bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional Development of the Rat Urinary Bladder after Pre- or Postpubertal Castration
Authors: Longhurst Penelope A.
Published: April 2003

Experiments were done to evaluate the role of sex hormones in the functional development of the rat urinary bladder. Rats were orchiectomized or ovariectomized at 30 (prepubertal) or 70 (postpubertal) days of age and bladders were removed 1 month later. An additional group of immature male and female rats was used in which the bladders were removed at 30 days of age. There were only minor differences in contractile responses of bladder strips from any group to electrical field stimulation, ATP, carbachol, or KCl compared to age-matched controls. There were no differences in responses of bladder strips from immature females or males to the adrenergic agonists, isoproterenol, norepinephrine, or methoxamine. Bladders from the pre- and postpubertally castrated rats and their controls relaxed fully in response to isoproterenol, but strips from prepubertally castrated rats relaxed significantly less in response to norepinephrine than those from other groups. Approximately one half of the bladder strips from prepubertally castrated rats failed to relax by at least 50% in response to norepinephrine; these same strips responded to methoxamine with exaggerated contractions. Our data indicate that the normal development of rat bladder α-adrenergic responsiveness is adversely altered by prepubertal castration. We postulate that this may result from an alteration in the relative expression of α1-adrenergic receptor subtypes.
Inhibition of Prostaglandin Biosynthesis in Human Endotoxin-Stimulated Peripheral Blood Monocytes: Effects of Caffeine
Authors: Ulcar R. , Schuligoi R. , Heinemann A. , Santner B. , Amann R.
Published: April 2003

There is an ongoing debate about possible advantages of the coadministration of caffeine with cyclooxygenase (COX) inhibitors in the treatment of pain. There are results suggesting interference by caffeine with COX expression and activity in rat immune cells. In the present study, we have used, therefore, human endotoxin-stimulated monocytes to investigate a possible influence of caffeine on indometacin-induced inhibition of prostaglandin E2 (PGE2) formation. Endotoxin caused a concentration- and time-dependent increase in immunoreactive PGE2 that was dependent on CD14-mediated mechanisms. In order to investigate pharmacological inhibition of the COX activity, a submaximal concentration of 1 ng/ml endotoxin (4 h exposure time) was used. Indometacin caused a concentration-dependent inhibition of PGE2 with an apparent IC50 of 8.9 ± 1.4 × 10–9 mol/l and an Imax of 1 x 10–7 mol/l. Caffeine (5 × 10–6 to 1.5 × 10–4 mol/l) on its own produced no statistically significant effect on endotoxin-induced PGE2 formation. In the presence of caffeine (5 × 10–6 to 1.5 × 10–4 mol/l), inhibition of PGE2 biosynthesis by indometacin (1 × 10–8 mol/l) was not significantly altered. These results show that, in human monocytes, caffeine, up to concentrations severalfold higher than those reached in patients, has no significant effect on endotoxin-induced PGE2 formation nor on its inhibition by indometacin.
Vinorelbine and Carboplatin in Inoperable Non-Small Cell Lung Cancer: A Monoinstitutional Phase II Study
Authors: Cremonesi M. , Mandalà M. , Cazzaniga M. , Rezzani C. , Gambera M. , Barni S.
Published: April 2003

Chemotherapy regimens for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) provide typically palliation or limited symptom-free survival. We investigated the efficacy, in terms of response rate and time to progression, of a combination chemotherapy containing carboplatin and vinorelbine as a first-line treatment for inoperable NSCLC. Fifty-two consecutive patients with advanced NSCLC were treated with carboplatin AUC 6 according to Calvert’s formula on day 1, combined with vinorelbine, 25 mg/m2 on days 1 and 8. Therapy was given every 3 weeks. The median age was 66 years (range, 40–80); ECOG performance status was 0 in 20, 1 in 25 and 2 in 7 patients. According to an intent-to-treat analysis, response rate (partial and complete responses) in 52 assessable patients was 18/52 (34.6%; 95% confidence interval, 22–47%). In addition, 16 patients (30.8%) had stable disease and 18/52 (34.6%; 95% CI, 22–47%) progressed while on treatment. Median time to progression and overall survival were 7, 5 and 12.3 months, respectively. Grade 3/4 granulocytopenia was observed in 18/8 patients (34.6/15.4%). Grade 3/4 nadirs generally lasted no more than 7 days, and no neutropenic fever was reported. The treatment was generally very well tolerated: grade 1 or 2 nausea and vomiting was observed in 12 and 4 patients, respectively, and grade 2 neuropathy in 5% of cases. Statistical analysis did not highlight any significant differences in clinical benefit (partial and complete responses and stable disease), time to progression, or grade 3–4 hematologic and non-hematological toxicity according to age (≤65 vs. >65 years). Carboplatin AUC 6 and vinorelbine was found to be an efficacious regimen as a first-line treatment for inoperable lung cancer patients and was also subjectively very well tolerated in aged patients. The regimen warrants further investigation in the emerging subgroup of aged patients in order to draw firm conclusions.
Prevention of Anemia in Patients with Solid Tumors Receiving Platinum-Based Chemotherapy by Recombinant Human Erythropoietin (rHuEpo): A Prospective, Open Label, Randomized Trial by the Hellenic Cooperative Oncology Group
Authors: Bamias A. , Aravantinos G. , Kalofonos C. , Timotheadou N. , Siafaka V. , Vlahou I. , Janinis D. , Pectasides D. , Pavlidis N. , Fountzilas G.
Published: April 2003

Objectives: Platinum compounds are commonly associated with significant anemia. Erythropoietin administration has been found effective in correcting anemia in patients with solid tumors receiving chemotherapy. We conducted a randomized, open label study to assess the efficacy of erythropoietin in preventing transfusions and significant anemia (hemoglobin <10 g/dl) in patients with solid tumors receiving platinum-based chemotherapy. Methods: One hundred forty-four patients with hemoglobin <13 g/dl were included in this study (72 in each arm). Patients in the treatment arm received 10,000 U of recombinant human erythropoietin (rHuEPO) thrice weekly s.c. during platinum-based chemotherapy, while patients in the control arm received no treatment. Results: All patients were evaluable for efficacy. Transfusions were reduced by the administration of rHuEPO (15.3 vs. 33.3%, p = 0.019), and fewer patients developed significant anemia (16.6 vs. 45.8%, p < 0.0001). Subgroup analysis showed that patients with observed to predicted (O/P) serum erythropoietin levels ≤0.9 and responders to chemotherapy benefited from erythropoietin administration in contrast to patients with O/P >0.9 or non-responders. Conclusions: rHuEPO at a dose of 10,000 U thrice weekly prevents transfusions and development of significant anemia in patients with solid tumors receiving platinum-based chemotherapy.
A Case-Control Study of Endometrial Cancer after Antipsychotics Exposure in Premenopausal Women
Authors: Yamazawa Koji , Matsui Hideo , Seki Katsuyoshi , Sekiya Souei
Published: April 2003

Objective: Most endometrial cancers are related to hormonal imbalance, and antipsychotics are a common cause of hyperprolactinemia. We investigated the possible relation between the use of antipsychotics and the risk of endometrial cancer. Methods: A case-control study was conducted on premenopausal women at the Chiba University Hospital between 1989 and 2000. The cases were 41 patients with histologically confirmed endometrial cancer. For each case, there were 3 controls matched by age and date of visit. Subsequently 123 women without endometrial cancer were enrolled as controls. Detailed information including obesity, parity, hypertension, diabetes mellitus, use of exogenous estrogen and use of antipsychotics was analyzed. Odds ratios, two-sided p values and 95% confidence intervals were estimated by a conditional logistic regression analysis. Radioimmunoassays of serum luteinizing hormone, follicle-stimulating hormone, prolactin, estradiol and progesterone were performed in 4 of 5 patients with endometrial cancer who were using antipsychotics. Results: Use of antipsychotics, diabetes mellitus and obesity were identified as independent variables with risk estimates of 5.4, 9.3 and 4.9, respectively. Serum progesterone, estradiol and prolactin levels ranged from 0.4 to 0.7 ng/ml, 32 to 110 pg/ml and 34 to 258 ng/ml, respectively. Conclusions: Use of antipsychotics is a risk factor for endometrial cancer, and hyperprolactinemia associated with antipsychotics may impart the risk of endometrial cancer in premenopausal women.
Phase II Study of Concurrent Administration of Doxorubicin and Docetaxel as First-Line Chemotherapy for Metastatic Breast Cancer
Authors: Aihara Tomohiko , Takatsuka Yuichi , Itoh Kuniaki , Sasaki Yasutsuna , Katsumata Noriyuki , Watanabe Toru , Noguchi Shinzaburo , Horikoshi Noboru , Tabei Toshio , Sonoo Hiroshi , Hiraki Shunkichi , Inaji Hideo
Published: April 2003

Objective: To evaluate the efficacy and toxicity of concurrent administration of doxorubicin and docetaxel, without prophylactic use of granulocyte colony-stimulating factor, as first-line chemotherapy in patients with metastatic breast cancer (MBC). Methods: This multi-institutional study enrolled 40 women; 37 were assessable for efficacy and all 40 patients were evaluated for toxicity. Treatment consisted of 50 mg/m2 doxorubicin and 60 mg/m2 docetaxel on day 1 every 3–4 weeks. Results: Patients received a total of 251 cycles of chemotherapy (median, 5 cycles; range, 1–13 cycles). Of the 37 patients assessable for efficacy, 2 had a complete response and 24 had partial responses, which accounted for a 70% objective response rate (95% confidence interval, 53–84%). The median time to treatment failure was 30.1 weeks (range, 3.3–80.7 weeks). Grade 4 neutropenia was observed in 88% of patients and was the most frequent haematological toxicity. Febrile neutropenia was seen in 40% of patients, but no severe infections were observed. Non-haematological toxicity was generally tolerable. There were 2 grade 4 adverse events, which included 1 bleeding duodenal ulcer and 1 hypersensitivity reaction, but grade 3 episodes were infrequent. None of the patients developed congestive heart failure or asymptomatic decrease of left ventricular ejection fraction to less than 50%. Fluid retention syndrome ≤ grade 2 was observed in 25% of patients at a median cumulative dose of docetaxel of 270 mg/m2. Conclusion: Concurrent administration of 50 mg/m2 doxorubicin and 60 mg/m2 docetaxel is active with a manageable toxicity profile as first-line chemotherapy for MBC.
Weekly Gemcitabine and 24-Hour Infusional 5-Fluorouracil in Advanced Pancreatic Cancer: A Phase I–II Study
Authors: Barone C. , Cassano A. , Corsi D.C. , Pozzo C. , Longo R. , Schinzari G. , Quirino M. , Battelli C. , Basso M.
Published: April 2003

Objective: In this phase I–II study we explored the potential of the combination of weekly gemcitabine (GEM) and 24-hour continuous infusion of 5-fluorouracil (5-FU) in order to determine the toxicity profile in pancreatic cancer. The efficacy of this drug combination was studied as a secondary endpoint. Methods: Twenty-one patients with histologically or cytologically proven unresectable or metastatic previously untreated pancreatic adenocarcinoma were included in this study. Two dose levels of GEM and two dose levels of 5-FU were evaluated in three cohorts of patients who received GEM 1,000 mg/m2 and 5-FU 2,000 mg/m2, GEM 1,200 mg/m2 and 5-FU 2,000 mg/m2, or GEM 1,200 mg/m2 and 5-FU 2,250 mg/m2, on days 1, 8, and 15, every 4 weeks, respectively. Results: Grade 3–4 neutropenia was observed in 10% of the cycles. Non-myelosuppressive toxicities included fatigue (22%), grade 1–2 diarrhea (12%) and grade 1 liver toxicity. There was no limiting toxicity and the maximum tolerated dose has not been reached. Two patients experienced a partial response (9.5 ± 12.6%) and 12 patients had stable disease (57.1 ± 21.2%). Seven of the 14 symptomatic patients improved their disease-related symptoms and 4 of the 8 patients evaluable for clinical benefit had a clinically beneficial response (50 ± 34.6%). The median progression-free survival was 6 months (range 2–28), median survival was 11 months (range 3–32+), and the actuarial 1-year survival rate 33%. Conclusion: The weekly administration of GEM combined with 24-hour continuous infusion of 5-FU shows a good safety profile at the dose levels evaluated. Some partial responses had also been achieved, disregarding the dose level of the two drugs. Survival confirms the activity of this drug combination.
The Metaphors of Development
Authors: Super Charles M. , Harkness Sara
Published: April 2003

Pepper''s [1942] conceptualization of `root metaphors´ offers developmentalists a scheme for organizing theories of child behavior held by both parents and professionals. In this paper, we identify the root metaphors underlying current perspectives on human develoment, and present evidence for their role in interpretations of child behavior by parents and mental health professionals. Study 1 demonstrates that there are stable individual differences in root metaphor preference among US parents (n = 224), and these differences are influenced by experience in predictable ways. Study 2 describes similar differences among 32 mental health professionals at a US psychiatric clinic, and confirms relationships expected on the basis of theoretical analysis between metaphoric orientation and therapeutic specialization. Study 3 replicates these findings with a broader sample of 55 mental health professionals at a Dutch psychiatric treatment center and further relates metaphoric orientation to the daily task demands of their occupational roles. Thus the studies reported here provide strong support for the proposition that Pepper''s metaphoric analysis of philosophical systems can be applied meaningfully to the cognitive systems used by both parents and professionals in interpreting children''s behavior. We discuss the implications for understanding the socially regulated nature of partents'' belief systems, the origins of individual variation, the `goodness of fit´ between mental health practitioners and their clients, and the role of theory in the developmental sciences.
Modulating the Modulators: Parasites, Neuromodulators and Host Behavioral Change
Authors: Adamo Shelley A.
Published: April 2003

Neuromodulators can resculpt neural circuits, giving an animal the behavioral flexibility it needs to survive in a complex changing world. This ability, however, provides parasites with a potential mechanism for manipulating host behavior. This paper reviews three invertebrate host-parasite systems to examine whether parasites can change host behavior by secreting neuromodulators. The parasitic wasp, Cotesia congregata, suppresses host feeding partly by inducing the host (Manduca sexta) to increase the octopamine concentration in its hemolymph. The increased octopamine concentration disrupts the motor pattern produced by the frontal ganglion, preventing the ingestion of food. Polymorphus paradoxus (Acanthocephalan) alters the escape behavior of its host, Gammarus lacustris (Crustacea), possibly through an effect on the host’s serotonergic system. The trematode Trichobilharzia ocellata inhibits egg-laying in its snail host (Lymnaea stagnalis), partly by inducing the host to secrete schistosomin. Schistosomin decreases electrical excitability of the caudodorsal cells. The parasite also alters gene expression for some neuromodulators within the host’s central nervous system. In at least two of these three examples, it appears that the host, not the parasite, produces the neuromodulators that alter host behavior. Producing physiologically potent concentrations of neuromodulators may be energetically expensive for many parasites. Parasites may exploit indirect less energetically expensive methods of altering host behavior. For example, parasites may induce the host’s immune system to produce the appropriate neuromodulators. In many parasites, the ability to manipulate host behavior may have evolved from adaptations designed to circumvent the host’s immune system. Immune-neural-behavioral connections may be pre-adapted for parasitic manipulation.
P2X7 Receptors Are Redistributed on Human Monocytes after Pore Formation in Response to Prolonged Agonist Exposure
Authors: Connon Che J. , Young Robert D. , Kidd Emma J.
Published: April 2003

The P2X7 cell surface receptor is responsible for adenosine triphosphate-dependent lysis of immune cells following the formation of non-selective membrane pores. This study examined changes in P2X7 receptor distribution following agonist treatment. Human THP-1 monocytes were exposed to the agonist 2′-3′-O-(4-benzoyl-benzoyl) adenosine 5′-triphosphate for 1–40 min after which P2X7 receptors were immunogold labelled. The number and distribution of P2X7 receptors on the cell membrane were quantified using transmission electron microscopy. Increasing the time of agonist exposure resulted in clustering of P2X7 receptors, a decrease in individual P2X7 receptors and no change in the total number of P2X7 receptors. These results suggest that pore formation does not involve further insertion or initial movement of receptors in the membrane but that P2X7 receptors do cluster together after prolonged activation.
Aminoglycoside-Induced Reversible Tubular Dysfunction
Authors: Alexandridis George , Liberopoulos Evagelos , Elisaf Moses
Published: April 2003

Nonoliguric renal insufficiency is a well-known nephrotoxic consequence of aminoglycosides, although reversible tubular damage in the absence of any change in the renal function has been occasionally found. Reported herein are 2 representative cases of a reversible tubular damage due to prolonged aminoglycoside administration: a patient with a Fanconi-like syndrome of proximal tubular dysfunction and a patient with a syndrome of hypokalemic metabolic alkalosis associated with hypomagnesemia.
Self-Administration of both Ethanol and Nicotine in Rats
Authors: Marshall Cheryl E. , Dadmarz Mitra , Hofford James M. , Gottheil Edward , Vogel Wolfgang H.
Published: April 2003

Self-administration of either nicotine (NIC) or ethanol (ETH) has been extensively studied. This study addressed for the first time the self-administration of both substances when offered together. Male and female rats of different ages were offered NIC and ETH using the two- or three-bottle free-choice method. When NIC and ETH were offered together at different concentrations to young male rats (about 45 days old), intake of NIC increased with increasing NIC concentrations, and intake of ETH increased with decreasing ETH concentrations, but these effects were independent of the presence of the second drug. These rats also consumed the same amounts of NIC or ETH regardless of whether offered individually or together. A prior choice of only NIC or ETH did not affect a subsequent intake of both drugs offered together. A choice of both drugs for 24 h for several days followed by a choice for only 2 h for several days showed the same intake of NIC but a decreased intake of ETH for the shorter period. Young female rats (about 45 days old) and older male rats (about 75 days old) consumed the same amounts of NIC but less ETH than did the young male rats. These results show that young male rats voluntarily consume NIC and ETH independently of each other and that preexposure to one drug does not affect the subsequent intake of both drugs in combination. The data also suggest that these drugs act on different reward centers which have to be ‘satisfied’ independently of each other.
Update and Future of Hormonal Therapy in Acne
Authors: Thiboutot Diane , Chen WenChieh
Published: April 2003

Hormonal therapy is an important component in the treatment of women with acne who may or may not have elevated serum androgens. The mainstays of hormonal therapy include oral contraceptives and antiandrogens such as cyproterone acetate, flutamide or spironolactone. Recent research over the past several years has unraveled some of the details regarding the way that the skin and sebaceous glands synthesize and metabolize hormones. The knowledge gained from this work may provide an impetus for future drug discovery in the hormonal treatment of acne and lead to improvements in the care of our patients with acne.
Nuclear Receptors and Co-Regulators in Adrenal Tumors
Authors: Shibata Hirotaka , Kobayashi Sakiko , Kurihara Isao , Saito Ikuo , Saruta Takao
Published: April 2003

We have reported that excessive steroid hormone production in adrenal cortical tumors results from the disordered expression and activity of specific steroidogenic enzymes. Since no genetic mutations in these steroidogenic enzymes have as yet been identified, disordered expression at the transcription level may be crucial for excessive hormone production in adrenocortical tumors. Nuclear receptors SF-1 and COUP-TF/DAX-1 have been shown to activate and repress, respectively, the transcription of CYP17 gene in a mutually exclusive manner in Y-1 cells. Interestingly, the expression of COUP-TF and DAX-1 is significantly decreased in the cortisol-producing adenomas, in which CYP17 is overexpressed. Conversely, DAX-1 is highly expressed in deoxycorticosterone-producing adenomas, where CYP17 expression is almost absent. These expression profiles indicate the possibility that COUP-TF and DAX-1 play important roles in the transcriptional repression of CYP17 in adrenal tumors. To clarify the mechanisms of COUP-TF-mediated repression, we therefore screened for COUP-TF-interacting proteins using a yeast two-hybrid system from a cortisol-producing adenoma cDNA library. We then cloned a novel COUP-TF-interacting protein-1 (CIP-1), which interacts with COUP-TFI, COUP-TFII, and SF-1. Functionally, CIP-1 can act as a transcriptional co-repressor for COUP-TF repression activity. CIP-1 expression profiles parallel those of COUP-TFI in steroidogenic tissues, strongly suggesting that, together, COUP-TFI and CIP-1 play an important role in steroidogenesis.
SF1 in the Development of the Adrenal Gland and Gonads
Authors: Ozisik Gokhan , Achermann John C. , Meeks Joshua J. , Jameson J. Larry
Published: April 2003

SF1 (steroidogenic factor-1; NR5A1) is an orphan nuclear receptor that is expressed in the adrenal gland, gonads, spleen, ventromedial hypothalamus and pituitary gonadotroph cells. Combined approaches of targeted mutagenesis in mice and examination of the effects of naturally occurring mutations in humans have clarified the role of SF1 in steroidogenesis and development. Targeted disruption of Sf1 (Ftzf1) in mice prevents gonadal and adrenal development and causes male-to-female sex reversal. A heterozygous loss-of-function human SF1 mutation (G35E) was described in a patient with adrenal failure and complete 46,XY sex reversal, indicating that haploinsufficiency of this transcription factor is sufficient to cause a severe clinical phenotype. In an infant with a similar clinical phenotype, a homozygous SF1 mutation (R92Q) was identified. In functional assays, this mutant SF1 protein exhibited partial loss of DNA binding and transcriptional activity when compared with the more severe G35E P-box mutant. These patients reveal the exquisite sensitivity of SF1-dependent developmental pathways to gene dosage and function in humans.
Radiation-Induced Growth Hormone Deficiency
Authors: Darzy Ken H. , Shalet Stephen M.
Published: April 2003

Deficiency of one or more anterior pituitary hormones may follow treatment with external irradiation when the hypothalamic-pituitary axis falls within the fields of irradiation. Hypopituitarism occurs in patients who receive radiation therapy for pituitary tumours, nasopharyngeal cancer and primary brain tumours, as well as in children who undergo prophylactic cranial irradiation for acute lymphoblastic leukaemia, or total body irradiation for a variety of tumours and other diseases. The degree of pituitary hormonal deficit is related to the radiation dose received by the hypothalamic-pituitary axis. Thus, after lower radiation doses isolated growth hormone deficiency ensues, whilst higher doses may produce hypopituitarism. The timing of onset of the radiation-induced pituitary hormone deficit is also dose-dependent. The main site of radiation damage is the hypothalamus rather than the pituitary, although the latter may be affected directly.
Graves’ Disease 1835–2002
Authors: Weetman A.P.
Published: April 2003

This brief review describes the history of Graves’ disease, starting with the original descriptions by Parry, Graves and von Basedow. The true aetiology of the disorder was uncovered in the 1950s and 1960s, based on the search for a novel thyroid stimulator which turned out to be an immunoglobulin G autoantibody. Assays for these thyroid stimulatory antibodies have been continually refined and their epitopes on the thyroid stimulating hormone receptor are increasingly well characterized. We also understand far more about the genetic and environmental susceptibility factors that predispose to disease, and even thyroid-associated ophthalmopathy has now been better defined as primarily a T-cell-mediated disease resulting from cytokine stimulation of orbital fibroblasts. These advances should improve treatment options for Graves’ disease in the foreseeable future.
Restoration of Fertility after Treatment for Cancer
Authors: Radford John
Published: April 2003

The late effects of chemotherapy and radiation treatment on fertility are an important issue for long-term survivors of cancer who may not have started or completed a family at the time of diagnosis. Attempts at protecting reproductive function using hormonal manipulation have proved largely unsuccessful and other strategies have to be considered. For men, semen cryopreservation allows subsequent artificial insemination of a female partner or ivf but cryopreserved semen is a finite resource, does not allow natural conception and is not an option for prepubertal boys. In an effort to overcome this, research is in progress to investigate whether testicular cells harvested and cryopreserved before the start of chemotherapy can be reintroduced to the testis after treatment and resume normal spermatogenesis. This has been achieved in a mouse model and the results of experimental protocols in men are awaited with interest. For women, harvested mature oocytes are only poorly tolerant of the freezing process although immediate in vitro fertilization and cryopreservation of embryos can be successful. An experimental technique of great interest is the harvesting and cryopreservation of ovarian cortex before the start of sterilizing treatment. In ewes, the reimplantation of autologous ovarian cortical tissue into surgically castrated animals has resulted in resumption of oestrus, conceptions after normal matings and the birth of live offspring. Recently, ovarian function has been re-established using a similar technique in a patient following treatment for Hodgkin’s lymphoma, but so far pregnancy has not been reported.
The Genetics of Neonatal Hyperinsulinism
Authors: Fournet Jean-Christophe , Junien Claudine
Published: April 2003

Congenital hyperinsulinism (CHI) is the most important cause of persistent hypoglycaemia in the neonate and infant. It is a clinically and genetically heterogeneous entity. The clinical heterogeneity is manifested by severity ranging from extremely severe life-threatening disease to very mild clinical symptoms which may even be difficult to identify. Furthermore, clinical responsiveness to medical and surgical management is extremely variable. Two histopathological forms have been described: a diffuse form of CHI and a focal form of CHI. Recent discoveries have begun to clarify the molecular aetiology of the disease and therefore the mechanisms responsible for its clinical heterogeneity are becoming clearer. Mutations in four different genes have been identified in patients with CHI. Most cases are caused by mutations in genes coding for either of the two subunits of the β-cell KATP channel (ABCC8 and KCNJ11). In the diffuse form of CHI, the hyperinsulinism is due to a recessive mutation of both alleles of these genes (rare dominant mutations have been described). In the focal form of CHI, two events intervene: first, the inheritance of a paternal ABCC8/KCNJ11 mutation; second, the focal reduction to homozygosity of the mutation during pancreatic development by a localized loss of the maternal 11p15 region. Others cases of CHI are due to rare mutations in the β-cell enzymes glucokinase (only one family described) and glutamate dehydrogenase in hyperammonaemia-associated hyperinsulinism. However, in as many as 50% of cases, no genetic aetiology has yet been identified.
Diabetes insipidus
Authors: Maghnie Mohamad
Published: April 2003

Diabetes insipidus is a heterogeneous condition characterized by polyuria and polydipsia caused by a lack of secretion of vasopressin, its physiological suppression following excessive water intake, or kidney resistance to its action. In many patients, it is caused by the destruction or degeneration of the neurons that originate in the supraoptic and paraventricular nuclei of the hypothalamus. Known causes of these lesions include: germinoma or craniopharyngioma; Langerhans cell histiocytosis and sarcoidosis of the central nervous system; local inflammatory, autoimmune or vascular diseases; trauma following surgery or accident; and, rarely, genetic defects in vasopressin biosynthesis inherited as autosomal dominant or X-linked recessive traits. Thirty to fifty percent of cases are considered idiopathic. Magnetic resonance imaging (MRI) allows identification of the posterior pituitary hyperintensity and of hypothalamic-pituitary abnormalities. Thickening of the pituitary stalk is the second most common finding on MRI scans in several local inflammatory pathologies and autoimmune diseases or germinoma, but it is not specific to any single subtype. A progressive increase in the size of the anterior pituitary gland should alert physicians to the possibility that a germinoma is present, whereas a decrease can suggest the presence of an inflammatory or autoimmune process. Most children with acquired central diabetes insipidus and a thickened pituitary stalk have anterior pituitary hormone deficiencies during follow-up. Biopsy of enlarged pituitary stalk should be reserved for patients with a hypothalamic-pituitary mass and progressive thickening of the pituitary stalk, since spontaneous recovery may occur.
Clinical and Genetic Aspects of Phaeochromocytoma
Authors: Opocher Giuseppe , Schiavi Francesca , Conton Pierantonio , Scaroni Carla , Mantero Franco
Published: April 2003

Phaeochromocytoma is a tumour of the adrenal medulla, which, although rare, is a major cause of correctable hypertension with a prevalence of 0.1–0.5% in the hypertensive population. Clinical symptoms include attacks of paroxysmal headache, sweating, palpitations, stress and a sense of imminent death. Often associated with the above is an increase in blood pressure. Despite the fact that the underlying genetic mechanisms of phaeochromocytoma have been well investigated, they are still incompletely understood. In approximately 80% of cases the tumour occurs sporadically, but it may occur in association with type 2 multiple endocrine neoplasia, type 1 neurofibromatosis or von Hippel-Lindau disease. Molecular evidence suggests that other genes such as SDHD or SDHB may control its development; the possibility of other putative phaeochromocytoma genes is currently being investigated.
Hemodialysis Vascular Access Dysfunction: From Pathophysiology to Novel Therapies
Authors: Roy-Chaudhury Prabir , Kelly Burnett S. , Zhang Jianhua , Narayana Ashwath , Desai Pankaj , Melhem Murad , Duncan Heather , Heffelfinger Sue C.
Published: April 2003

Hemodialysis vascular access dysfunction is a major cause of morbidity and hospitalization in the hemodialysis population at a cost of over USD 1 billion per annum. Most hemodialysis grafts fail due to a venous stenosis (venous neointimal hyperplasia) which then results in thrombosis of the graft. Despite the magnitude of the clinical problem there are currently no effective therapies for this condition. The current review (a) describes the pathogenesis and pathology of venous stenosis in dialysis access grafts and (b) discusses the development and application of novel therapeutic interventions for this difficult clinical problem. Special emphasis is laid on the fact that PTFE dialysis access grafts could be the ideal clinical model for testing out novel local therapies to block neointimal hyperplasia.
Recent Concepts in the Molecular Biology of the Peritoneal Membrane – Implications for More Biocompatible Dialysis Solutions
Authors: Mortier Siska , De Vriese An S. , Lameire Norbert
Published: April 2003

This paper reviews some important recent findings on the molecular biology of the peritoneal membrane. It attempts to correlate in vitro and in vivo experimental results with the possible clinical consequences. The most common functional alteration during long-term CAPD is increased peritoneal small-solute transport rate, resulting in impaired ultrafiltration and decreased dialysis efficiency. This contribution first discusses the most relevant advances in the biochemistry and molecular biology of the peritoneal membrane following peritonitis and as consequence of the continuous exposure to unphysiological dialysis fluids. In a second part the preliminary experimental and clinical experience with more biocompatible fluids is summarized. The most relevant structural and functional alterations of the membrane following repeated peritonitis is the consequence of the response of the peritoneum to infective organisms involving the inflammatory cytokines and the interaction between membrane resident cell populations: macrophages, mesothelial cells and fibroblasts. In this setting, human biopsy studies and animal experiments have identified an increase in the peritoneal-associated vasculature, which seems to be the primary cause of increased solute transport. The structural and functional alterations in the membrane in long-term peritoneal dialysis are thought to be the consequence of the toxicity of glucose, either directly or indirectly through the generation of glucose degradation products or the formation of advanced glycation end-products. In particular, an important role for vascular endothelial growth factor and nitric oxide as downstream mediators of the alterations has been suggested. Finally, the last part of this paper reviews the actual and future research aimed at an amelioration of the biocompatibility of the dialysis fluids. Replacing glucose by other osmotic agents, changing the sterilization process, replacing the lactate buffer by bicarbonate, blocking the formation of reactive carbonyl products and of the neoangiogenesis are the most promising changes to enhance the biocompatibility. Finally, gene therapy may in the future have an important contribution. Ex vivo gene therapy involves harvesting peritoneum samples to isolate mesothelial cells that will be genetically modified before re-implantation into the peritoneal cavity.
Activated Protein C Resistance in Normal and Pre-Eclamptic Pregnancies
Authors: Paternoster D.M. , Stella A. , Simioni P. , Girolami A. , Snijders D.
Published: April 2003

Objectives: A lower ratio in the classic activated protein C resistance (APC-R) test has been reported during pregnancy, which has been called ‘acquired’ APC-R. However, little is known about the cause of the lowered ratio, and whether or not there is a correlation with blood coagulation activation. The primary objective of our study was to determine changes in APC-R levels in each of the trimesters of normal pregnancy. The secondary objective was to confirm whether APC-R levels were lower in pregnancies complicated by pre-eclampsia than in a control group. Finally, this prospective study was performed to investigate the prevalence of APC-R among pregnant women and to elucidate its obstetric consequences. Methods: We enrolled 35 healthy pregnant women and 47 pregnant women affected by pre-eclampsia in our study. The following laboratory tests were performed: prothrombin time, partial thromboplastin time, fibrinogen levels, antithrombin III, plasmatic fibronectin (as a marker of endothelial damage), haptoglobin (as a marker of intravascular haemolysis), a functional test for APC-R and analysis of factor V Leiden mutation by polymerase chain reaction. Results: The activated protein C sensitivity ratio was lower in the pathological group than in the control group (p = 0.008 and p = 0.02, respectively). Plasmatic fibronectin was found to be higher in the pathological group than in the control group (p = 0.05). Finally, the overall prevalence of factor V Leiden mutation was 5.4%, i.e. 2/35 women (5.7%) in the control group and 3/47 women in the pathological group (6.38%). Conclusions: The APC ratio decreased after 20 weeks of gestation until week 42. This decrease was most pronounced in the third trimester, in which resistance was demonstrated in 34.2% of control group patients. In pre-eclampsia, we found a greater reduction of the APC ratio than in controls. We hypothesise that this is due to a decrease in the plasmatic levels of coagulation inhibitors and an increase in coagulatory factors.
Transvaginal Bone Anchors in Female Stress Urinary Incontinence: Poor Results
Authors: Schostak M. , Miller K. , Müller M. , Schrader M. , Steiner U. , Gottfried H.W.
Published: April 2003

Objective: This study evaluates the results of a minimally invasive technique for correcting female stress urinary incontinence by transvaginal implantation of pubic bone anchors. Patients and Methods: Female stress urinary incontinence was treated by fixing a gelatin-coated Dacron sling between two miniature titanium anchors with Prolene sutures. Results: A total of 26 patients (median age 57.2 years) underwent the sling procedure. The follow-up examination was performed after 11.4 months on average. Stress incontinence showed a median improvement from grade 2 to grade 0.5 (p = 0.01), although only 16 of the 26 patients were completely continent. Urethral pressure and functional length were not significantly influenced. Impaired vaginal wound healing was seen in 14 of the 26 patients (53.8%), and 13 of them underwent revision. All patients affected (15/26, 57.7%) as well as 1 with uneventful healing showed sensory urge symptoms or detrusor instability (7/26, 26.9%). The correlation between impaired wound healing and detrusor instability was highly significant (p < 0.003). 17 of the 26 patients (65.3%) were dissatisfied or very dissatisfied with the intervention. The unfavorable results did not significantly correlate with the patients’ age, the number of previous operations, or the surgeon’s skill. Conclusion: In view of the poor vaginal wound healing and the resultant irritative symptoms, transvaginal bone anchoring with fixation of a Dacron sling must be regarded as an unsuitable technique.
Immunogenic Effects of Woodchuck Hepatitis Virus Surface Antigen Vaccine in Combination with Antiviral Therapy: Breaking of Humoral and Cellular Immune Tolerance in Chronic Woodchuck Hepatitis Virus Infection
Authors: Menne Stephan , Roneker Carol A. , Tennant Bud C. , Korba Brent E. , Gerin John L. , Cote Paul J.
Published: April 2003

Objective: A rational treatment strategy for chronic hepatitis B virus (HBV) infection might involve the modulation of immunity after the reduction of viremia and antigenemia. This strategy was tested in woodchucks chronically infected with the woodchuck hepatitis virus (WHV) by combining antiviral treatment with 1-(2-fluoro-5-methyl-β-L-arabinofuranosyl)-uracil (L-FMAU) and therapeutic vaccination with WHV surface antigen (WHsAg). Methods: Chronic WHV carriers were treated with L-FMAU or placebo for 32 weeks. Half the woodchucks in each group then received four injections of a conventional WHsAg vaccine during the next 16 weeks. Results: Vaccination alone elicited low-level antibody to WHsAg (anti-WHs) in most carriers but did not affect serum WHV DNA, WHsAg or liver enzyme responses. Carriers treated first with L-FMAU to reduce WHV DNA and WHsAg and then vaccinated developed similar low-level anti-WHs and normalized liver enzymes. Following vaccinations, WHsAg-specific cell-mediated immunity (CMI) was demonstrated in both groups, but was significantly enhanced in carriers treated with L-FMAU, and was broadened to include WHV core antigen (WHcAg) and selected peptide epitopes of WHcAg and WHsAg. Anti-WHs and associated CMI to WHcAg and WHsAg were observed after drug discontinuation in half of the carriers that received L-FMAU alone. Conclusions: Vaccination with WHsAg following treatment with L-FMAU disrupted virus-specific humoral and cell-mediated immune tolerance in chronic WHV infection and enhanced the immune response profiles beyond those seen with monotherapies alone. The combination therapy resulted in immune response profiles that resembled those observed during resolution of WHV infection. The results in woodchucks demonstrate the feasibility of using such a combination therapy for the control of chronic HBV infection in humans.
Age-Related Changes in Catecholaminergic Nerve Fibers of Rat Heart and Coronary Vessels
Authors: Bruzzone P. , Cavallotti C. , Mancone M. , Tranquilli Leali Francesca Maria
Published: April 2003

Background: Age-related changes of catecholaminergic nerve fibers supplying the myocardium and the coronary vessels were studied in adult and in old rats. Objective: The purpose of this study was to investigate whether there are quantitative changes in myocardial and/or coronary catecholaminergic nerve fibers and related neurotransmitters. Methods: Samples of myocardium and/or coronary vessels were studied by means of glyoxylic acid induced fluorescence, aldehyde-induced fluorescence, and neuropeptide Y immunoreactivity. All morphological results were submitted to quantitative analysis of images. Biochemical dosage of proteins and of norepinephrine was also performed, and morphological data were compared with biochemical ones. Finally, all data were subjected to statistical analysis. Results: Our findings are indicative of an age-related decrease of all types of fluorescent sympathetic nerve fibers in rat heart and coronary arteries. Moreover, our data show that aging induces a strong decrease of norepinephrine levels in tissue homogenates of rat heart and coronary vessels. The majority of the catecholaminergic nerve fibers that show strong age-related changes are not contiguous with contractile cells of myocardium and/or of vascular wall. In fact, these fibers are located in adventitial (or epicardial) and in endothelial (or endocardial) layers. Conclusion: The decrease of the catecholaminergic innervation of heart and coronary vessels of old rats can be in close relationships to the poor cardiac and/or coronary functions observed in old animals.
Assessment of the Single-Occlusion Technique for Measurements of Respiratory Mechanics and Respiratory Drive in Healthy Term Neonates Using a Commercially Available Computerized Pulmonary Function Testing System
Authors: Reiterer F. , Müller W.
Published: April 2003

In this study, a critical assessment of the single-occlusion technique as a means of measuring passive respiratory mechanics and respiratory drive (P0.1) was performed in nonintubated spontaneously breathing healthy term neonates using commercially available computerized equipment (PEDS system). In general, we found that quality parameters only partially conformed to the international established standards for measuring passive respiratory mechanics. There was a failure rate of technically acceptable occlusions of about 50% for respiratory mechanics measurements and 20% for P0.1 measurements. Intersubject variability of the data was between 10 and 40%. After studying different lengths of occlusion times (Tocc; 0.2, 0.3, 0.4 and 0.5 s), it was found that acceptable occlusions for passive respiratory mechanics were obtained only if the expiratory Tocc exceeded 0.2 s. Increasing the Tocc had no effect on the absolute values of respiratory mechanics but showed a significant trend towards more technically acceptable occlusions. We speculate that a Tocc of at least 0.4 s may be a prerequisite for obtaining reliable results for respiratory mechanics in healthy term neonates.
Maturation Alters Cyclic Nucleotide and Relaxation Responses to Nitric Oxide Donors in Ovine Cerebral Arteries
Authors: Nauli Surya M. , White Charles R. , Hull Andrew D. , Pearce William J.
Published: April 2003

To examine the hypothesis that maturation modulates nitric oxide (NO)-induced relaxation in cerebral arteries, we quantified concentration-relaxation relations and the corresponding dynamic responses of guanosine 3′:5′-cyclic monophosphate (cGMP) and adenosine 3′:5′-cyclic monophosphate (cAMP) levels following administration of nitroglycerin and S-nitroso-N-acetyl-penicilamine (SNAP), an NO donor, in posterior communicating and middle cerebral arteries from newborn (3–7 days) and adult sheep. The results offer 5 main observations: (1) the efficacy and potency of NO donors were generally greater in newborn than in adult cerebral arteries; (2) rates of relaxation, and presumably rates of NO release, were faster for equimolar concentrations of SNAP than for nitroglycerin in both newborn and adult arteries; (3) basal concentrations were greater for cAMP than for cGMP, and both were greater in newborn than adult cerebral arteries; (4) in adult cerebral arteries, NO-induced increases in cGMP occurred faster but relaxation developed more slowly than in newborn cerebral arteries, and (5) responses to NO donors involved significant cross-reactivity between cGMP and cAMP, the characteristics of which were age, artery, and agent specific. From these results, we conclude that postnatal changes in reactivity to NO reflect corresponding changes in soluble guanylate cyclase activity and possible decreases in NO half-life. We also conclude that maturation slows the mechanisms mediating NO-induced relaxation, and that this effect is more pronounced in distal than in proximal cerebral arteries. The data also suggest that the rate-limiting step governing rates of response to NO is probably downstream from cGMP synthesis. From the basal cyclic nucleotide levels, we conclude that basal ratios of synthesis to hydrolysis were greater in fetal than adult arteries. Because NO increased both cGMP and cAMP, we speculate that Type III phosphodiesterase has a possible influence upon cerebrovascular responses to NO, and that this influence varies with postnatal age and artery type. Together, these findings emphasize that the cerebrovascular effects of NO are highly age dependent and artery specific, and should be carefully considered when administering NO therapeutically in the neonate.