bluuebunny/crossref_metadata_2025 huggingface dataset:
Aging Liver
Authors: Anantharaju Abhinandana , Feller Axel , Chedid Antonio
Published: April 2003

Aging is characterized by a progressive decline of cellular functions. The aging liver appears to preserve its function relatively well. Aging is associated in human liver with morphological changes such as decrease in size attributable to decreased hepatic blood flow. Ultrastructural analysis of the human liver has revealed that the integrity of mitochondria and enzymatic activity remain mostly unchanged with aging. Reactive oxygen species (ROS) are involved in the aging process and result mainly from nonenzymatic processes in the liver. Endogenous free radicals are generated within mitochondria and suspected to cause severe injury to mitochondrial DNA. This damaged DNA accumulates with aging. In addition, polyunsaturated fatty acids, highly sensitive to ROS, decrease in liver mitochondria from human centenarians, a feature acquired during evolution as a protective mechanism to favor longevity. Diet is considered the main environmental factor having effect on lifespan. It has a major impact on aging liver, the central metabolic organ of the body. The ubiquitin proteolytic pathway in the liver serves to destroy many proteins, among them p21 which is encoded by abundant mRNA in senescent cells, can inhibit cell proliferation and favors DNA repair. Drug therapy in the elderly may be complicated by several factors such as decline in body weight, renal function, liver mass and hepatic blood flow, making adverse drug reactions more frequent. Hepatic drug metabolism is mainly mediated by the cytochrome P450 system and drug interactions in the elderly are likely related to the progressive decline of this system after the fifth decade of life and another decrease in individuals aged >70. Antihypertensive therapy in the elderly depends upon either hepatic or renal function and should be adjusted accordingly. Finally, telomerases are the biological clocks of replicative lifespan. Shortening of telomeric ends of chromosomes correlates with aging and decline in the replicative potential of the cell: replicative senescence. Telomere DNA of human somatic cells shortens during each cell division thus leading to a finite proliferation. Transfection of the telomerase reverse transcriptase gene results in elongation of telomeres and extension of lifespan. This also applies to humans. Replicative senescence in human cells evolved as a mechanism to protect them from continuous divisions leading to multiple mutations. Longer-lived species such as humans had to develop replicative senescence to ensure that they would have the increased protection that their longevity necessitates.
Moricizine, an Antiarrhythmic Agent, as a Potent Inhibitor of Hepatic Microsomal CYP1A
Authors: Konishi Hiroki , Morita Kunihiko , Minouchi Tokuzo , Yamaji Akira
Published: April 2003

We examined the inhibitory effect of moricizine (MOR) on hepatic cytochrome P-450 (CYP) in mice. Spectrophotometric analysis revealed that MOR had a relatively high affinity for CYP molecules. MOR most potently inhibited the CYP1A1-dependent ethoxyresorufin O-deethylation and the CYP1A2-dependent methoxyresorufin O-demethylation, among the metabolic reactions mediated by CYP1A, CYP2A, CYP2B, CYP2C, CYP2D, CYP2E, and CYP3A subfamilies expressed in untreated and CYP-inducer-treated hepatic microsomes. The inhibition constants (Ki) for ethoxyresorufin and methoxyresorufin O-dealkylations were 0.43 and 0.98 µmol/l, respectively. These Ki values were one to three orders of magnitude lower than those of cimetidine (CIM) and mexiletine (MEX) that have been accepted as the clinical inhibitors of CYP1A2 and were below the therapeutic serum concentration of MOR. Theophylline 3-demethylation and 8-hydroxylation in untreated hepatic microsomes, clinical probes for CYP1A2 activities, were subjected to marked and competitive inhibition by MOR with Ki values similar to that of methoxyresorufin O-demethylation, and the inhibitory potency of MOR was much higher than those of CIM and MEX. In addition, the zoxazolamine paralysis time, an in vivo measure of the hepatic CYP1A2 capacity, was markedly prolonged by pretreatment of mice with MOR rather than CIM and MEX, while the prolonging effect of MOR on the pentobarbital sleeping time, an indicator of the metabolic function of phenobarbital-inducible CYP species, was not so pronounced as compared with the zoxazolamine paralysis time. These results indicate that MOR acts as a potent and preferential inhibitor of hepatic CYP1A enzymes in vitro and in vivo.
An Evaluation of the Efficacy of Vasoactive Intestinal Polypeptide Antagonists in vivo in the Anaesthetized Dog
Authors: Markos F. , Hennessy B.A. , Fitzpatrick M. , O’Sullivan J. , Snow H.M.
Published: April 2003

The effectiveness of competitive peptide vasoactive intestinal polypeptide (VIP) receptor antagonists was evaluated on heart rate in the anaesthetized dog. Two specific antagonists, VIP (6–28) and [D-p-Cl-Phe6, Leu17]-VIP, and a nonspecific antagonist, pituitary adenylate cyclase activating peptide fragment (6–27) (PACAP), were studied. VIP (6–28) and [D-p-Cl-Phe6, Leu17]-VIP (100 µg i.c.) increased the heart rate, whereas PACAP (100 µg i.c.) reduced the baseline heart rate. All three shifted the VIP dose-response curve to the right by two- to threefold for 30 min. In conclusion, PACAP, VIP (6–28), and [D-p-Cl-Phe6, Leu17]-VIP have a direct effect on the heart rate, are equally effective, and the effects last approximately 30 min in vivo.
Urological Complications in Renal Transplantation: Long-Term Follow-Up of the Woodruff Ureteroneocystostomy Procedure in 433 Patients
Authors: Göğüs Çağatay , Yaman Önder , Soygür Tarkan , Bedük Yaşar , Göğüs Orhan
Published: April 2003

Purpose: The two major types of urologic problems after renal transplantation are urinary leakage and obstruction. In this study, we report the urological complications of renal transplantations performed in our hospital during a 22-year period. Patients and Methods: Between 1978 and 2000, 433 consecutive patients underwent renal transplantation. Of those transplants, 50 were cadavers and 383 were living-related donor transplantation. All ureteroneocystostomies were performed with the same technique described by Woodruff. Results: Urological complications developed in 19 (4.23%) recipients. Those complications were urinary leakage in 9 (2%), ureteral obstruction in 9 (2%) and ureteral necrosis in 1 patient (0.23%). All complications occurred during the 6-month postoperative period and after re-operation or conservative management no graft or patient was lost due to urological complications. Conclusion: The quoted overall rate of urological complications varies from 2.9 to 12.5%; our complication rate was 4.23%. This relatively low rate is probably due to the Woodruff ureteroneocystostomy technique.
Chromosomal Aberrations in Transitional Cell Carcinoma: Its Correlation with Tumor Behavior
Authors: Yu Dah-Shyong , Chen Hong-I , Chang Sun-Yran
Published: April 2003

Objective: Fluorescence in situ hybridization (FISH) was used to study numerical aberrations of chromosomes 1, 3, 7, 9, 11, 15, 17, X and Y in interphase nuclei of 16 transitional cell carcinoma (TCC) cell lines of the urinary tract. The number of chromosomal signal copies was compared with the DNA ploidy and correlated with the cellular grading and original tumor staging. Methods: The single-target FISH with the repetitive DNA probes for chromosomes 1, 3, 5, 7, 9, 11, 15, 17, X and Y were performed in 16 human TCC cell lines. For each test specimen, a minimum of 200 nuclei were analyzed. The number of fluorescent signals per nucleus was recorded. Tumor ploidy was analyzed using the DNA propidium iodide flow cytometric method. These results were correlated with tumor grade and stage. Results: In two diploid TCC cell lines, on average 67% of detected chromosomes were di-(i)somic. In 14 aneuploid TCC cell lines, on average only 10% (0–44%) of detected chromosomes were di-(i)somic. Chromosome X was completely changed into polysomism in 16 TCC cell lines (native male:female ratio = 12:4) but was unrelated to tumor grade or stage. Chromosome Y was lost in 10 out of 12 (83%) TCC cell lines which originated from male patients but was unrelated to tumor grade or stage too. 31% of chromosomes 11 and 15 were disomic in 16 TCC cell lines, 38% of chromosome 3 was monosomic, and 81–88% (83 in average) of chromosomes 1, 7, 9, 17 were polysomic. Disomic chromosome 11 associated with lower grade TCC and disomic chromosome 15 associated with higher grade TCC were noted (p < 0.01). Higher incidence of low stage tumors was observed in TCC cell lines with disomic chromosome 11 or chromosome 15 (p < 0.01). There was no correlation in somatic status of chromosomes 1, 7, 9, 17 with tumor grade and stage. Conclusions: The results of the study demonstrate that polysomism of chromosomes 1, 7, 9, 17 and X occurs in most of the TCC cells with aneuploidy. The stability of chromosomes 11 and 15 is closely related to tumor grade and stage. The role of chromosome Y loss and monosomism of chromosome 3 in oncogenic relevant of bladder cancer is still unclear.
Ovarian Ultrasound and Ovarian and Adrenal Hormones before and after Treatment for Hyperthyroidism
Authors: Skjöldebrand Sparre Lottie , Kollind Magnus , Carlström Kjell
Published: April 2003

Objective: To relate thyroid, steroid and pituitary hormones to ovarian ultrasonographic findings in hyperthyroid patients before and during treatment. Study Design: Ultrasonography of the ovaries and serum hormone determination by immunoassay were performed before and during thiamazole therapy in 18 women of fertile age treated for hyperthyroidism at the Danderyd Hospital from 1996 to 1998. Results: When hyperthyreotic, the patients had elevated serum levels of sex hormone-binding globulin (SHBG) and subnormal values of cortisol, free testosterone (fT) and dehydroepiandrosterone (DHEA). In the euthyreotic state following treatment, endocrine variables were normalized. Patients with a short duration of the disease had higher pretreatment levels of free thyroxine (fT4), SHBG and testosterone and lower corticosteroid binding globulin (CBG) and cortisol levels compared to patients with a long duration of the disease. The pretreatment ultrasonographic picture was abnormal in 16 of 18 patients. Of the 8 patients who were examined by ultrasonography after 3 months of treatment, all but 1 showed a normal picture. Samples from patients showing an abnormal ultrasonographic picture had significantly higher fT4 and lower free testosterone (fT) values than samples from patients with a normal ultrasonographic picture. Conclusion: Ultrasonographic findings showing a multicystic/multifollicular picture, resembling polycystic ovaries (PCO), in hyperthyroidism may be related to direct effects of thyroid hormones on the ovaries and/or altered intraovarian androgen environment due to elevated SHBG levels. It is highly recommended to assess the thyroid status in patients with multicystic/multifollicular ovaries/PCO.
Gene Therapy in Soft Tissue Reconstruction
Authors: Hoeller Daniela , Petrie Nicola , Yao Feng , Eriksson Elof
Published: April 2003

Gene therapy is defined as the introduction of a therapeutic gene into a cell, whose expression can lead to a cure of a disease or offer a transient advantage for tissue growth and regeneration. The delivery of genes can be undertaken for a number of purposes, usually it is attempted to enhance or add a function to a cell or a tissue or to delete or reduce another function. In this brief overview we describe various vehicles and techniques that have been developed to deliver therapeutic genes into cells, such as viral vectors and physical/chemical gene delivery methods including naked DNA and particle-mediated gene transfer, the microseeding technique and the application of lipids. Furthermore we review the potential utility of gene therapy from the perspective of a reconstructive surgeon. Several tissues will be discussed, particularly muscle, tendon, nerve, bone, skin and wounds.
In vitro Effect of Fluticasone Propionate on Interleukin 8 Production by Monocytes Obtained from Patients Affected by Moderate-Severe Allergic Asthma
Authors: Gangemi Sebastiano , Ruello Antonella , Arena Adriana , Minciullo Paola , Pirazzoli Antonella , Di Blasi Patrizia , Purello-D’Ambrosio Francesco , Merendino Rosaria Alba
Published: April 2003

Background: Interleukin-8 (IL-8), a potent chemotactic and activating factor for neutrophils and eosinophils, may be a crucial factor in severe asthma. The aim of this study was to evaluate the effect of fluticasone propionate (FP), a corticosteroid with potent anti-inflammatory activity, on the in vitro release of IL-8 by monocytes obtained from asthmatic patients. Methods: Monocytes from 15 non-atopic healthy donors and from 15 patients affected by moderate-severe allergic asthma were isolated and incubated (37°C, 5% CO2) for 24 h with varying combinations of lipopolysaccharide (LPS) from Escherichia coli (1 µg/ml) and FP (100 nmol/l). IL-8 concentration in the culture supernatant was measured by an immuno-enzymatic method (ELISA). Results: A highly significant inverse correlation between FEV1 (forced expiratory volume) values before withdrawal and in vitro IL-8 production by unstimulated monocytes from asthmatic patients was observed (Rho = –0.787; p = 0.0032). IL-8 production by either LPS-stimulated or unstimulated monocytes from asthmatic subjects was statistically increased compared to monocytes from healthy donors (p < 0.05). FP addition reduced IL-8 production by monocytes from asthmatic patients and also from healthy donors (p < 0.05). Conclusions: The partial IL-8 inhibition by FP could be closely related to the anti-inflammatory activity of this corticosteroid. Based on these results, we propose that the clinical improvement of asthma, observed following FP administration, may depend, at least in part, on the ability of this drug to modulate cytokine production by monocytes.
Smooth Muscle, Neurons and Interstitial Cells of Guinea Pig Ileum: Are There Tachykinin Neurokinin 1 Receptor Subtypes?
Authors: Matuszek Maria A. , Burcher Elizabeth
Published: April 2003

Binding and autoradiographic studies were carried out in guinea pig ileum to examine neurokinin (NK) 1 receptor location and subtypes using the NK-1-selective radioligand [125I]Bolton-Hunter[Sar9,Met(O2)11]SP. Two membrane preparations were made: (1) longitudinal muscle containing the myenteric plexus and (2) circular muscle containing the interstitial cells of Cajal. In saturation binding studies, the KD was estimated as 1.3 and 1.0 nmol/l in each preparation, respectively. In competition binding, the rank order of potency was similar in both membrane preparations: SR140333 ≈ CP99994 ≧ [Sar9,Met(O2)11]SP ≈ physalaemin ≈ CP96345 (pIC50 9.5–8.7) >> neuropeptide γ ≧ septide (pIC50 7.8–7.4). Similarly, scyliorhinin I displayed equal affinity in both preparations, although binding was at two sites, of high affinity (pIC50 9.1, 30%) and low affinity (pIC50 7.2–6.6, 70%). The only competitor to bind differently in the two muscle preparations was scyliorhinin II, which bound to one site with low potency in the circular muscle (pIC50 6.9) but to high-affinity (pIC50 9.0, 17%) and low-affinity (pIC50 6.7, 83%) sites in the longitudinal muscle. In autoradiographic studies, dense specific binding was associated with the myenteric plexus and the inner circular muscle containing the interstitial cells of Cajal, with minimal specific binding to longitudinal and circular smooth muscle. These results suggest that the NK-1 receptor on the interstitial cells and the myenteric plexus is similar. The apparently low numbers of binding sites on intestinal smooth muscle may be due to a low expression of the NK-1 receptor. Alternatively, the radioligand may not recognize the guinea pig ileum muscle NK-1 receptors due to possible minor differences in their sequence or glycosylation.
Cytogenetic and Molecular Genetic Aspects of Chronic Myeloid Leukaemia
Authors: Barnes David J. , Melo Junia V.
Published: April 2003

Chronic myeloid leukaemia (CML) is caused by the product of the BCR-ABL oncogene, located on the Philadelphia (Ph) chromosome. BCR-ABL is generated as a result of a reciprocal t(9;22) chromosomal translocation. The mechanisms responsible for this illegitimate recombination event remain elusive but are presumed to require a close spatial association of the translocation partners (chromosomes 9 and 22). BCR-ABL fusion transcripts can be detected by a sensitive reverse transcription-polymerase chain reaction (RT-PCR) in the leucocytes of some healthy individuals suggesting that chromosomal translocations may occur frequently in the general population. The presence of BCR-ABL fusion transcripts does not imply that the individual will inevitably develop CML since other conditions must be favourable for expansion of the abnormal clone. Breakpoints in the ABL gene occur within a 5′ segment. BCR-ABL fusion transcripts lack ABL exon a1 and consist of BCR exons fused directly to ABL exon a2. The breakpoints in the BCR gene on chromosome 22 are found within three defined regions. Depending on the position of the BCR breakpoint, fusion genes are generated that encode 190-, 210- or 230-kD forms of the Bcr-Abl tyrosine kinase. Since the ABL component of the fusion gene is largely invariant, it follows that variability in disease phenotype may be due to protein sequences encoded by the translocation partner, BCR. Different disease phenotypes are associated with each of the three Bcr-Abl oncoproteins, p190Bcr-Abl, p210Bcr-Abl and p230Bcr-Abl. Mechanisms associated with malignant transformation include altered cellular adhesion, activation of mitogenic signalling pathways, inhibition of apoptosis and proteasomal degradation of physiologically important cellular proteins. CML is subject to an inexorable progression from an ‘indolent’ chronic phase to a terminal blast crisis. Disease progression is presumed to be associated with the phenomenon of genomic instability.
The Glycosylphosphatidylinositol Anchor and Paroxysmal Nocturnal Haemoglobinuria/Aplasia Model
Authors: Hall Claire , Richards Stephen J. , Hillmen Peter
Published: April 2003

Paroxysmal nocturnal haemoglobinuria (PNH) is unique because it is an acquired haemolytic anaemia, resulting from an intrinsic red cell membrane disorder. The disease has been shown to be due to a somatic mutation of the phosphatidylinositol glycan complementation class A (pig-a) gene at the level of the haemopoietic stem cell. The defect in synthesis of the glycosylphosphatidylinositol (GPI) anchor results in a deficiency of all proteins that are GPI-bound to red cell, leucocyte and platelet membranes. The function of these proteins is extremely varied but a critical role is the protection of the cell from complement and it is the unopposed action of the complement cascade that results in the intravascular haemolysis and venous thrombosis which are hallmarks of the disease. The relationship between PNH and aplastic anaemia remains intriguing. It appears likely that an insult to a haemopoietic progenitor alters it in such a way that it becomes vulnerable to immune-mediated attack by cytotoxic T cells and/or cytokines. This attack requires one or more GPI-anchored molecules to be effective. Thus a GPI-negative clone would be at a relative advantage, and it is the balance between bone marrow impairment and proliferation of the GPI-negative clone(s) that determines the clinical picture. Prospects for molecular therapy continue to improve. Cell-to-cell transfer of GPI-linked proteins has been demonstrated in murine studies and recombinant CD59 has been expressed on GPI-deficient lymphocytes in vitro. Gene therapy remains a tantalising possibility, although a greater understanding of the pathophysiology of PNH is required, as well as advances in gene therapy techniques, before such an approach can be seriously considered.
Effect of Increasing Doses of Aspirin on Platelet Aggregation among Stroke Patients
Authors: Gan Robert , Teleg Rosalia A. , Florento Leila , Bitanga Ester S.
Published: April 2003

Background and Purpose: Aspirin has been shown to reduce the risk of myocardial infarction and stroke. Some investigators believe that low-dose aspirin inhibits platelet aggregation to the same degree as high-dose aspirin. Our study aimed to assess the effect of increasing doses of aspirin on the degree of platelet aggregation induced by collagen and adenosine diphosphate (ADP) among stroke patients. Methods: Sixteen poststroke patients were prescribed aspirin at daily doses of 40, 80, 160, 325, 650, and 1,300 mg, each dose to be taken for 14 days (total duration 12 weeks). Platelet aggregation studies using 2 µg/ml collagen and 2 µM ADP were performed on platelet-rich plasma at baseline and on the 14th day of each dose. Results: Platelet aggregation studies using 2 µg/ml collagen at the start of treatment and at the 14th day of each dose revealed dose-dependent inhibition by aspirin starting at 40 mg/day, but was optimal at 80– 160 mg/day. ADP-induced platelet aggregation inhibition appears to be dose dependent up to 1,300 mg/day. Conclusion: Inhibition of collagen-induced platelet aggregation by aspirin appears to be optimal at 80–160 mg/day, while ADP-induced platelet aggregation inhibition by aspirin appears to be dose dependent up to 1,300 mg/day in our poststroke patients, albeit to a less remarkable degree at higher doses.
Apoferritin Attenuates Experimental Allergic Encephalomyelitis in SJL Mice
Authors: LeVine Steven M. , Maiti Smarajit , Emerson Mitchell R. , Pedchenko Tetyana V.
Published: April 2003

Ferritin has been shown to attenuate iron-catalyzed oxidative damage in several experimental conditions. Since oxidative damage has been implicated in the pathogenesis of multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE), an animal model of MS, we tested the hypothesis that ferritin would act to attenuate disease. The experimental design was to increase plasma ferritin levels during the active stage of EAE by giving systemic injections of apoferritin and then compare disease activity between these mice and EAE mice administered vehicle. Additional mice received systemic injections of iron, which induces ferritin synthesis, in order to test the effects of exogenous iron on the disease course. Although plasma levels of ferritin were found to be elevated in both apoferritin and iron-injected EAE mice, only apoferritin treatment resulted in a reduction in disease activity compared to EAE mice given vehicle. The suppressive effects of apoferritin administration suggest that the increase in endogenous ferritin levels that have been previously observed in the cerebrospinal fluid of chronic progressive MS patients with active disease might be functioning to limit the severity and spread of tissue damage.
Iron: A Pathological Mediator of Alzheimer Disease?
Authors: Bishop Glenda M. , Robinson Stephen R. , Liu Quan , Perry George , Atwood Craig S. , Smith Mark A.
Published: April 2003

Brains from patients with Alzheimer disease (AD) show a disruption in the metabolism of iron, such that there is an accumulation of iron in senile plaques, and an altered distribution of iron transport and storage proteins. One of the earliest events in AD is the generation of oxidative stress, which may be related to the generation of free radicals by the excess iron that is observed in the disease. Iron has also been shown to mediate the in vitro toxicity of amyloid-β peptide, and the presence of iron in most in vitro systems could underlie the toxicity that is normally attributed to amyloid-β in these studies. In contrast, several recent studies have suggested that amyloid-β may decrease oxidative stress and decrease the toxicity of iron. Continued examination of the complex interactions that occur between iron and amyloid-β may assist in the elucidation of the mechanisms that underlie the neurodegeneration that leads to dementia in AD.
Protein Oxidation and Heme Oxygenase-1 Induction in Porcine White Matter following Intracerebral Infusions of Whole Blood or Plasma
Authors: Wagner Kenneth R. , Packard Benjamin A. , Hall Cathy L. , Smulian A. George , Linke Michael J. , de Courten-Myers Gabrielle M. , Packard Lori M. , Hall Nathan C.
Published: April 2003

Spontaneous or traumatic intracerebral hemorrhage (ICH) in the white matter of neonates, children and adults causes significant mortality and morbidity. The detailed biochemical mechanisms through which blood damages white matter are poorly defined. Presently, we tested the hypothesis that ICH induces rapid oxidative stress in white matter. Also, since clot-derived plasma proteins accumulate in white matter after ICH and these proteins can induce oxidative stress in microglia in vitro, we determined whether the blood’s plasma component alone induces oxidative stress. Lastly, since heme oxygenase-1 (HO-1) induction is highly sensitive to oxidative stress, we also examined white matter HO-1 gene expression. We infused either whole blood or plasma (2.5 ml) into the frontal hemispheric white matter of pentobarbital-anesthetized pigs (∼1 kg) over 15 min. We monitored and controlled physiologic variables and froze brains in situ between 1 and 24 h after ICH. White matter oxidative stress was determined by measuring protein carbonyl formation and HO-1 gene expression by RT-PCR. Protein carbonyl formation occurred rapidly in the white matter adjacent to both blood and plasma clots with significant elevations (3- to 4-fold) already 1 h after infusion. This increase remained through the first 24 h. HO-1 mRNA was rapidly induced in white matter with either whole blood or plasma infusions. These results demonstrate that not only whole blood but also its plasma component are capable of rapidly inducing oxidative stress in white matter. This rapid response, possibly in microglial cells, may contribute to white matter damage not only following ICH, but also in pathophysiological states in which blood-brain-barrier permeability to plasma proteins is increased.
Ferritin Binding in the Developing Mouse Brain Follows a Pattern Similar to Myelination and Is Unaffected by the Jimpy Mutation
Authors: Hulet S.W. , Menzies S. , Connor J.R.
Published: April 2003

We have previously provided evidence that ferritin binds selectively to white matter tracts in adult mouse and human brains. In cell culture experiments, ferritin binding is specifically localized to oligodendrocytes. The goal of the present study is to test the hypothesis that the developmental pattern for ferritin binding will coincide with the onset and progression of myelination. The first evidence of ferritin binding in the mouse brain is at 12 days of age and occurs within the brainstem. Ferritin binding persisted in the brainstem and expanded to the corpus callosum by 15–16 days of age. By 23–24 days of age ferritin binding had further extended to the striatal white matter. By adulthood, ferritin binding was strongly and selectively expressed throughout all white matter tracts. To begin to identify which factors may be involved in the induction of ferritin-binding proteins on oligodendrocytes, brains from the myelin mutant jimpy mice and unaffected littermates were examined at postnatal days 16–18. Jimpy mice were chosen because their oligodendrocytes fail to produce myelin or accumulate iron. Thus, using jimpy mice would elucidate whether these factors are necessary for ferritin-binding protein expression. Both the jimpy mutants and their controls exhibited saturable ferritin binding with similar binding densities and dissociation constants. Dissociation constants for ferritin binding in the unaffected littermates and jimpy mutant mice were 0.38 ± 0.04 and 0.32 ± 0.06 nM, respectively and binding densities were similar (1.1 ± 0.09 and 0.96 ± 0.12 fmol/mg, respectively). Our results demonstrate that expression of ferritin binding is dependent on the age of the oligodendrocytes and not dependent upon iron accumulation by oligodendrocytes or myelin production. We propose that iron delivery to oligodendrocytes is predominantly via ferritin and this method of iron uptake is unique to oligodendrocytes in the brain.
Esophageal, Tracheal and Pulmonary Parenchymal Alterations in Experimental Esophageal Atresia and Tracheoesophageal Fistula
Authors: Otcu S. , Kaya M. , Ozturk H. , Buyukbayram H. , Dokucu A.I. , Onen A. , Yucesan S.
Published: April 2003

Pulmonary complications are among the most important causes of morbidity and mortality in neonates with esophageal atresia and tracheofistula. We aimed to investigate the possible causes of respiratory complications encountered in esophageal atresia (EA) and tracheoesophageal fistula (TEF) in an experimental model. Sprague-Dawley fetal rats treated with adriamycin were used for the experiment. Time mated pregnant rats were given 1.75 mg/kg of adriamicyn intraperitoneally on days 6–9 of gestation. The fetuses were sacrified on day 21, weighed, and dissected under the surgical microscope. The animals were divided into four groups: (1) control group; (2) saline-injected group; (3) adriamycin-induced EA group, and (4) adriamycin administered but without development of EA. The lungs, esophagus, and trachea were excised and underwent histological examination. The mucosa of distal esophagus was thickened (p < 0.05); the submucosa was thinner (p < 0.05); and the muscular layer was thickened (p < 0.05) in fetuses with EA and TEF. In adriamycin-treated rats, in which EA and TEF developed, tracheal cartilage was loosened and formed into a D or C shape. The cartilage was fragmented into several segments on transverse sections in most fetuses. Alveolar septa were thin in lungs of fetus with EA and TEF (p < 0.05), without any fibrosis or evidence of parenchymal abnormality microscopically. Our findings suggest that respiratory complications may contribute to structural lesions in the trachea and particularly in the distal esophagus but not in the pulmonary parenchyma itself.
Isolated Leptomeningeal Carcinomatosis (Carcinomatous Meningitis) after Taxane-Induced Major Remission in Patients with Advanced Breast Cancer
Authors: Kosmas Christos , Malamos Nikolaos A. , Tsavaris Nikolas B. , Stamataki Melina , Gregoriou Achilleas , Rokana Sofia , Vartholomeou Maria , Antonopoulos Minas J.
Published: April 2003

Objectives: To identify the incidence of leptomeningeal carcinomatosis (LMC), as the first site of systemic progression, in breast cancer patients after having obtained a major response (CR or near CR) to first-line taxane-based chemotherapy and compare these findings in retrospect with a matched-pair group of historical control patients from our database treated with nontaxane regimens. Patients and Methods: Patients with histologically proven breast cancer having either metastatic disease or high-risk locoregional disease that were entered into treatment protocols with first-line taxane (paclitaxel or docetaxel) plus anthracyclines or mitoxantrone combinations and developed LMC as the first evidence of progression after major response (CR or >80% PR) were analyzed in the present study (n = 155), and compared, as regards the incidence of LMC, to a matched-pair retrospective group of 155 patients treated with nontaxane regimens in our unit. Results: Seven patients with a median age of 54 years (range 40–70) developed LMC as their first evidence of progression after taxane-based regimens with a median interval of 6 months (range 2–18) from start of treatment to diagnosis of LMC. Five patients received intrathecal (i.t.) methotrexate treatment and whole brain radiotherapy (RT), while 1 patient received i.t. methotrexate and RT to the lumbar spine. Two patients responded to treatment for LMC, while 2 achieved stable disease and 3 progressed. Two patients had elevated cerebrospinal fluid tumor markers (more than serum marker levels) that proved useful in monitoring response to treatment. Median survival after LMC was 3.6 months (range 1–17+) and correlated positively to the interval from the initiation of taxane-based therapy to LMC (r = 0.84, p = 0.019). Seven out of 86 responders (8.13%) in the taxane group versus 1 out of 72 responders (1.4%) in the non-taxane-treated group developed LMC as the first sign of progression after a major response to first-line chemotherapy (p < 0.1). Conclusions: LMC after a major response to front-line taxane-based regimens represents a grave disease manifestation and its incidence appears increased, but not significantly so, when compared retrospectively to non-taxane-treated patients. Prospective evaluation of the incidence of LMC after taxane versus non-taxane-based treatment from large randomized multi-institutional trials is warranted and identification of potential prognostic factors might help to identify patients requiring appropriate prophylactic therapy.
Vinorelbine and Cisplatin for the Treatment of Recurrent and/or Metastatic Carcinoma of the Uterine Cervix
Authors: Gebbia Vittoria , Caruso Michele , Testa Antonio , Mauceri Gaetano , Borsellino Nicolò , Chiarenza Maurizio , Pizzardi Nicoletta , Palmeri Sergio
Published: April 2003

Background: To test the clinical activity and toxicity profile of the combination regimen of vinorelbine and cisplatin in a series of patients with carcinoma of the cervix uteri with de novo metastatic disease or recurrent disease after previous therapy. The main aims of the study included analysis of objective response rates, toxicity, and time to progression. Patients and Methods: Forty-two eligible patients were enrolled into the trial and treated with cisplatin 80 mg/m2 on day 1 and vinorelbine 25 mg/m2 on day 1 and 8. This regimen was repeated every 21 days upon resolution of toxicity for 3 cycles before response assessment. Enrolled patients had a median age of 53 years, a median ECOG performance status of 1, and mostly a squamous cell histology (86%). Sixteen patients (38%) were treatment-naive since first diagnosed with widespread metastatic disease, 7% had only previous surgery, 31% radiotherapy, and 24% both radiation and surgical therapy. In previously radiated patients, 21% of patients had disease only within the radiation fields, 21% only outside the radiation fields, and 12% both inside and outside the radiotherapy portals. Results: All patients were evaluable for response analysis. A complete response was achieved in 5 patients (12%), and a partial response in 15 cases (36%) for an overall response rate of 48% (95% CL 22–52%). Patients with recurrent disease within the previous radiation field (including those also with disease outside the radiation fields) showed a 28% overall response rate with no complete response, while patients with disease previously untreated with radiotherapy or with tumour deposits only outside of ratiation portals yielded a 57% overall response rate with a 18% complete response rate. Only 1 out of 8 patients with performance status 2 showed a major response (12%). Median time to progression was 5.6 months (range 2.0–14 months). The median overall survival of the whole series was 9.1 months. Hematological toxicity was the most frequent side-effect. Grade 3 vomiting was recorded in 9 patients (21%), and mild mucositis in 14% of patients. Grade 3 neutropenia was observed in 21% of patients, while grade 4 in 12% of cases with neutropenic fever was seen in 4 cases. Sixteen patients (38%) complained of grade 1–2 constipation, while grade 1–2 peripheral neuropathy was seen in 8 patients (19%). Conclusions: The results achieved in this trial suggest that the combination regimen of vinorelbine and cisplatin may be safely given to patients with metastatic and/or recurrent carcinoma of the uterine cervix. This regimen is active at least in terms of objective response rates. Although satisfactory results are still lacking, these results suggest that the vinorelbine-cisplatin regimen is worthy of further studies and may represent the basis for the development of new active regimens.
Nonmalignant Oral Keratinocytes from Patients with Head and Neck Squamous Cell Carcinoma Show Enhanced Metabolism of Retinoic Acid
Authors: Klaassen Ingeborg , Cloos Jacqueline , Smeets Serge J. , Brakenhoff Ruud H. , Tabor Maarten P. , Snow Gordon B. , Braakhuis Boudewijn J.M.
Published: April 2003

Background and Objective: Retinoids show promise in the treatment of various (pre)malignancies, including head and neck squamous cell carcinoma (HNSCC). It has been shown that metabolic pathways of retinoids are important in their anticancer effect and that these pathways may change during HNSCC carcinogenesis. We have previously reported that HNSCC cells have a 17-fold greater turnover rate of retinoic acid (RA) than normal oral keratinocytes from noncancer controls, and that the formation of polar metabolites such as 4-oxo-RA and 4-hydroxy-RA is only seen in HNSCC cell lines. We aimed to establish whether this altered retinoid metabolism is an intrinsic characteristic of HNSCC patients. Methods: The normal mucosa of cancer and noncancer patients was the source of keratinocyte cultures. The cells were exposed to RA for various time periods, and the levels of various retinoids were measured in the culture medium and cell pellets with reverse-phase liquid chromatography. Results: Cells from cancer patients were morphologically normal and showed no genetic aberrations (i.e. loss of heterozygosity). The RA turnover rate in normal oral keratinocytes of cancer patients was 15 times higher (p = 0.003) than that in normal oral keratinocytes of noncancer controls, with average turnover rates of 218.6 and 14.8 pmol/mg protein/h, respectively. Specific profiles of RA metabolites were similar. Conclusion: The observed higher RA metabolism in noncancer cells of HNSCC patients suggests that individuals with a relatively high RA turnover have an increased risk of developing HNSCC.
5′-End RET Splicing: Absence of Variants in Normal Tissues and Intron Retention in Pheochromocytomas
Authors: Le Hir Hervé , Charlet-Berguerand Nicolas , de Franciscis Vittorio , Thermes Claude
Published: April 2003

The Ret tyrosine kinase is implicated in neuronal cell survival, kidney development and tumorigenesis. Several 3′ and 5′ transcript variants have been described resulting from alternative splicing of the RET pre-mRNA. The 3′ variants code for three C-terminal isoforms, RET51, RET9 and RET43. The 5′ variants RET2/4, RET2/5 and RET2/6 result from skipping exons 3, 3–4 and 3–5, respectively. These variants code for putative Ret proteins differing in their extracellular ligand-binding domains, and their expression is strongly regulated during kidney development. Here we analyzed the presence of these RET 5′ variants in normal tissues and in MEN2 and sporadic pheochromocytomas. In all tissues examined, the abundance of these transcripts remained extremely low (less than 1% of all RET transcripts) thus indicating these species as rare variants with little biological meaning. On the other hand, in tumors, the 5′ RET splicing pattern differed from that of normal tissues. Indeed, we identified a RET-derived transcript that results from the aberrant retention of intron 2. This transcript is enriched in tumor samples of both familial and sporadic origin, and indicates RET as a target for RNA splicing deregulation in tumor cells.
Diaphragm Disease of the Small Bowel – A Case Report and Literature Review
Authors: Onwudike M. , Sundaresan M. , Melville D. , Wood J.J.
Published: April 2003

A 75-year-old man who had an emergency laparotomy for small bowel obstruction was found at operation to have multiple mid-ileal strictures. Histology of the resected specimen confirmed diaphragm disease of the bowel. The pathogenesis of this disease remains unclear but it is associated with long-term use of NSAID. Diagnosis is often difficult as many clinicians are unaware of this condition. The relevant literature has been reviewed.
Clinicopathologic Features of Gastric Cancers Producing Alpha-Fetoprotein
Authors: Kono Koji , Amemiya Hideki , Sekikawa Takayoshi , Iizuka Hidehiko , Takahashi Akihiro , Fujii Hideki , Matsumoto Yoshiro
Published: April 2003

Background: Patients with gastric cancers producing alpha-fetoprotein (AFP) were reported to have a poor prognosis with high rates of liver metastasis. The purpose of the present study was to clarify the clinicopathological features of AFP-producing gastric cancers, in particular characteristics of liver metastasis, and to evaluate treatment of these cancers. Methods: In 27 of the 29 cases with elevated preoperative serum AFP levels among a total of 974 primary gastric cancers, AFP production was confirmed in gastric cancer cells by immunohistochemistry. These cases were included in the AFP-positive gastric cancer group (AFP(+), 2.7%). The remaining 945 cases with normal serum AFP levels were designated the AFP-negative gastric cancer group (AFP(–)). Results: There was a higher incidence of lymph node metastasis, a deeper invasion of the gastric wall, a higher frequency of advanced stage, a more marked lymphatic invasion and a higher rate of liver metastasis in the AFP(+) group than in the AFP(–) group. The patients received curative resection in AFP(+) group had a significantly worse survival rates in comparison to that in AFP(–) group. With respect to liver metastasis (n = 17) in AFP(+) group, of 3 cases who received curative hepatic resection, 1 patient survived more than 3 years, while the remaining 2 died in less than 3 years due to multiple liver recurrence. The patients (n = 5) who received palliative resection for liver metastasis followed by transarterial continuous infusion chemotherapy all died in less than 1 year. Conclusion: AFP-producing gastric cancers had aggressive behavior and their clinical or biological features were quite different from the common AFP-negative gastric cancers. Surgical resection of liver metastasis from AFP-producing gastric cancers was unsatisfactory. The development of a novel multimodal therapy against AFP-producing gastric cancers is needed.
Progressive Histiocytosis: Description of a Case of Slow-Course Non-Langerhans Cell Histiocytosis
Authors: Caputo R. , Brezzi A. , Vaccari G. , Cavicchini S. , Gianotti R.
Published: April 2003

We describe the case of a 37-year-old male patient who in 1992 started developing a skin eruption characterized by dark red to red-yellow papulonodular lesions that showed no tendency to spontaneous resolution. Visceral organs were not involved and the lipid pattern was basically normal. Histological examination revealed an infiltrate in the mid and upper dermis mainly consisting of mononucleated and multinucleated histiocytes with an abundant eosinophilic cytoplasm and a ground glass appearance, admixed with numerous xanthomatized cells and Touton and foreign-body giant cells. Immunohistochemical studies showed positivity for CD68 and negativity for CD1a and S-100 protein, whereas at the electron microscopy level the only peculiar finding was the presence of many desmosome-like junctions. The authors believe this to be a borderline form between papular xanthoma and reticulohistiocytosis.
Upregulation of Ku Expression in Human Neuroectodermal Tumor Cells after Retroviral DNA Integration
Authors: Liu Xuan , Lin Junji , Huang Jia , Li Lishu , Liu Lei , Xu Ping
Published: April 2003

Objective: To examine the expression of DNA-dependent protein kinase (DNA-PK); including DNA-PKcs, Ku70 and Ku80 in human neuroectodermal tumor cells with or without retroviral DNA integration. Methods: RT-PCR assay was used to examine the transcript of DNA-PK. Western blot and immunocytochemistry assays were used to examine the protein level of DNA-PK. Results: The expression of DNA-PKcs was similar in the cells with or without retroviral DNA integration, but the expression of Ku (both mRNA and protein for Ku70 and only protein for Ku80) was higher in cells with retroviral DNA integration than in cells without retroviral DNA integration. Conclusion: The expression of Ku but not the expression of DNA-PKcs is induced by retroviral DNA integration. Ku70 may play an important role in the regulation of Ku function in response to retroviral DNA integration.
Atopic and Nonatopic IgE-Mediated Allergy: A New Interpretation of Old Facts?
Authors: de Weck A.L.
Published: April 2003

Coined 80 years ago, the term ‘atopy’ to designate a group of diseases associated with IgE and a hereditary background has raised many discussions. In particular, it is difficult to consider as part of an atopic syndrome cases of IgE-mediated allergies to isolated allergens without evidence of a familial inheritance. The postulate expressed in this essay is that in humans we are essentially dealing with an atopic IgE-mediated allergy, which is the equivalent of a genetically determined high IgE response, and with a nonatopic IgE-mediated allergy, which is the equivalent of a low IgE response in mammals and rodents.
Individual Hymenoptera Venom Compounds Induce Upregulation of the Basophil Activation Marker Ectonucleotide Pyrophosphatase/Phosphodiesterase 3 (CD203c) in Sensitized Patients
Authors: Binder Marc , Fierlbeck Gerhard , King Te Piao , Valent Peter , Bühring Hans-Jörg
Published: April 2003

Background: Bee and wasp venom extracts contain potent allergens capable of inducing severe clinical reactions. To analyze immediate-type hypersensitivity to defined hymenoptera venom components, a recently developed in vitro test was applied that is based on the upregulation of CD203c expression on basophils. Methods: CD203c expression on blood basophils of 9 healthy donors and 39 patients allergic to bee and/or wasp venom was analyzed by flow cytometry before and after activation with the purified bee venom allergens phospholipase A2 (Api m 1), hyaluronidase (Api m 2) and melittin (Api m 4), or the purified wasp venom allergens phospholipase A1 (Ves v 1), hyaluronidase (Ves v 2) and the recombinant antigen 5 (Ves v 5). Venom-induced CD203c upregulation on basophils was compared with skin tests and assessment of specific IgE. Basophils of nonresponders were preincubated with 10 ng/ml interleukin-3 (IL-3) prior to allergen stimulation. Results: CD203c upregulation on basophils was induced by defined hymenoptera venom components in 35/39 patients with a diagnosed allergy to wasp and/or bee venom. Twenty-seven of the 34 tested patients with wasp allergy showed CD203c upregulation in response to Ves v 5, 26 of these patients also reacted with Ves v 2 and 17 with Ves v 1. Nine of 13 patients with bee allergy reacted with Api m 1, 13 individuals with Api m 2 and none of these patients with the minor allergen Api m 4. A diagnosed wasp allergy could also be confirmed in the prestimulated basophils (IL-3) of 2 nonresponder individuals who failed to upregulate CD203c in response to IgE receptor cross-linking prior to culture with IL-3. Conclusions: Flow-cytometric determination of CD203c upregulation on basophils activated by molecularly defined allergens is a powerful method to identify the precise allergen reactivity in sensitized individuals.
Ozone-Induced Release of Neuropeptides from Human Nasal Mucosa Cells
Authors: Schierhorn Katrin , Hanf Gerald , Fischer Axel , Umland Beate , Olze Heidi , Kunkel Gert
Published: April 2003

Studies examining the effect of pharmacological agents on respiratory responses to ozone support the concept that the effects are mediated, at least in part, by neural mechanisms, including neuropeptide release. Using a special tissue culture system the influence of ozone (0.1 ppm/24 h) on nasal mucosa from allergic and nonallergic patients undergoing surgery for chronic nasal obstruction was examined. Substance P (SP)-immunoreactive nerves were found in air-exposed as well as in ozone-exposed tissue samples. The content of neurokinin A (NKA) and SP in the culture supernatants was significantly increased following ozone exposure compared to controls. Tissue of allergic patients showed an ozone-induced increase in the release of NKA and SP compared to tissue of nonallergic patients. These results suggest that the mode of action of ozone results in an increased activity of sensory nerves in the upper airways with a subsequent increased release of neuropeptides. In addition to the known ozone-induced release of proinflammatory mediators, these mechanisms may explain the increased responsiveness of patients with hypersensitive airways.