bluuebunny/crossref_metadata_2025 huggingface dataset:
A Population-Based Estimate of the Prevalence of Consanguineous Marriage in Western Australia
Authors: Port K. , Bittles A.H.
Published: April 2003

Objective: To determine the current prevalence of consanguineous marriage in Western Australia, as a means of assessing the associated requirement for genetic counselling services. Subjects and Methods: The records of all intended marriages in Western Australia were examined over a 6-year period (1994–1999), with the numbers and types of consanguineous unions collated and analysed by year, current domicile and countries of origin. Results and Conclusions: Of the 62,549 proposed marriages, 144 (0.23%) were between couples who identified themselves as biological relatives, 82 (0.13%) of whom were first cousins. The mean coefficient of inbreeding α for the total sample was 0.00009. In 75.7% of cases either one or both of the partners had been born outside Australia. Given the patterns of recent migration to Australia, it is suggested that these figures should be treated as minimal estimates of the actual levels of consanguinity in the population.
Participation in Maternal Marker Screening for Down Syndrome: Contribution of the Information Delivered to the Decision-Making Process
Authors: Seror Valérie , Costet Nathalie , Aymé Ségolène
Published: April 2003

Objective: In France, health care providers now have to fulfill two requirements before serum marker screening for Down syndrome can be carried out: provide a written statement confirming that they informed the pregnant woman about the test and obtain the woman’s written consent. A survey was designed to assess: (1) women’s opinion on the explanations they received when the screening test was offered and when test results were given, and (2) the decisions women planned to make in light of the test results (i.e. to carry out amniocentesis or not). Methods: The survey was intended for all French pregnant women who underwent the serum marker screening test during the first week of October 1998. The questionnaire was sent to women via clinical laboratories (3,825 questionnaires were sent to the 54 laboratories authorized for Down syndrome screening in France). Besides χ2 tests and tests of comparisons of paired proportions, we conducted a hierarchical clustering analysis and qualitatively analyzed the free comments provided by women. Results: The response rate was 39% (n = 1,473). Explanations given by the provider at the time the test was offered were not clear and ample enough for 38.8% of women. Furthermore, 45.9% of women stated the same opinion about the explanations provided with the test results. Based on the test results, amniocentesis was recommended to 125 high-risk women; 20.8% of them were going to decline the offer or had not yet decided. Among low-risk women, 13% requested amniocentesis or had not yet decided. The opinion of these high- or low-risk women on the clarity and ampleness of the explanations provided with the test results was similar to that of high-risk women who wished to carry out amniocentesis. The hierarchical clustering analysis led us to identify clusters of women who mainly differed according to their opinion (anxious or reassured) on the explanations provided, regardless of their risk (high or low). Conclusion: Women’s decision regarding screening for Down syndrome requires them to promptly integrate complex information on what the test is and entails. The question is then raised as to the type of information that is actually disclosed or that could be disclosed, based on how women value its contribution to decision-making.
Neurons and Their Dendrites in Frontotemporal Dementia
Authors: Ferrer I.
Published: April 2003

Regional and areal patterns of cell vulnerability (manifested as cell death and neuron loss) and cell sensitivity (as revealed by the presence of intracytoplasmic inclusions) are described in patients with frontotemporal dementia (FTD) and FTD+ motor neuron disease (MND). This is followed by studies geared to learning about possible mechanisms involved in selective neuron loss and studies focused on recognizing the identity of vulnerable populations of local-circuit neurons and the impact of FTD on individual cells as well as on postsynaptic and presynaptic terminals in the frontal cortex. Neuron loss is not associated with increased vulnerability to nuclear DNA fragmentation, and nor is it accompanied by modifications in the expression of the proteins Bcl-2 and Bax, and transcription factors c-Fos and c-Jun, thus suggesting that these proteins are probably not involved in cell death in these disorders. In the frontal and temporal cortices, glutamatergic pyramidal cells and calbindin-D28k-immunoreactive GABAergic local-circuit neurons are lost in the upper cortical layers. Parvalbumin-immunoreactive cells are preserved. In addition, reduction of putative postsynaptic sites (as inferred from the decreased numbers of dendritic branches in both pyramidal and nonpyramidal neurons, and of dendritic spines in pyramidal cells) in remaining neurons of the upper layers, as well as reduction of presynaptic terminals (as suggested by the decreased expression of synaptic vesicle-associated proteins, synaptophysin, synaptotagmin, rab 3a and synapsin 1, and presynaptic plasma membrane proteins SNAP-25 and syntaxin 1) in the upper layers of the frontal cortex, but not of the posterior parietal cortex, demonstrate the combined devastating effects of FTD on cortico-cortical connections.
Role of Oxidative Stress in Frontotemporal Dementia
Authors: Gerst Jennifer L. , Siedlak Sandra L. , Nunomura Akihiko , Castellani Rudy , Perry George , Smith Mark A.
Published: April 2003

Recent reports have established oxidative stress and damage as playing a role in the pathogenesis of a number of neurodegenerative diseases including Alzheimer disease, Parkinson disease, corticobasal degeneration, Pick’s disease and Alexander’s disease. Here we present evidence that oxidative damage is also one of the earliest cytopathological markers of neuronal dysfunction in frontotemporal dementia.
Allosteric Modulation of Nicotinic Receptors as a Treatment Strategy for Alzheimer’s Disease
Authors: Maelicke Alfred
Published: April 2003

Impairment of the central cholinergic system has a pivotal role in the cognitive decline observed in patients with Alzheimer’s disease (AD). One of the most prominent cholinergic deficits is the reduced number of nicotinic acetylcholine receptors (nAChR) in the brain. Since these receptors are important for memory and learning, enhancing nicotinic neurotransmission is a promising treatment strategy for AD. The two most common approaches to correcting these cholinergic deficits are to increase the synaptic availability of acetylcholine (ACh) by inhibiting acetylcholinesterase (AChE), or to mimic the effects of ACh (nicotinic agonists) by acting directly on nicotinic receptors. Clinical studies suggest that AChE inhibitors produce only short-term symptomatic improvement. Similarly, long-term use of nicotinic agonists may induce desensitization of nicotinic receptors, leading to tolerance and therefore limiting the duration of efficacy. Allosteric modulation of nAChR is a novel approach, which circumvents the development of tolerance. Allosteric modulators bind to a site on nAChR that is different to the binding site of the natural agonist, ACh. This allosteric interaction amplifies the actions of ACh at post- and presynaptic nAChR. In particular, presynaptic nAChR are capable of modulating the release of ACh and other neurotransmitters, such as glutamate, serotonin and GABA, which may contribute to symptoms of the illness. Allosteric modulation of nAChR could therefore produce significant therapeutic benefit in AD. One of the most potent of these allosteric modulators is galantamine. As well as modulating nAChR, galantamine inhib- its AChE. The extent to which the clinical benefits of galantamine are attributable specifically to its nicotinic effects is uncertain and requires further investigation. However, galantamine maintains patients’ level of cognitive and daily function for at least 1 year, which has not been reported for other AChE inhibitors. Galantamine’s modulatory effects on nAChR may influence transcriptional regulation, resulting in an increased synthesis of nAChR. This may account for galantamine’s sustained efficacy.
Responder Characteristics to a Single Oral Dose of Cholinesterase Inhibitor: A Double-Blind Placebo-Controlled Study withTacrine in Alzheimer P atients
Authors: Almkvist O. , Jelic V. , Amberla K. , Hellström-Lindahl E. , Meurling L. , Nordberg A.
Published: April 2003

A proportion of Alzheimer’s disease (AD) patients treated for several months with cholinesterase (ChE) inhibitors have shown some favorable response on cognition, but the characteristics of the responders are still unclear. This study attempts to identify the characteristics of individuals with a positive behavioral response after a double-blind randomized administration of a single oral dose of tacrine (40 mg) and placebo to AD patients. Furthermore, the relationship between single-dose and long-term responders are examined. Twenty-four mildly to very mildly demented AD patients participated in the study. They all fulfilled the diagnosis of probable AD according to NINCDS-ADRDA criteria. Active treatment (tacrine 40 mg) and placebo was administered in random order on 2 consecutive days, and the effects were evaluated within 2 h using neuropsychological tests (assessing visuospatial ability, episodic memory and attention), registration of EEG activity and measurement of red blood cells (RBC) acetylcholinesterase (AChE), ChE activity and concentrations of tacrine and its metabolites in plasma. Results demonstrated significant improvement, tacrine compared to placebo, in measures of attention, but not in episodic memory or visuospatial ability. A single-dose response was therefore defined in terms of improvement in attention. The tacrine plasma concentration (pcTHA) showed a positively skewed distribution (mean ± SD: 10.5 ± 11.8, range: 1.0–51.8 ng/ml). There were no significant differences between single-dose responders compared to nonresponders in pcTHA, metabolites of tacrine, inhibition of AChE in RBC, tau levels in CSF, AChE activity in CSF or plasma and demographic variables. However, single-dose responders showed a higher right frontal alpha/theta ratio on EEG and had lower glucose metabolism in the parietal-temporal association cortex at baseline. In addition, the frequency of apolipoprotein E (APOE) Ε4 alleles was higher in responders. Interestingly, the single-dose response was related to the long-term response, although not significantly, which probably was due to lack of power. To conclude, the present study identified single-dose responders in terms of improved attentional performance associated with a relatively higher alpha/theta activity in the right frontal regions of the brain measured on EEG and predominance of APOE Ε4 allele.
APOE Genotype: No Influence on Galantamine Treatment Efficacy Nor on Rate of Decline in Alzheimer’s Disease
Authors: Aerssens Jeroen , Raeymaekers Peter , Lilienfeld Sean , Geerts Hugo , Konings Frank , Parys Wim
Published: April 2003

Apolipoprotein E (APOE) has been extensively demonstrated to be a genetic risk factor for Alzheimer’s disease (AD). Associations of APOE genotype have been reported with age at AD onset, rate of decline, and responsiveness to therapy. This study aimed to test these hypotheses in a large study population of AD patients. APOE genotype was determined from 1,528 Caucasian subjects, diagnosed by NINCDS/ADRDA criteria as probable AD patients, enrolled in four international placebo-controlled clinical trials of 3–12 months duration, designed to evaluate efficacy of treatment with galantamine or sabeluzole. In addition to patient demographics and baseline scores for Mini Mental State Examination, scores on the Disability Assessment for Dementia (DAD) and the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) were recorded at the start, during, and at the end of the study. APOE Ε4 homozygotes had a significantly lower age at disease onset compared to patients with other APOE genotypes. The Ε4 allele was significantly over-represented in females compared to males, and in the group of subjects with an AD family history. Based on longitudinal data of 504 placebo-treated AD patients, the linear annual rate of change in score was 5 points on the ADAS-cog scale and 11 on the DAD scale. The Ε4 allele copy number did not influence these rates of decline. Sabeluzole treatment was not effective in the overall group compared to the placebo-treated group, nor in any subgroup stratified by Ε4 allele count. Galantamine produced cognitive and functional improvement that were not affected by Ε4 allele count. In conclusion, our data confirm a strong association between Ε4 homozygotes and age at onset of AD but do not support an effect of Ε4 allele copy number on rate of cognitive and functional decline nor on the efficacy of galantamine in patients with AD.
Relationship between Both IQ and Mini-Mental State Examination and the Regional Cerebral Glucose Metabolism in Clinically Diagnosed Alzheimer’s Disease: A PET Study
Authors: Kawano Masami , Ichimiya Atsushi , Ogomori Koji , Kuwabara Yasuo , Sasaki Masayuki , Yoshida Tsuyoshi , Tashiro Nobutada
Published: April 2003

In order to clarify the hypofunction in which brain areas demonstrate a decline in Intelligence Quotient (IQ), we examined correlations between the IQ and Mini-Mental State Examination (MMSE) and regional cerebral metabolic rate of glucose (rCMRglc) measured using positron emission tomography (PET) in 26 patients with clinically diagnosed Alzheimer’s disease (AD). The MMSE scores and full-scale IQ (FSIQ) showed significant correlations with the rCMRglc in the temporal and parietal lobes on both sides and in the left frontal lobe, which were significantly reduced in comparison to those in the normal controls. A multiple regression analysis showed only the MMSE score to predict verbal IQ (VIQ), performance IQ (PIQ) and FSIQ. VIQ was also predicted by the rCMRglc in the left parietal lobe, while PIQ was predicted by the age at onset. The results suggested MMSE to be an index of dementia severity reflected by general intelligence as shown by IQ in AD, and a reduction in the VIQ can thus be used as an index of the left parietal dysfunction, which is not expressed by MMSE.
Early Detection and Differential Diagnosis of Alzheimer’s Disease and Depression with Neuropsychological Tasks
Authors: Swainson R. , Hodges J.R. , Galton C.J. , Semple J. , Michael A. , Dunn B.D. , Iddon J.L. , Robbins T.W. , Sahakian B.J.
Published: April 2003

The development of novel treatments for Alzheimer’s disease (AD), aimed at ameliorating symptoms and modifying disease processes, increases the need for early diagnosis. Neuropsychological deficits such as poor episodic memory are a consistent feature of early-in-the-course AD, but they overlap with the cognitive impairments in other disorders such as depression, making differential diagnosis difficult. Computerised and traditional tests of memory, attention and executive function were given to four subject groups: mild AD (n = 26); questionable dementia (QD; n = 43); major depression (n = 37) and healthy controls (n = 39). A visuo-spatial associative learning test accurately distinguished AD from depressed/control subjects and revealed an apparent sub-group of QD patients who performed like AD patients. QD patients’ performance correlated with the degree of subsequent global cognitive decline. Elements of contextual and cued recall may account for the task’s sensitivity and specificity for AD.
Tolerance Profile of Retinol, Retinaldehyde and Retinoic Acid under Maximized and Long-Term Clinical Conditions
Authors: Fluhr J.W. , Vienne M.-P. , Lauze C. , Dupuy P. , Gehring W. , Gloor M.
Published: April 2003

Background: Topical retinoic acid (RA) causes irritation of the skin. To prevent this side effect, natural precursors of RA have been proposed. The aim of the present study was to compare the local tolerance profiles of retinol (ROL), retinaldehyde (RAL) and RA. Methods: ROL, RAL and RA were studied using repeated insult patch tests for 14 days (n = 6). Similarly, RAL and RA were assessed in long-term clinical use for 44 weeks (n = 355). Clinical scoring on irritation, measurement of transepidermal water loss (barrier function) and laser Doppler blood flow perfusion units (irritation) were performed. Results: Under maximized conditions, an equally low irritation potential for ROL and RAL and a more pronounced irritant effect with RA could be demonstrated clinically (p < 0.05 in the intergroup analysis). Furthermore, RAL and RA induced more scaling than ROL (p < 0.05), and ROL and RA tended to induce more burning/pruritus than RAL (nonsignificant). The TEWL values were low with ROL and high with RAL and RA (nonsignificant, intergroup analysis). The laser Doppler measurements confirmed pro-irritating effects of RA and the nonirritating effects of ROL and RAL (p = 0.001, intergroup analysis). The long-term clinical study showed that the study population developed a high frequency of erythema (44% of the population), scaling (35%) and burning/pruritus (29%) with RA in the first 4 weeks of treatment, whereas these 3 parameters were significantly less frequent with RAL (p < 0.0001 in the intergroup analysis). Conclusion: The natural retinoids ROL and RAL do have a good tolerance profile, in contrast with the irritating potential of RA.
Costello Syndrome with Decreased Gene Expression of Elastin in Cultured Dermal Fibroblasts
Authors: Hatamochi A. , Nagayama H. , Kuroda K. , Shinkai H. , Ishikiriyama S. , Kobayashi M. , Kobayashi K.
Published: April 2003

We report a case of Costello syndrome. A 2-year-old Japanese boy presented with a ‘coarse‘ face, curly hair and loose skin of the dorsal aspect of the hands and feet with dark pigmentation. A skin biopsy of the dorsal aspect of the left hand revealed hyperkeratosis and papillomatosis of the epidermis, hyperpigmentation of the basal layer, and shortening and rupture of elastic fibers of the dermis. Electron microscopy of dermal elastic fibers showed a decreased amount of elastin with an exposed appearance of microfibrils. In Northern blot analysis of cultured dermal fibroblasts, elastin mRNA levels were reduced, suggesting a decrease in elastin production at the lesions of loose skin.
Cutaneous Leukocytoclastic Vasculitis in Dermatomyositis Suggests Malignancy
Authors: Hunger Robert E. , Dürr Caroline , Brand Christoph U.
Published: April 2003

Background: Dermatomyositis (DM) is a rare connective tissue disease which has been shown to be associated with an underlying malignancy. Objective: Evaluation of the prevalence of malignancy in DM at our clinic and search for characteristics of the paraneoplastic form of disease. Methods: Retrospective review of patient files and histology reports over the period from 1991 to 1998. Results: 23 patients (14 women and 9 men) with DM could be identified in this time period with a median age at diagnosis of 48 years. Malignancies were found in 5 (22%) cases. The skin biopsies of all patients showed features of DM; in 7 cases, a leukocytoclastic vasculitis was detected. Four of the 5 cases with an associated malignancy demonstrated histologically a vasculitis in lesional skin, compared to only 3 out of 18 cases without malignancy (p < 0.05, Fisher’s exact test). Conclusion: Our data suggest that vasculitis in lesional skin biopsies has a predictive value for the presence of underlying malignancy.
Hyperkeratosis lenticularis perstans (Flegel’s Disease) – Lack of Response to Treatment with Tacalcitol and Calcipotriol
Authors: Blaheta Hans-Jürgen , Metzler Gisela , Rassner Gernot , Garbe Claus
Published: April 2003

Hyperkeratosis lenticularis perstans (HLP) or Flegel’s disease is a rare dermatosis characterized by asymptomatic hyperkeratotic papules predominantly located on the lower extremities. Lesional and non-lesional epidermis samples were studied by light- and electron-microscopic examination. The main ultrastructural finding was the presence of structurally altered Odland bodies/membrane-coating granules. Different therapeutic options for HLP have been reported, but none of the treatments was shown to be consistently effective. Here, we report on a patient with Flegel’s disease who did respond to topical 5-fluorouracil, whereas topical vitamin D3 synthetics were ineffective.
Cold Agglutinin Disease – The Importance of Cutaneous Signs
Authors: Läuchli S. , Widmer L. , Lautenschlager S.
Published: April 2003

We present the case of a woman where the diagnosis of cold agglutinin disease could be made after we had noticed slight cutaneous manifestations during a routine examination. Leading symptoms were livedo reticularis of the thighs and a history of acrocyanosis and Raynaud’s phenomenon upon cold exposure. The current knowledge about the etiology, clinical presentation and treatment of the disease is briefly discussed.
Acute Genitocrural Intertrigo: A Sign of Primary Human Immunodeficiency Virus Type 1 Infection
Authors: Calikoglu E. , Soravia-Dunand V.A. , Perriard J. , Saurat J.-H. , Borradori L.
Published: April 2003

We describe a 49-year-old male patient who presented with an acute illness associated with a widespread maculopapular eruption and eroded lesions in the inguinal folds consistent with an acute intertrigo, for which search of mycological and bacteriological causes remained negative. Serological tests disclosed a high viral HIV-1 load and p24 antigenemia, while anti-HIV-1 antibodies were absent, a profile typical of acute HIV-1 infection. Since the maculopapular eruption regressed concomitantly with the orogenital lesions as well as the eroded inguinal lesions prior to specific therapy, our observation indicates that intertriginous lesions may constitute one of the early cutaneous markers of primary HIV-1 infection.
Familial Lymphocytic Infiltration of the Skin: Histochemical and Molecular Analysis in Three Brothers
Authors: Dippel E. , Poenitz N. , Klemke C.-D. , Orfanos C.E. , Goerdt S.
Published: April 2003

Background: Lymphocytic infiltration of the skin (Jessner and Kanof) is a T cell pseudolymphoma characterized by the occurrence of recurrent asymptomatic papules and plaques and by a coat-sleeve-like perivascular lymphoid infiltrate. Rarely, familial cases have been reported. Objectives: Our study was performed to address the question of a genetic predisposition in a case of familial lymphocytic infiltration by histochemical and molecular analysis. Results: We report on 3 brothers with typical clinical and histological features of Jessner’s lymphocytic infiltration of the skin. Immunohistochemical analysis revealed a mixed lymphocytic infiltrate with a predominance of CD8+ T cells in all 3 patients. Molecular determination of T cell clonality by PCR-based GeneScan analysis of the T cell receptor (TCR)-γ-chain showed oligoclonal, pseudomonoclonal or polyclonal TCR-γ rearrangement patterns in lesional skin and in peripheral blood of all 3 brothers, while no common TCR idiotype was detected. Conclusion: Inherited deviations in TCR usage seem unlikely as a special cause of familial Jessner’s lymphocytic infiltration of the skin; lack of clonality furthermore supports the notion that this variant of the disease is as true a pseudo-T-cell lymphoma as are the spontaneous cases.
Low Systemic Exposure after Repeated Topical Application of Pimecrolimus (Elidel®, SD Z ASM 981) in Patients with Atopic Dermatitis
Authors: van Leent Edwin J.M. , Ebelin Marie-Eve , Burtin Pascale , Dorobek Birgit , Spuls Phyllis I. , Bos Jan D.
Published: April 2003

Background: Pimecrolimus is a cell-selective inhibitor of inflammatory cytokine release developed specifically for the treatment of inflammatory skin diseases. Aim: The objective of this study was to evaluate blood concentrations and tolerability of pimecrolimus during topical treatment. Methods: Twelve adult patients with extensive atopic dermatitis were enrolled in an open-label, noncontrolled, pharmacokinetic study. The patients were treated twice daily for 3 weeks with pimecrolimus cream 1% on all lesions. Pimecrolimus blood concentrations were measured at regular time points, and the safety and tolerability were monitored throughout the study. Results: In 78% of the 444 blood samples evaluated, pimecrolimus concentrations remained below the limit of quantitation (0.5 ng/ml). The highest concentration measured was 1.4 ng/ml. There was no indication of drug accumulation. Pimecrolimus was well tolerated locally and systemically. Conclusion: The 3-week twice daily treatment with pimecrolimus cream 1% results in consistently low pimecrolimus blood concentrations with no accumulation. Pimecrolimus cream appears suitable for the long-term management of atopic dermatitis.
Somatostatin Receptors
Authors: Benali Naoual , Ferjoux Geraldine , Puente Elena , Buscail Louis , Susini Christiane
Published: April 2003

Somatostatin is a neuropeptide produced by neuroendocrine, inflammatory and immune cells in response to different stimuli. Somatostatin inhibits various cellular functions including secretions, motility and proliferation. Its action is mediated by five specific somatostatin receptors (sst1-sst5) which belong to the G protein-coupled receptor family. The five receptors bind the natural peptide with high affinity but only sst2, sst5 and sst3 bind the short synthetic analogues used to treat patients with neuroendocrine tumors. The five receptors are expressed in various normal and tumor cells, the expression of each receptor being receptor subtype and cell-type specific. In neuroendocrine tumors, sst2 is highly expressed whereas in advanced pancreatic adenocarcinoma as well as high-grade colorectal carcinomas, its expression is lost. Each receptor subtype is coupled to different signal transduction pathways through G protein-dependent and -independent mechanisms. The synthesis of selective agonists for each receptor and the recent development of genetic animal models with selective deletion of receptor subtype provide tools for establishing some of the biological roles of the receptors. sst1, 2 and 5 mediate inhibition of GH secretion whereas sst2 and sst5 mediate inhibition of glucagon secretion and insulin secretion, respectively.
Interferon in the Management of Neuroendocrine GEP-Tumors
Authors: Öberg Kjell
Published: April 2003

Interferon has been known to be an effective antiviral and antitumor agent since the 1960s. However, a large majority of solid tumors did not respond to this kind of treatment. In early 1980s, alpha interferon was introduced in the management of classical midgut carcinoids with promising results. Since then, more than 500 patients have been treated with alpha interferon worldwide and published in the literature. The median dose has been 5 million units 3–5 times per week subcutaneously. The subjective response rate is about 60%, biochemical responses in 44% and tumor responses in 11% of the patients. There are very few randomized control trials at the moment which make survival analysis difficult but in different centers median survivals from start of treatment in malignant midgut carcinoids has been reported to be more than 3 years. The mechanisms of action of alpha interferon are direct effects on the tumor cells by inhibiting the cell proliferation via cell cycle block G1-S phase. Induction of interferon inducable genes, such as p-21, p-27, 2-5-A-synthetase, PKR, IRF-1, IRF-2. All these contribute to reduction of the growth potential of the tumor. Furthermore, alpha interferon exerts an immunomodulatory effect stimulating natural killer cells, macrophages and also presents anti-angiogenetic effects. In the future, long-acting formulations of recombinant alpha interferons will come into clinical use, such as polyethylene glycosylated interferons. It will facilitate the treatment for the patients and also perhaps reduce the side effects, which are sometimes significant during treatment with alpha interferon. It might also be possible to give higher doses of alpha interferon with hopefully improved clinical efficacy.
Helicobacter pylori Infection Increases Mucosal Permeability of the Stomach and Intestine
Authors: Fukuda Yoshihiro , Bamba Hiroko , Okui Masanori , Tamura Kazutami , Tanida Noritoshi , Satomi Masamichi , Shimoyama Takashi , Nishigami Takashi
Published: April 2003

It is important to study the effect of Helicobacter pylori infection on the permeability of the intestine. Permeability was evaluated by oral sucrose tolerance test using sucrose 25 g in 200 ml of water. Existence of H. pylori itself was associated with increased permeability of sucrose. Also, the permeability of sucrose increased as polymorphonuclear and lymphocyte infiltration increased. The increase of mucosal permeability suggests that antigens like protein penetrate into the body and result in systemic reactions. Thus, it is important to study the implication of increased permeability in relation not only to gastric diseases but also certain systemic diseases.
Gastrointestinal Stromal Tumors: Experience of an Emergency Surgery Department
Authors: Catena Fausto , Pasqualini Eddi , Campione Orazio
Published: April 2003

Background/aims: Gastrointestinal stromal tumors (GISTs) are a rare group of neoplasias of the gastrointestinal tract that have not yet been fully investigated. In this article the authors present the experience of an emergency surgery department in the diagnosis and treatment of patients with such neoplasms and discuss the approaches to these ‘strange’ tumors. Methods: A review of our 4-year experience in emergency surgery was performed and 9 patients were found with the diagnosis of GIST. The median follow-up was 32.3 (range 18–45) months. Results: 7 patients had evidence of gastrointestinal blood loss, 1 patient had abdominal pain, and the last patient had anorexia, vomiting and fever. Five tumors were located in the stomach and 4 in the small bowel. All the patients underwent complete resection. On histological examination 5 tumors were of myogenic origin, 1 was a gastrointestinal autonomic nerve tumor and 1 was a mixed neural-myoid tumor. The remaining 2 could not be differentiated. Of the 9 patients who underwent curative resections, 1 had a recurrence and died. Conclusion: GIST treatment mainly involves surgical resection with the goal of complete removal which can be curative. The histologic grade and tumor size are the most important prognostic factors.
Comparison of Buprenorphine and Methadone Maintenance in Opiate Addicts
Authors: Eder Harald , Fischer Gabriele , Gombas Wolfgang , Jagsch Reinhold , Stühlinger Georg , Kasper Siegfried
Published: April 2003

As a maintenance agent for opioid dependency, buprenorphine offers advantages such as a lower level of dependence and minimal withdrawal symptoms, due to its partial agonist properties at the µ-opioid receptor. Previous studies have shown 8 mg sublingual buprenorphine to be equivalent to 60 mg oral methadone in terms of retention rate and opioid-negative urine levels. In a 24-week, ongoing European study, 34 opioid-dependent subjects were assessed; 16 receiving buprenorphine and 18 methadone. A free dosing schedule was used with no upper limit for methadone dosing but with a maximum buprenorphine dose of 8 mg. Screening prior to the study excluded subjects with polysubstance dependence, somatic disease and/or HIV infection. Primary outcome measures were abstinence from other drugs, for which subjects provided weekly urine samples for analysis of opioids, cocaine and benzodiazepines, and retention in treatment. Patients in the buprenorphine group provided a greater proportion of negative urine samples, in particular cocaine-negative samples, compared with the methadone group, although this was not statistically significant. Retention in the buprenorphine group was significantly lower than in the methadone group, suggesting that the 8 mg buprenorphine limit may have biased the results in favour of methadone, and that this dose may have been too low for those subjects with high levels of dependence. However, buprenorphine is clearly effective in the more motivated subjects and further investigation in this subgroup is recommended.
Brucellar Spinal Epidural Abscess of Cervical Location: Report of Four Cases
Authors: Pina M.A. , Modrego P.J. , Uroz J.J. , Cobeta J.C. , Lerin F.J. , Baiges J.J.
Published: April 2003

Spinal epidural abscesses account for 1 or 2 of every 10,000 hospital admissions, Staphylococcus aureus being the bacterium most frequently involved. Brucellosis is a disorder of worldwide distribution, relatively frequent in South America and in Mediterranean countries in Europe and Africa. Whilst in the USA only 200 cases are reported every year, in Spain it is the most frequent zoonosis. This systemic disease seldom produces spondylodiscitis which in a minority of cases may be complicated by spinal epidural abscesses, in general of lumbar location. The purpose of this article is to analyse 4 cases of brucellar spinal epidural abscess of cervical location and diagnosed in the Province of Teruel, Spain, an endemic area for the disease, through 10 consecutive years (1990–1999). We consider noteworthy the following facts: the first case was a technical employee who acquired the infection in our laboratory of microbiology, the second presented with an extensive purulent collection invading prevertebral and retropharyngeal regions, the third case was cured only with antibiotics without residual deficits. In the fourth case we were not able to demonstrate spondylodiscitis accompanying the epidural abscess at the C2–C6 levels. We discuss especially the epidemiological aspects of brucellosis, the existence of epidural abscess without spondylodiscitis, the clinical manifestations, the diagnosis by means of magnetic resonance imaging, specific serological tests for Brucella, antibiotic treatment and the prognosis of our cases.
Neutrophils Mediate Acute Lung Injury in Rabbits: Role of Neutrophil Elastase
Authors: Kinoshita M. , Ono S. , Mochizuki H.
Published: April 2003

We investigated the roles of neutrophil and neutrophil elastase in acute lung injury (ALI) to elucidate the mechanism of ALI. We designed two protocols. Protocol I: Experimental ALI was induced by endotoxin (0.02 mg/kg) and platelet-activating factor (8 µg/kg/4 h) in untreated rabbits (control group I), in neutropenic rabbits pretreated with nitrogen-N-oxide hydrochloride, and in untreated rabbits infused with a neutrophil elastase inhibitor (ONO-5046; 20 mg/kg/4 h). Protocol II: ALI was induced by smaller doses of endotoxin (0.015 mg/kg) and platelet-activating factor (7 µg/kg/4 h) than those used in protocol I in untreated rabbits (control group II), in neutrophilic rabbits pretreated with human recombinant granulocyte colony-stimulating factor, and in neutrophilic rabbits infused with ONO-5046 (as in protocol I). The severity of ALI was assessed by the protein concentration, the elastase activity in the bronchoalveolar lavage fluid, and the histologic pulmonary edema ratio. The degree of pulmonary neutrophil accumulation was assessed by pulmonary myeloperoxidase activity and histological findings. Both ALI and pulmonary neutrophil accumulation were suppressed by neutropenia (protocol I), while they were exacerbated by neutrophilia (protocol II). The neutrophil elastase inhibitor could suppress ALI, but it could not suppress pulmonary neutrophil accumulation in both untreated and neutrophilic rabbits (protocols I and II). These findings indicate that neutrophils play an important role in the pathogenesis of ALI via neutrophil elastase.
Reciprocal Functions of Liver Tumor Cells and Endothelial Cells
Authors: Okamoto H. , Ohigashi H. , Nakamori S. , Ishikawa O. , Imaoka S. , Mukai M. , Kusama T. , Fujii H. , Matsumoto Y. , Akedo H.
Published: April 2003

Background: The mechanism by which tumor cells interact with endothelial cells at the primary site in metastasis remains obscure. Materials and Methods: To disclose the precise mechanisms and processes of metastasis and angiogenesis, we investigated the interactions of endothelial cells (CPAE; calf pulmonary arterial endothelial cells) with two mouse liver tumor cell lines, G-5, a highly metastatic clone, and G-1, a poorly metastatic clone, based on the difference in their angiogenic activities in vivo at a primary site. Results: G-5 cell cultured conditioned medium (CM) promoted migration of endothelial cells more than did G-1 cell CM, in migration assay using modified Boyden chambers. Anti-basic FGF antibody inhibited G-5-induced endothelial cell migration. Furthermore, endothelial cells stimulated proliferation of G-5 cells more than that of G-1 cells in coculture assay using Transwell chambers (pore size; 0.4 µm). Pretreated endothelial cells with bFGF enhanced tumor cell proliferation, suggesting the ability of activated endothelial cells to support tumor growth. In addition, incubation with endothelial cell CM also improved the proliferative activity of G-5 cells more than that of G-1 cells in a concentration-dependent fashion, indicating production and secretion of liver tumor cell growth substance by endothelial cells. Conclusion: These results provide evidence that liver tumor cells stimulate endothelial cell migration and migrated endothelial cells facilitate liver tumor cell proliferation. Tumor growth at a primary site may initially be dependent on migrated endothelial cells rather than vascularization or blood nutrient supply. This bi-directional paracrine relationship between liver tumor cells and endothelial cells may influence their metastatic ability.
Induction of Renal Cell Apoptosis by Antibodies and Complement
Authors: Roos Anja , Sato Toshinobu , Maier Holly , van Kooten Cees , Daha Mohamed R.
Published: April 2003

Renal diseases are in many cases associated with the presence of increased numbers of apoptotic cells in the kidney. Apoptosis has been proposed as an important mechanism involved in the resolution of a proliferative response. Furthermore, recent studies indicate its possible involvement in progression of renal disease, leading to sclerosis. Moreover, in an experimental model of acute mesangioproliferative glomerulonephritis in the rat, induced via antibodies directed to Thy-1, evidence was obtained for the occurrence of apoptosis coinciding with the very early induction of mesangial injury. The present review is focused on apoptosis in relation to this model, and discusses recent findings concerning direct involvement of triggering of Thy-1 as well as deposition of terminal complement complexes in the induction of mesangial cell apoptosis.
Extracellular Signal-Regulated Kinase and the Small GTP-Binding Protein p21Rac1 Are Involved in the Regulation of Gene Transcription by Angiotensin II
Authors: Huszár Tamás , Mucsi István , Antus Balázs , Terebessy Tamás , Jeney Csaba , Masszi András , Hunyady László , Mihalik Balázs , Goldberg Howard J. , Thekkumkara Thomas J. , Rosivall László
Published: April 2003

To study the role of extracellular-signal-regulated kinase (ERK) cascade and the small GTP-ase proteins in the activation of the c-fos promoter by angiotensin II (AII), transient transfection experiments were performed in CHO cells stably expressing the rat AT1A receptor. In this system AII activated ERK in 1 min and also increased the transcriptional activity of the c-fos promoter-luciferase reporter gene construct. The activation of the promoter proved to be dependent on the Ras-Raf-ERK cascade as cotransfection of expression vectors known to specifically inhibit this cascade blocked the effect of AII. Dominant-negative p21Rac1 mutant partially blocked the activation of the c-fos promoter by AII. However, activation of the c-fos promoter was independent of protein kinase C (PKC) as bisindolylmaleimide I, a specific PKC inhibitor did not block the effect of AII. These results suggest that AII activates the transcription of the c-fos through the Ras-Raf-ERK cascade. Furthermore, p21Rac1 is involved in the modulation of the c-fos promoter by AII.
Direct in vivo Visualization of Renal Microcirculation by Intravital CCD Videomicroscopy
Authors: Yamamoto Tokunori , Hayashi Koichi , Tomura Yuichi , Tanaka Hiyoshi , Kajiya Fumihiko
Published: April 2003

Several types of experimental techniques have been developed for the evaluation of renal microcirculation. Although each methodology possesses excellent and unique characteristics, it requires substantial artificial manipulation that might alter the renal microvascular responsiveness. To circumvent such limitation of previous ex vivo or in vitro approaches to glomerular microcirculation, we have developed a pencil lens-probe charge-coupled device (CCD) intravital videomicroscopic system which allows us to evaluate both systemic hemodynamics and renal microcirculation. Furthermore, real-time images of afferent and efferent arterioles as well as glomeruli can be continuously assessed, which would facilitate the functional characterization of these microvessels in vivo. Finally, the tapered nature of the CCD probe of this videomicroscopy may allow direct observation of the renal microvasculature in small animals (e.g., rats and mice). In conclusion, this novel technique is a valuable tool for unveiling the in vivo, in situ and intact renal microvascular behavior, and may provide further approaches to the understanding of renal microcirculation.
Molecular Mechanisms by Which Iron Induces Nitric Oxide Synthesis in Cultured Proximal Tubule Cells
Authors: Chen Liguang , Wang Yiping , Kairaitis Lukas K. , Wang Yang , Zhang Bao-Hong , Harris David C.H.
Published: April 2003

Nitric oxide (NO) levels are increased after exposure of cultured proximal tubule cells (PTC) to non-haem iron, potentially contributing to PTC injury in disease states associated with increased iron exposure, including proteinuric renal disease. The mechanisms underlying this observed increase were investigated. After 3 h exposure to 400 µM nitrilotriacetate (NTA)-Fe, inducible nitric oxide synthase (iNOS) mRNA expression was significantly increased, with a corresponding increase in iNOS protein after 12 h. The nuclear binding activity of NFĸB with 400 µM NTA-Fe was increased, and pyrrolidine dithiocarbamate (PDTC), an antioxidant inhibitor of NFĸB, prevented both activation of NFĸB and NO production in response to NTA-Fe. Inhibition of protein tyrosine kinase reduced iNOS mRNA, iNOS protein levels and NO production in response to NTA-Fe. The effect of tyrosine kinase inhibition on NFĸB activation was variable, with herbimycin but not genistein having an inhibitory effect. Activation of either protein kinase A or C increased iNOS mRNA and protein levels, and NO production in response to NTA-Fe, whereas only the protein kinase C activator phorbol dibutyrate (PDBu) had a stimulatory effect on NFĸB activation. The protein kinase A activator forskolin did not alter iron-induced activation of NFĸB. These data suggest that the observed increase in NO production by PTC in response to iron is due to increased transcription of iNOS. The transcriptional regulation of this response is complex and involves NFĸB, protein tyrosine kinase and the protein kinases A and C.
Regulation of Tubular Cell MCP-1 Production by Intracellular Ions: A Role for Sodium and Calcium
Authors: Harris Davis C.H. , Wang Yao , Campbell David
Published: April 2003

Proximal tubule cells (PTC) in chronic renal disease produce chemokines which cause renal interstitial inflammation, and also transport more Na+ than normal. To investigate whether these two events might be related, monocyte chemoattractant protein-1 (MCP-1) production was examined in rat PTC in primary culture. Amiloride reduced, while ouabain increased levels of MCP-1 mRNA and protein. Amiloride reduced MCP-1 in cells stimulated with ouabain, lipopolysaccharide (LPS) or albumin. Intracellular Na+ rose with ouabain, but not LPS or albumin. Effects of amiloride, ouabain, LPS and albumin were abrogated by sodium-free but not chloride-free culture medium, and were not explained by changes in intracellular pH. Intracellular Ca2+ rose with ouabain, LPS or albumin and sodium-free medium. BAPTA-AM reduced intracellular Ca2+ and MCP-1 mRNA levels in unstimulated cells, and cells stimulated with ouabain, LPS or albumin. Thus, amiloride and ouabain may alter tubular cell MCP-1 by changing intracellular Na+, with secondary changes in intracellular Ca2+, whereas stimulation by LPS and albumin may involve Ca2+ directly.
1,25-Dihydroxyvitamin D3 Differentially Regulates IL-1α-Stimulated IL-8 and MCP-1 mRNA Expression and Chemokine Secretion by Human Primary Proximal Tubular Epithelial Cells
Authors: Krüger S. , Kreft B.
Published: April 2003

Beside its role in calcium homeostasis, 1,25-D3 modulates multiple immunological functions in cells of the immune system. In tubular epithelial cells, it increases the expression of HLA-DR and ICAM-1 molecules. Since production of chemokines, such as IL-8 and MCP-1, by tubular epithelial cells is crucial for the inflammatory response in acute transplant rejection and interstitial nephritis, we tested whether 1,25-D3 influences the production of IL-8 and MCP-1 by primary human tubular epithelial cells (TEC). For chemokine detection we used enzyme-linked immunosorbent assays. We differentiated between chemokine secretion directed to the apical and basolateral environment by using cell culture inserts as a model for the tubular basement membrane. mRNA of IL-8 and MCP-1 after stimulation of TEC with IL-1α and/or 1,25-D3 was isolated and compared by competitive RT-PCR. We found that basolateral production of IL-8 was higher than luminal secretion. 1,25-D3 (10–8M) alone and in combination with IL-1α suppressed IL-8 production after 48 h. Basolateral compared to luminal MCP-1 secretion was higher after stimulation either with IL-1α alone or combined with 1,25-D3. After 72 h, 1,25-D3 enhanced the IL-1α-stimulated MCP-1 secretion. Increased IL-8 mRNA expression after stimulation with IL-1α was suppressed by coincubation with 1,25-D3, while MCP-1 mRNA synthesis was enhanced by 1,25-D3 alone and in combination with IL-1 α . We conclude that 1,25-D3 differently modulates the expression of CXC-chemokine IL-8 and CC-chemokine MCP-1 by human TEC. The differential effects of 1,25-D3 on renal tubular cytokine secretion have to be considered in therapeutic dials on this hormone, e.g. in renal transplant rejection.
Insights into the Role of the von Hippel-Lindau Gene Product
Authors: Maxwell P.H. , Pugh C.W. , Ratcliffe P.J.
Published: April 2003

Many adaptive responses to hypoxia involve changes in gene transcription mediated by the hypoxia-inducible factor 1 complex. Central to this is oxygen-dependent proteolysis of the α subunit, which has recently been shown to require the von Hippel-Lindau tumour-suppressor protein. This observation provides one mechanism by which inherited defects in the von Hippel-Lindau gene could cause features of the clinical syndrome, and offers insight into the events leading to sporadic clear cell renal cancer. Furthermore, it clearly implicates the von Hippel-Lindau tumour-suppressor protein in the biochemistry of oxygen sensing.