions appeared on the legs. Eight years after the diagnosis of uveitis, gastric and bronchial biopsies revealed noncaseating epithelioid cell granulomas, whilst a cutaneous biopsy showed Kaposi's disease. Sarcoidosis-associated alteration of immune regulation and corticosteroid therapy may have promoted the development of disease.
Acute respiratory distress syndrome due to methicillin-resistant Staphylococcus aureus sepsis in hyper-IgE syndrome
Authors: Sato E , Yamamoto H , Honda T , Koyama S , Kubo K , Sediguchi M
Published: July 2003

We report the case of a 34 year old woman with acute respiratory distress syndrome (ARDS) and disseminated intravascular coagulation (DIC) due to methicillin-resistant Staphylococcus aureus (MRSA) sepsis with hyperimmunoglobulin E syndrome (HIES). Although chemotactic activity of neutrophils was impaired in this patient, neutrophils accumulated in the lungs as assessed by bronchoalveolar lavage fluid (BALF) counts. In addition to antibiotics and oxygen therapy, the administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF) resulted in a remarkable recovery.
Phase I/II Trial of Epratuzumab (Humanized Anti-CD22 Antibody) in Indolent Non-Hodgkin’s Lymphoma
Authors: Leonard John P. , Coleman Morton , Ketas Jamie C. , Chadburn Amy , Ely Scott , Furman Richard R. , Wegener William A. , Hansen Hans J. , Ziccardi Heather , Eschenberg Michael , Gayko Urte , Cesano Alessandra , Goldenberg David M.
Published: July 2003

Purpose: This single-center, dose-escalation study examines the safety, efficacy, and pharmacokinetics of epratuzumab (anti-CD22 humanized monoclonal antibody) in patients with recurrent indolent non-Hodgkin’s lymphoma (NHL).

Patients and Methods: Patients had indolent NHL and recurrent disease after at least one chemotherapy regimen. Epratuzumab was administered intravenously at 120 to 1,000 mg/m2over 30 to 60 minutes weekly for four treatments.

Results: Fifty-five patients received epratuzumab and were assessable for safety; 51 patients were assessable for response. Patients were heavily pretreated (50% had at least four prior regimens) and 49% had bulky disease (≥ 5 cm). Epratuzumab was well tolerated, with no dose-limiting toxicity. Circulating B cells transiently decreased without significant effects on T cells or immunoglobulin levels. More than 95% of infusions were completed in approximately 1 hour. Mean serum half-life was 23 days. Across all dose levels and histologies, nine patients (18%; 95% confidence interval, 8% to 31%) achieved objective response, including three complete responses (CRs). All responses were in patients with follicular NHL: 24% of these patients responded, including 43% in the 360 mg/m2dose group and 27% in the 480 mg/m2dose group. No responses were observed in other indolent histologies. Median duration of objective response was 79.3 weeks (range, 11.1 to 143.3 weeks), with median time to progression for responders of 86.6 weeks by Kaplan-Meier estimate.

Conclusion: Epratuzumab was well tolerated at up to 1,000 mg/m2/wk (for 4 weeks) and had clinical activity. One third of responding patients achieved CR. A 43% objective response rate in follicular NHL patients treated at 360 mg/m2/wk indicates that this dose should be explored in additional studies.
Meeting Highlights: Updated International Expert Consensus on the Primary Therapy of Early Breast Cancer
Authors: Goldhirsch Aron , Wood William C. , Gelber Richard D. , Coates Alan S. , Thürlimann Beat , Senn Hans-Jörg
Published: July 2003

This account of the highlights of the eighth St Gallen (Switzerland) meeting in 2003 emphasizes new information that has emerged during the 2 years since the seventh meeting in 2001. This article should be read in conjunction with the report of that earlier meeting. Recommendations for patient care are so critically dependent on assessment of endocrine responsiveness that the importance of high-quality steroid hormone receptor determination and standardized quantitative reporting cannot be overemphasized. The International Consensus Panel modified the risk categories so that only endocrine receptor–absent status was sufficient to reclassify an otherwise low-risk, node-negative disease into the category of average risk. Absence of steroid hormone receptors also was recognized as indicating endocrine nonresponsiveness. Some important areas highlighted at the recent meeting include: (1) recognition of the separate nature of endocrine-nonresponsive breast cancer—both invasive cancers and ductal carcinoma-in-situ; (2) improved understanding of the mechanisms of acquired endocrine resistance, which offer exciting prospects for extending the impact of successful sequential endocrine therapies; (3) presentation of high-quality evidence indicating that chemotherapy and tamoxifen should be used sequentially rather than concurrently; (4) availability of a potential alternative to tamoxifen for treatment of postmenopausal women with endocrine-responsive disease; and (5) the promise of newly defined prognostic and predictive markers.
Gemcitabine Plus Vinorelbine Compared With Cisplatin Plus Vinorelbine or Cisplatin Plus Gemcitabine for Advanced Non–Small-Cell Lung Cancer: A Phase III Trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group
Authors: Gridelli Cesare , Gallo Ciro , Shepherd Frances A. , Illiano Alfonso , Piantedosi Francovito , Robbiati Sergio Federico , Manzione Luigi , Barbera Santi , Frontini Luciano , Veltri Enzo , Findlay Brian , Cigolari Silvio , Myers Robert , Ianniello Giovanni P. , Gebbia Vittorio , Gasparini Giampietro , Fava Sergio , Hirsh Vera , Bezjak Andrea , Seymour Lesley , Perrone Francesco
Published: July 2003

Purpose: Platinum-containing chemotherapy regimens are the standard treatment for patients with advanced non–small-cell lung cancer (NSCLC), although toxicity is common and may significantly affect the patient’s quality of life (QoL). This trial aimed to assess whether a combination of gemcitabine and vinorelbine had benefits in terms of QoL, without influencing negatively on survival, compared with cisplatin-containing regimens.

Patients and Methods: Patients with stage IIIB (effusion and supraclavicular nodes) or IV documented NSCLC who were younger than 70 years of age were randomly assigned gemcitabine plus vinorelbine (GemVin) or either gemcitabine plus cisplatin or vinorelbine plus cisplatin (cisplatin-based). European Organization for Research and Treatment of Cancer scales were used for QoL analysis.

Results: Five hundred one patients were randomly assigned to treatment. The median age was 62 years. There were no significant differences in global QoL scores between the two arms after 2 months of treatment. However, worsening scores for appetite, vomiting, and alopecia were significantly more common in the cisplatin-based arm. Median survival was 38 v 32 weeks and median progression-free survival was 23 v 17 weeks in the cisplatin-based versus GemVin arms, respectively. For the GemVin arm the hazard ratio for death was 1.15 (90% confidence interval [CI], 0.96 to 1.37) and the hazard ratio for progression was 1.29 (90% CI, 1.10 to 1.52). Grade 3 or 4 myelosuppression, vomiting, alopecia, and ototoxicity were significantly more frequent with cisplatin-based treatment.

Conclusion: Global QoL is not improved with GemVin, although advantages in some components of QoL were apparent. GemVin is less toxic than standard cisplatin-based chemotherapy. There is a nonsignificant slight survival advantage with cisplatin-based chemotherapy. GemVin could be offered to advanced NSCLC patients who express concern about toxicity.
Randomized, Multinational, Phase III Study of Docetaxel Plus Platinum Combinations Versus Vinorelbine Plus Cisplatin for Advanced Non–Small-Cell Lung Cancer: The TAX 326 Study Group
Authors: Fossella Frank , Pereira Jose R. , von Pawel Joachim , Pluzanska Anna , Gorbounova Vera , Kaukel Eckhard , Mattson Karin V. , Ramlau Rodryg , Szczęsna Aleksandra , Fidias Panagiotis , Millward Michael , Belani Chandra P.
Published: July 2003

Purpose: To investigate whether docetaxel plus platinum regimens improve survival and affect quality of life (QoL) in advanced non–small-cell lung cancer (NSCLC) compared with vinorelbine plus cisplatin as first-line chemotherapy.

Patients and Methods: Patients (n = 1,218) with stage IIIB to IV NSCLC were randomly assigned to receive docetaxel 75 mg/m2 and cisplatin 75 mg/m2 every 3 weeks (DC); docetaxel 75 mg/m2 and carboplatin area under the curve of 6 mg/mL • min every 3 weeks (DCb); or vinorelbine 25 mg/m2/wk and cisplatin 100 mg/m2 every 4 weeks (VC).

Results: Patients treated with DC had a median survival of 11.3 v 10.1 months for VC-treated patients (P = .044; hazard ratio, 1.183 [97.2% confidence interval, 0.989 to 1.416]). The 2-year survival rate was 21% for DC-treated patients and 14% for VC-treated patients. Overall response rate was 31.6% for DC-treated patients v 24.5% for VC-treated patients (P = .029). Median survival (9.4 v 9.9 months [for VC]; P = .657; hazard ratio, 1.048 [97.2 confidence interval, 0.877 to 1.253]) and response (23.9%) with DCb were similar to those results for VC. Neutropenia, thrombocytopenia, infection, and febrile neutropenia were similar with all three regimens. Grade 3 to 4 anemia, nausea, and vomiting were more common (P < .01) with VC than with DC or DCb. Patients treated with either docetaxel regimen had consistently improved QoL compared with VC-treated patients, who experienced deterioration in QoL.

Conclusion: DC resulted in a more favorable overall response and survival rate than VC. Both DC and DCb were better tolerated and provided patients with consistently improved QoL compared with VC. These findings demonstrate that a docetaxel plus platinum combination is an effective treatment option with a favorable therapeutic index for first-line treatment of advanced or metastatic NSCLC.
Immunotoxic Destruction of Distinct Catecholaminergic Neuron Populations Disrupts the Reproductive Response to Glucoprivation in Female Rats
Authors: I’Anson Helen , Sundling Lois A. , Roland Shannon M. , Ritter Sue
Published: July 2003

We tested the hypothesis that hindbrain catecholamine (norepinephrine or epinephrine) neurons, in addition to their essential role in glucoprivic feeding, are responsible for suppressing estrous cycles during chronic glucoprivation. Normally cycling female rats were given bilateral injections of the retrogradely transported ribosomal toxin, saporin, conjugated to monoclonal dopamine β-hydroxylase antibody (DSAP) into the paraventricular nucleus (PVN) of the hypothalamus to selectively destroy norepinephrine and epinephrine neurons projecting to the PVN. Controls were injected with unconjugated saporin. After recovery, we assessed the lesion effects on estrous cyclicity under basal conditions and found that DSAP did not alter estrous cycle length. Subsequently, we examined effects of chronic 2-deoxy-d-glucose-induced glucoprivation on cycle length. After two normal 4- to 5-d cycles, rats were injected with 2-deoxy-d-glucose (200 mg/kg every 6 h for 72 h) beginning 24 h after detection of estrus. Chronic glucoprivation increased cycle length in seven of eight unconjugated saporin rats but in only one of eight DSAP rats. Immunohistochemical results confirmed loss of dopamine β-hydroxylase immunoreactivity in PVN. Thus, hindbrain catecholamine neurons with projections to the PVN are required for inhibition of reproductive function during chronic glucose deficit but are not required for normal estrous cyclicity when metabolic fuels are in abundance.
Fasting Activates the Nonhuman Primate Hypocretin (Orexin) System and Its Postsynaptic Targets
Authors: Diano Sabrina , Horvath Balazs , Urbanski Henryk F. , Sotonyi Peter , Horvath Tamas L.
Published: July 2003

In rodents, hypocretin (HCRT, also called orexin) influences a variety of endocrine, autonomic, and metabolic functions. The present study was undertaken to determine whether the HCRT-producing circuit is involved in the hypothalamic regulation of homeostasis in primates as well. We studied female monkeys (Cercopithecus aethiops) that were either fed or fasted for 24 h. Immunocytochemistry revealed HCRT-producing perikarya exclusively in the lateral hypothalamus-perifornical region and dorsomedial hypothalamus of the monkey brain. HCRT axons and axon terminals were present in different parts of the hypothalamus and adjacent forebrain and thalamic nuclei. The 24-h fast resulted in an approximately 50% decline in circulating leptin levels and significantly elevated c-fos expression in the perifornical region; in the dorsomedial, ventromedial, and arcuate nuclei; and in the medial preoptic area. In the dorsomedial nucleus and perifornical region of fasted monkeys, three times more HCRT-neurons expressed nuclear c-fos than those of the normally fed controls. Neurons in different parts of the hypothalamus and basal forebrain that expressed c-fos, but did not contain HCRT, were targets of HCRT-immunopositive boutons establishing asymmetric synapses. In the arcuate nucleus, subsets of these HCRT-targeted c-fos-expressing cells contained neuropeptide Y. The present study provides the first experimental evidence to implicate HCRT in the hypothalamic regulation of homeostasis in primates. The fact that these lateral hypothalamic cells have leptin receptors and can be activated by a metabolic challenge and that they innervate diverse brain regions indicates that the HCRT system may be a key integrator of environmental cues in their regulation of diverse brain activity.
Glucagon-Like Peptide-2 Receptor Activation in the Rat Intestinal Mucosa
Authors: Walsh Natalie A. , Yusta Bernardo , DaCambra Mark P. , Anini Younes , Drucker Daniel J. , Brubaker Patricia L.
Published: July 2003

Glucagon-like peptide-2 (GLP-2) increases small intestinal growth and function in rodents and human subjects. GLP-2 exerts its effects through a seven-transmembrane domain, G protein-coupled receptor (GLP-2R), stimulating cAMP generation and activating protein kinase A signaling in heterologous cell lines transfected with the GLP-2R. As intestinal cell lines expressing the GLP-2R have not been identified, we developed methods for studying GLP-2R signaling in the rat small intestinal mucosa in vitro. Isolated rat intestinal mucosal cells expressed mRNA transcripts for the GLP-2R, as well as for chromogranin A and β-tubulin III, markers for enteroendocrine and neural cells, respectively. cAMP production in response to [Gly2]GLP-2, a degradation-resistant analog of GLP-2, was maximal at 10−11m (268 ± 93% of control, P < 0.001), with reduced cAMP accumulation observed at higher doses. The cAMP response was diminished by pretreatment with 10−9m GLP-2, and was abolished by pretreatment with 10−6m GLP-2 (P < 0.05), indicating receptor desensitization. GLP-2 treatment of isolated mucosal cells increased 3H-thymidine incorporation (to 128 ± 8% of controls, P < 0.05), and this was prevented by inhibition of the protein kinase A pathway with H89. In contrast, GLP-2 did not affect p44/p42 MAPK phosphorylation or the levels of cytosolic calcium in the mucosal cell preparation. These results provide the first evidence that activation of the endogenous rat mucosal GLP-2 receptor is linked to activation of a cAMP/protein kinase A-dependent, growth-promoting pathway in vitro.
Endogenous Melanocortin Antagonist in Fish: Structure, Brain Mapping, and Regulation by Fasting of the Goldfish Agouti-Related Protein Gene
Authors: Cerdá-Reverter José Miguel , Peter Richard Ector
Published: July 2003

Agouti-related protein (AGRP) is a naturally occurring antagonist of melanocortin. In mammals, central AGRP expression is restricted to the arcuate nucleus in which it plays a key role in the control of energy balance by antagonizing melanocortin effects at melanocortin 4 receptors. In goldfish, melanocortin 4 receptor is profusely expressed within the main brain areas for the control of energy balance, and central administration of agonist or antagonist analogs inhibits or stimulates food intake, respectively. Here we demonstrate that the goldfish genome has a homologous gene to mammalian AGRP. Detailed brain mapping by in situ hybridization shows that AGRP is exclusively expressed in the ventrobasal hypothalamic lateral tuberal nucleus, the teleostean homolog of the arcuate nucleus. Fasting up-regulates its mRNA levels in the lateral tuberal nucleus. In the periphery, AGRP is expressed in several tissues including ovary, muscle, and ventral skin, suggesting that AGRP might regulate peripheral actions of melanocortin peptides. The results provide the first evidence for an endogenous melanocortin antagonist in nontetrapod species and suggest that hypothalamic overexpression during fasting might regulate the inhibitory effects of melanocortin peptides on food intake in goldfish.
Short-Term Activation by Low 17β-Estradiol Concentrations of the Na+/H+ Exchanger in Rat Aortic Smooth Muscle Cells: Physiopathological Implications
Authors: Incerpi Sandra , D’Arezzo Silvia , Marino Maria , Musanti Roberto , Pallottini Valentina , Pascolini Andrea , Trentalance Anna
Published: July 2003

Low physiological concentrations of 17β-estradiol increased the intracellular pH of rat aortic smooth muscle cells by a rapid nongenomic mechanism. This effect was due to stimulation of the Na+/H+ exchanger activity, measured using the intracellular pH-sensitive fluorescent probe 2′,7′-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein. The 17β-estradiol gave rise to a bell-shaped dose response, with a maximum at 10−12m and no significant effect at 10−9m. The specificity of the effect was verified by the use of the Na+/H+ exchanger inhibitor 5-(ethyl-N-isopropyl)amiloride and the lack of effect of the isomer 17α-estradiol. Inhibitors of the nuclear estrogen receptors, tamoxifen and ICI 182,780, completely prevented activation of the exchanger by 17β-estradiol. The effect of low estrogen concentrations on the intracellular pH was mimicked by both norepinephrine and phenylephrine, suggesting a connection between the increase of intracellular pH and the muscle contraction process. The transduction mechanism for this nongenomic effect of estrogens did not involve modulation of the cAMP content, whereas inositol 1,4,5-trisphosphate, protein kinase C and MAPK pathways appear to play a role, as indicated by both pharmacological approaches and immunoblot experiments on protein kinase C translocation and ERK phosphorylation. These results for the first time provide evidence for a nongenomic effect of low physiological concentrations of 17β-estradiol on intracellular pH that, together with other factors, may contribute to the development of hypertension and atherosclerosis in men and postmenopausal women and increase the risk of cardiovascular disease. Paradoxically, the lack of stimulation at high physiological estradiol levels could explain the protective effects found in premenopausal women.
High Prevalence of Cardiac Valve Disease in Acromegaly: An Observational, Analytical, Case-Control Study
Authors: Colao Annamaria , Spinelli Letizia , Marzullo Paolo , Pivonello Rosario , Petretta Mario , Di Somma Carolina , Vitale Giovanni , Bonaduce Domenico , Lombardi Gaetano
Published: July 2003

To characterize mitral and aortic valve abnormalities we performed M-mode, two-dimensional, and pulsed Doppler echocardiography in 42 patients with active acromegaly, 22 patients cured of acromegaly, and 64 controls pair-matched with the patients for sex and age. The overall prevalence of valve abnormalities was higher in both the active patients (86% vs. 24%; P < 0.0001) and the cured patients (73% vs. 9%; P < 0.0001) than in controls. Left ventricular hypertrophy was higher in active (81% vs. 29%; P < 0.0001), but not in cured (41% vs. 14%; P = 0.09) patients than in controls. Cardiac valve abnormalities were associated with left ventricular hypertrophy in both patients and controls, without any difference between them. Conversely, among subjects without left ventricular hypertrophy, mitral and aortic abnormalities were only present in the patients (75% of active and 54% of cured), but not in controls (3% of active controls and 0% of cured controls).

In conclusion, patients with active acromegaly and those cured of the disease have a high prevalence of mitral and aortic abnormalities. The persistence of valve disease in patients with cured acromegaly is likely to be correlated with the persistence of left ventricular hypertrophy, which should be carefully and continuously monitored as an aspect of the risk of cardiac dysfunction in these patients.
Association of Polymorphisms of Interleukin-6, Osteocalcin, and Vitamin D Receptor Genes, Alone or in Combination, with Bone Mineral Density in Community-Dwelling Japanese Women and Men
Authors: Yamada Yoshiji , Ando Fujiko , Niino Naoakira , Shimokata Hiroshi
Published: July 2003

We examined whether the −634C→G, 298C→T, and 2C→T polymorphisms of the IL-6, osteocalcin, and vitamin D receptor (VDR) genes, respectively, were associated, alone or in combination, with bone mineral density (BMD) in community-dwelling Japanese women (between 1108 and 1113) or men (between 1116 and 1130) aged 40–79 yr. The −634C→G polymorphism of the IL-6 gene and the 298C→T polymorphism of the osteocalcin gene were associated with BMD in postmenopausal women, with the respective GG and TT genotypes representing risk factors for reduced bone mass. IL-6 and osteocalcin genotypes showed additive effects on BMD for postmenopausal women. The 2C→T polymorphism of the VDR gene was associated with BMD in men, with the CT genotype contributing to reduced BMD. These results suggest that the IL-6 and osteocalcin genes are susceptibility loci for reduced BMD in postmenopausal women and that the VDR gene constitutes such a locus in men. The combined IL-6 and osteocalcin genotypes may prove informative for the assessment of osteoporosis in women.
Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Syndrome: Time to Review Diagnostic Criteria?
Authors: Buzi F. , Badolato R. , Mazza C. , Giliani S. , Notarangelo Lucia D. , Radetti G. , Plebani A. , Notarangelo Luigi D.
Published: July 2003

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an autosomal-recessive syndrome defined by two of the following conditions: chronic mucocutaneous candidiasis, hypoparathyroidism, or Addison’s disease. Other autoimmune conditions may be associated, such as hypothyroidism, hypogonadism, insulin-dependent diabetes mellitus, chronic active hepatitis, pernicious anemia, vitiligo, alopecia, biliary cirrhosis, and ectodermal dysplasia. APECED is caused by mutations in the autoimmune regulator gene, mapping to 21q22.3.

We report on three patients whose clinical and molecular features challenge the currently used diagnostic criteria for APECED. AR presented at 15 yr of age with a history of recurrent infections and mucocutaneous candidiasis. He is now 21 yr old, and no other signs or symptoms of APECED have appeared to date.

DR presented at 7 yr of age with hypocalcemia and a prolonged Q-T interval on the electrocardiogram. He also had minor facial dysmorphisms and mild mental retardation. Serum calcium levels were low, PTH levels were undetectable, and hypoparathyroidism was therefore diagnosed. All other biochemical, immunological, and endocrinological tests were normal. DR is now 8 yr old with no other signs or symptoms of APECED.

ST presented at 14 yr of age for alopecia aerata and pitted nail dystrophy and goiter. Thyroid function was normal in the presence of thyroid-specific antibodies. No other signs or symptoms of APECED have appeared to date.

Genetic analysis revealed a typical mutation (R257X) on a single allele in both AP and DR; in ST, heterozygosity for a novel mutation (V484M) involving one of the zinc fingers of the plant homeodomain of the protein was found. The finding of a typical APECED mutation in two patients presenting with one isolated major clinical APECED feature and of a novel mutation in a patient presenting with atypical features of APECED onset suggests that the time might have come for updating the diagnostic criteria of this syndrome.
Synthetic Exendin-4 (Exenatide) Significantly Reduces Postprandial and Fasting Plasma Glucose in Subjects with Type 2 Diabetes
Authors: Kolterman Orville G. , Buse John B. , Fineman Mark S. , Gaines Eling , Heintz Sonja , Bicsak Thomas A. , Taylor Kristin , Kim Dennis , Aisporna Maria , Wang Yan , Baron Alain D.
Published: July 2003

Despite the advent of new treatments, glucose control in the type 2 diabetes population is unsatisfactory. AC2993 (synthetic exendin-4; exenatide), a novel glucose-dependent insulinotropic agent, exhibited notable antidiabetic potential in two clinical studies in patients with type 2 diabetes. In study A, 24 subjects received sc injections of study medication (0.1 μg/kg AC2993 or placebo) twice daily with meals for 5 d. Statistically significant reductions in mean postprandial circulating concentrations of glucose, insulin, and glucagon occurred following treatment with AC2993. In study B, 13 subjects receiving a single dose of study medication (0.05, 0.1, or 0.2 μg/kg AC2993 or placebo) following an overnight fast had reduced fasting plasma glucose concentrations during the subsequent 8-h period. The relative glucose and insulin concentration profiles were consistent with glucose-dependent insulinotropism. AC2993 was well tolerated. Mild transient headache, nausea, and vomiting were the main adverse events. In conclusion, AC2993 acutely and markedly reduces fasting and postprandial glucose concentrations in patients with type 2 diabetes. During fasting, glucose-dependent enhancement of insulin secretion and suppression of glucagon secretion are the predominant mechanisms, and postprandially, slowing of gastric emptying is additionally operative. This robust antidiabetic effect warrants further evaluation of AC2993.
Dehydroepiandrosterone Supplementation Improves Endothelial Function and Insulin Sensitivity in Men
Authors: Kawano Hiroaki , Yasue Hirofumi , Kitagawa Akira , Hirai Nobutaka , Yoshida Toshiaki , Soejima Hirofumi , Miyamoto Shinzo , Nakano Masahiro , Ogawa Hisao
Published: July 2003

The dehydroepiandrosterone (DHEA) concentration decreases with age. There is evidence that DHEA has a protective effect against age-related disorders, including cardiovascular disease. Accordingly, we examined the effect of DHEA supplementation (25 mg/d) on endothelial function, insulin sensitivity, and fibrinolytic activity in 24 men with hypercholesterolemia (mean age, 54 ± 1 yr). All subjects were enrolled in a randomized, double-blind study. Flow-mediated dilation of brachial artery after transient occlusion, which was expressed as the percent change from the baseline value of the diameter, increased significantly with DHEA supplementation [DHEA: baseline, 3.9 ± 0.5%; 4 wk, 6.9 ± 0.7%; 8 wk, 7.9 ± 0.6%; 12 wk, 8.4 ± 0.7% (P < 0.01 vs. baseline for all, by ANOVA); placebo: 4.1 ± 0.6%, 4.5 ± 0.5%, 3.9 ± 0.5%, and 4.4 ± 0.6% (P < 0.01 for all, by ANOVA)]. There was a significant concurrent reduction in the plasma levels of plasminogen activator inhibitor type 1 during DHEA supplementation [DHEA: 9.1 ± 2.2, 6.4 ± 2.3, 5.5 ± 2.8, and 5.1 ± 2.0 IU/ml (P < 0.01 vs. baseline, by ANOVA); placebo: 9.0 ± 2.1, 10.4 ± 2.2, 9.5 ± 2.2, and 9.6 ± 2.1 IU/ml (P < 0.01, by ANOVA)]. DHEA supplementation also decreased steady state plasma glucose [DHEA: baseline, 178.9 ± 12.2; 12 wk, 132.0 ± 12.8 mg/dl (P < 0.01, by ANOVA); placebo: 181.0 ± 13.8 and 179.6 ± 12.4 mg/dl (P < 0.01, by ANOVA)]. In contrast, steady state plasma insulin did not change during the study in either group. The low dose DHEA supplementation improves vascular endothelial function and insulin sensitivity and decreases the plasminogen activator inhibitor type 1 concentration. These beneficial changes have the potential to attenuate the development of age-related disorders such as cardiovascular disease.
Bioavailable Estradiol and an Aromatase Gene Polymorphism Are Determinants of Bone Mineral Density Changes in Men over 70 Years of Age
Authors: Van Pottelbergh I. , Goemaere S. , Kaufman J. M.
Published: July 2003

The question of whether and to what extent the sex steroid deficiency in elderly men contributes to the pathogenesis of bone loss has not been fully explored. The aim of the present study was to assess the association of serum bioavailable (Bio) estradiol (E2) with the evolution of bone mineral density (BMD) in 214 community-dwelling men aged 71–86 yr as well as the possible modulation of estrogen effects by a tetranucleotide (TTTA)n-repeat polymorphism of the CYP19 gene, which encodes the aromatase enzyme that converts androgens into estrogens. BMD was measured at yearly intervals over a period of 4 yr using dual x-ray absorptiometry. Fasting blood was analyzed at baseline for testosterone (T), E2, and SHBG; the respective bioavailable fractions, BioT and BioE2, were calculated. Serum BioE2 was associated with baseline BMD at different assessed skeletal sites, with correlation coefficients ranging between 0.23 and 0.37 (P < 0.001). Estimated annual percentage change of BMD (%BMD) was −0.39% [95% confidence index (CI), −0.56, −0.22] at the total hip, −0.04% (95% CI, −0.29, 0.21) at the femoral neck, and −0.37% (95% CI, −0.45, −0.29) at the total distal forearm. Higher circulating BioE2 levels were associated with less bone loss at the forearm and the hip (P < 0.05). The CYP19 gene (TTTA)n-repeat length (determined by fragment analysis) was not associated with baseline BMD in the total group of elderly men. However, a significant association was observed between the CYP19 genotype and BMD change at the distal forearm; the highest bone loss was observed in subjects homozygotic for the shortest observed allele length of (TTTA)7-repeats (P < 0.02). The CYP19 (TTTA)n-repeat length was not associated with either baseline BioE2 or the BioT/BioE2 ratio. In multiple linear regression models, the CYP19 genotype and serum BioE2 were determinants of %BMD change at the forearm (P < 0.05). No significant contribution of BioT to %BMD change was evident. As to fracture risk, the allele containing the shortest (TTTA)n-repeat length was more represented not only in elderly men with a positive personal fracture history (Pearson’s χ2 test = 4.03; df = 1; P = 0.05) but also in study subjects with a positive fracture history in their first-degree relatives (Pearson’s χ2 test = 6.48; df = 1; P = 0.01). In conclusion, the results of this prospective observational study support the view that BioE2 is a determinant of bone density changes in elderly men and, furthermore, provide an indication that the aromatase enzyme may exert a direct modulatory action on bone metabolism at the tissue level in elderly men.
Troglitazone Induces CYP3A4 Activity Leading to Falsely Abnormal Dexamethasone Suppression Test
Authors: Dimaraki Eleni V. , Jaffe Craig A.
Published: July 2003

After evaluating a patient who appeared to have a falsely abnormal response to the dexamethasone suppression test while taking troglitazone, we examined the effects of troglitazone on the activity of hepatic CYP3A4 and the screening tests for Cushing’s syndrome. We studied five healthy women and three healthy men, aged 25 ± 2 yr, before and after treatment with troglitazone (600 mg daily) for 28 d. Baseline 0800 h cortisol and corticosterone were similar before and after troglitazone treatment. Before troglitazone treatment, all subjects suppressed 0800 h cortisol below 1.8 μg/dl (mean, 0.66 ± 0.08 μg/dl) during the 1-mg overnight dexamethasone suppression test (DST), whereas during troglitazone treatment none of the subjects suppressed 0800 h cortisol below 1.8 μg/dl (mean, 9.0 ± 1.8 μg/dl). Serum dexamethasone levels decreased by 66 ± 4%, and the erythromycin breath test measurements increased by 27 ± 8%, indicating increased CYP3A4 activity during troglitazone treatment. The hydrocortisone suppression test (HST) was performed by administering 50 mg hydrocortisone at 2300 h. Using the criterion of suppression of 0800 h plasma corticosterone by more than 50%, the specificity of the HST was 100% both before and after troglitazone treatment. In conclusion, troglitazone induced the activity of CYP3A4 leading to falsely abnormal DST. HST is a useful alternative to the DST in patients taking medications that increase the activity of CYP3A4.
Lovastatin, a 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitor, Induces Apoptosis and Differentiation in Human Anaplastic Thyroid Carcinoma Cells
Authors: Wang Chih-Yuan , Zhong Wen-Bin , Chang Tien-Chun , Lai Shu-Mei , Tsai Yuan-Feen
Published: July 2003

Although only 1% of differentiated thyroid cancers transform into anaplastic thyroid cancer, this disease is always fatal. Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells; these effects are unrelated to lipid reduction. Recently, we found that TNFα induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression; however, TNF is cytotoxic for normal human tissue. The aim of this study was to determine whether lovastatin, an HMG-CoA reductase inhibitor, could induce apoptosis and differentiation in anaplastic thyroid cancer cells. Anaplastic thyroid cancer cells were treated with lovastatin, then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation, phosphatidylserine externalization/flow cytometry, and electron microscopy. Thyroglobulin levels in the culture medium were also measured. Our results showed that at a higher dose (50 μm), lovastatin induced apoptosis of anaplastic thyroid cancer cells, whereas at a lower dose (25 μm), it promoted 3-dimensional cytomorphological differentiation. It also induced increased secretion of thyroglobulin by anaplastic cancer cells. Our results show that lovastatin not only induces apoptosis, but also promotes redifferentiation in anaplastic thyroid cancer cells, and suggest that it and other HMG-CoA reductase inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer.
Seasonal Variation of Testosterone and Waist to Hip Ratio in Men: The Tromsø Study
Authors: Svartberg Johan , Jorde Rolf , Sundsfjord Johan , Bønaa Kaare H. , Barrett-Connor Elizabeth
Published: July 2003

Studies of seasonal variation in male testosterone levels show contradictory results. We report here a cross-sectional study of the seasonal variation in total and free testosterone, LH, and SHBG levels in 1548 men living in north Norway, a population exposed to a wide seasonal variation in temperature and daylight. Total testosterone showed a bimodal seasonal variation (P < 0.001) with a small peak in February, the nadir in June, and a more prominent peak in October and November. Free testosterone also showed a significant seasonal pattern (P < 0.001), with the peak in December and the nadir in August. These patterns persisted after adjusting for age and waist to hip ratio (P < 0.001). Lowest testosterone levels occurred in months with the highest temperatures and longest hours of daylight. Waist to hip ratio paralleled the change in daylight and temperature, with the highest values during the summer and was thus inversely related to the seasonal testosterone variation. The variations in hormone levels were large, with a 31% difference between the lowest and highest monthly mean level of free testosterone. Prospective studies are needed to establish the direction of the association and its etiology.
Differential Regulation of Proopiomelanocortin and Pituitary-Restricted Transcription Factor (TPIT), a New Marker of Normal and Adenomatous Human Corticotrophs
Authors: Vallette-Kasic Sophie , Figarella-Branger Dominique , Grino Michel , Pulichino Anne-Marie , Dufour Henry , Grisoli François , Enjalbert Alain , Drouin Jacques , Brue Thierry
Published: July 2003

Since the identification of the pituitary-restricted transcription factor Tpit, a novel T-box factor that is only present in mouse in the two pituitary proopiomelanocortin (POMC)-expressing lineages, no information was available on its pattern of expression in human pituitary. We investigated by immunohistochemistry and in situ hybridization the expression of TPIT in normal human anterior pituitary tissue and in several types of human pituitary adenomas (n = 52).

TPIT expression was restricted to the nucleus of normal or adenomatous human corticotroph cells. No specific TPIT immunostaining was detectable in all prolactin (PRL)-, GH-, or gonadotropin-secreting adenomas. In situ hybridization studies demonstrated that TPIT transcripts were coexpressed with POMC mRNA in both secreting and silent corticotroph adenomas, and in normal corticotrophs, whereas TPIT mRNA was not detectable in other types of pituitary adenomas. Unlike POMC, TPIT was not up-regulated by adrenalectomy in rats and did not seem down-regulated in the normal pituitary adjacent to human corticotroph microadenomas.

TPIT is the only currently known transcription factor selectively expressed in human normal and adenomatous corticotrophs. In human and experimental models, TPIT and its target gene POMC were thus differentially regulated by glucocorticoids. Moreover, TPIT represents a new marker of POMC-expressing pituitary cells.
The Effect of Growth Hormone on the Insulin-Like Growth Factor System during Fasting
Authors: Nørrelund Helene , Frystyk Jan , Jørgensen Jens Otto Lunde , Møller Niels , Christiansen Jens Sandahl , Ørskov Hans , Flyvbjerg Allan
Published: July 2003

The present study investigates the possible stimulatory effect of endogenous GH on IGF and IGF-binding protein (IGFBP) levels during fasting. Eight normal subjects were examined on four occasions: 1) in the basal postabsorptive state; 2) after 40 h of fasting; 3) after 40 h of fasting with somatostatin suppression of GH; and 4) after 40 h of fasting with suppression of GH and exogenous GH replacement. The two somatostatin experiments were identical in terms of hormone replacement (except for GH). Short-term fasting led to a 50% reduction in free IGF-I. The reduction in free IGF-I was paralleled by an increase in IGFBP-1, an increase in the complex formation of IGFBP-1 and IGF-I, and a modest reduction in IGFBP-3 proteolysis. GH deprivation during fasting led to a 35% reduction in total IGF-I and a 70% reduction in free IGF-I. GH replacement increased free and total IGF-I to levels similar to those observed during plain fasting and decreased IGFBP-1, however, without affecting IGFBP-1-bound IGF-I. Finally, IGFBP-3 proteolysis was slightly increased by GH replacement. In conclusion, the major new finding of the present study is that the GH hypersecretion seen during short-term fasting is not merely secondary to a reduction in IGF bioactivity.
Fibroblast Growth Factors Regulate Prolactin Transcription via an Atypical Rac-Dependent Signaling Pathway
Authors: Jackson Twila A. , Koterwas David M. , Morgan Melissa A. , Bradford Andrew P.
Published: July 2003

Fibroblast growth factors (FGFs) play a critical role in pituitary development and in pituitary tumor formation and progression. We have previously characterized FGF signal transduction and regulation of the tissue-specific rat prolactin (rPRL) promoter in GH4 pituitary cells. FGF induction of rPRL transcription is independent of Ras, but mediated by a protein kinase C-δ (PKCδ)-dependent activation of MAPK (ERK). Here we demonstrate a functional role for the Rho family monomeric G protein, Rac1, in FGF regulation of PRL gene expression via an atypical signaling pathway. Expression of dominant negative Rac, but not RhoA or Cdc42, selectively inhibited FGF-induced rPRL promoter activity. Moreover, expression of dominant negative Rac also attenuated FGF-2 and FGF-4 stimulation of MAPK (ERK). However, in contrast to other Rac-dependent signaling pathways, FGF activation of rPRL promoter activity was independent of the c-Jun N-terminal kinase (JNK) and phosphoinositide 3-kinase/Akt cascades. FGFs failed to activate JNK1 or JNK2, and expression of dominant negative JNK or Akt constructs did not block FGF-induced PRL transcription. Consistent with the role of PKCδ in FGF regulation of PRL gene expression, activation of the rPRL promoter was blocked by an inhibitor of phospholipase Cγ (PLCγ) activity. FGF treatment also induced rapid tyrosine phosphorylation of PLCγ in a Rac-dependent manner. These results suggest that FGF-2 and FGF-4 activate PRL gene expression via a novel Rac1, PLCγ, PKCδ, and ERK cascade, independent of phosphoinositol-3-kinase and JNK.
Mammalian RanBP1 regulates centrosome cohesion during mitosis
Authors: Di Fiore Barbara , Ciciarello Marilena , Mangiacasale Rosamaria , Palena Antonella , Tassin Anne-Marie , Cundari Enrico , Lavia Patrizia
Published: July 2003

The Ran GTPase plays a central function in control of nucleo-cytoplasmic transport in interphase. Mitotic roles of Ran have also been firmly established in Xenopus oocyte extracts. In this system, Ran-GTP, or the RCC1 exchange factor for Ran, drive spindle assembly by regulating the availability of `aster-promoting activities'. In previous studies to assess whether the Ran network also influences mitosis in mammalian cells, we found that overexpression of Ran-binding protein 1 (RanBP1), a major effector of Ran, induces multipolar spindles. We now show that these abnormal spindles are generated through loss of cohesion in mitotic centrosomes. Specifically,RanBP1 excess induces splitting of mother and daughter centrioles at spindle poles; the resulting split centrioles can individually organize functional microtubule arrays, giving rise to functional spindle poles. RanBP1-dependent centrosome splitting is specifically induced in mitosis and requires microtubule integrity and Eg5 activity. In addition, we have identified a fraction of RanBP1 at the centrosome. These data indicate that overexpressed RanBP1 interferes with crucial factor(s) that control structural and dynamic features of centrosomes during mitosis and contribute to uncover novel mitotic functions downstream of the Ran network.
In yeast, the pseudohyphal phenotype induced by isoamyl alcohol results from the operation of the morphogenesis checkpoint
Authors: Martínez-Anaya Claudia , Dickinson J. Richard , Sudbery Peter E.
Published: July 2003

Isoamyl alcohol (IAA) induces a phenotype that resembles pseudohyphae in the budding yeast Saccharomyces cerevisiae. We show here that IAA causes the rapid formation of linear chains of anucleate buds, each of which is accompanied by the formation of a septin ring at its neck. This process requires the activity of Swe1 and Slt2 (Mpk1). Cdc28 is phosphorylated on tyrosine 19 in a Swe1-dependent manner, while Slt2 becomes activated by dual tyrosine/threonine phosphorylation. Tyrosine 19 phosphorylation of Cdc28 is not dependent on Slt2. However, the defective response in the slt2Δ mutant is rescued by an mih1Δ mutation. The IAA response still occurs in a cell containing a dominant non-phosphorylatable form of Cdc28, but no longer occurs in an mih1Δ slt2Δ mutant containing this form of Cdc28. These observations show that IAA induces the Swe1-dependent morphogenesis checkpoint and so the resulting pseudohyphal phenotype arises in an entirely different way from the formation of pseudohyphae induced by nitrogen-limited growth.