bluuebunny/crossref_metadata_2025 huggingface dataset:
Heat shock preconditioning modulates proliferation and apoptosis after superficial injury in isolated guinea pig gastric mucosa via an eicosanoid and protein synthesis‐dependent mechanism
Authors: OKSALA NIKU K. J. , OKSALA ANNI , PAAVONEN TIMO , ALHAVA ESKO , PAIMELA HANNU
Published: May 2003

Aim. In restitution after superficial injury of the gastric mucosa, the epithelial continuity is restored by cellular migration. We have shown that heat shock preconditioning inhibits restitution after superficial injury. This study investigates the effect of heat shock preconditioning on tissue proliferation and apoptosis. Experimental design. Paired guinea pig gastric mucosae were mounted and perfused in Ussing chambers (37 °C). After heat shock preconditioning (42 °C) (30 min) and normothermic recovery (37 °C) (150 min) or normothermic perfusion, a superficial injury was induced by luminal exposure to 1.25 mol/L NaCl (5 min) followed by a 3 h restitution. During perfusion, the mucosa was exposed to 30 μmol/L arachidonic acid (AA) to enhance heat shock response, to 50 μmol/L quercetin (Q) to inhibit the metabolism of arachidonic acid via lipoxygenases, to 50 μmol/L indomethacin (In) to inhibit the metabolism of arachidonic acid via cyclo‐oxygenases, or to 150 μmol/L cycloheximide (CHX) to inhibit de novo protein synthesis. After the experiment the mucosa was prepared for immunohistochemical analysis of the expression of Mib‐1 proliferation antigen and pro‐apoptotic protein Bax. Results. Heat shock decreased Mib‐1/Bax ratio and this effect was maintained after superficial injury and exposure to Q, to AA+CHX or to In+CHX. Exposure to CHX, to AA, to In+Q, to In+AA, In+AA+Q or to In+AA+CHX, however, blocked the effect of heat shock preconditioning. The decreasing effect of heat shock preconditioning on Mib‐1/Bax ratio could be reversed by exposure to AA+Q or to In. Conclusion. The heat‐preconditioning‐induced effects on the mucosa are reversible and sensitive to exogenous pharmacological modulation. Heat shock preconditioning inhibits proliferation of superficially injured isolated gastric mucosa by a mechanism involving eicosanoid pathways and de novo protein synthesis.
A study on forensic samples of Bartonella spp. antibodies in Swedish intravenous heroin addicts
Authors: McGILL SVENA , RAJS JOVAN , HJELM EVA , LINDQUIST OLLE , FRIMAN GÖRAN
Published: May 2003

Infection with Bartonella, an emerging bacterial pathogen which often affects immunodeficient patients, has been reported in Sweden over the past few years, with a high seroprevalence of B. elizabethae. A high prevalence of antibodies against B. elizabethae has also been found in urban intravenous drug users in the USA. Using immunofluorescence, we retrospectively examined serum samples taken at autopsy from 59 Swedish intravenous drug addicts from the Stockholm area for evidence of antibodies against 6 pathogenic strains of Bartonella. The 59 addicts died following heroin injection during the years 1987–1992 and include 24 individuals (41%) who were additionally HIV‐positive. An overall seropositivity rate for Bartonella spp. of 39% (23/59) was found with the following antigenic reactivities: B. elizabethae, 39% (23/59); B. grahamii, 3% (2/59); B. henselae (Houston‐1), 14% (8/59); and B. quintana, 3% (2/59). There were no positive reactions for B. henselae (Marseille) or B. vinsonii subsp. vinsonii. The Bartonella‐seropositive cases included 11/23 (48%) individuals who were HIV‐positive. Subacute to chronic myocarditis was seen in 2/11 microscopically investigated Bartonella‐seropositive cases that were HIV‐negative and in 1/14 seronegative cases. No cases of endocarditis or other common manifestations of Bartonella infection were found. An overall Bartonella seropositivity of 21% (9/44) was observed in control forensic autopsy samples.
Two‐year follow‐up of Helicobacter pylori infection in C57BL/6 and Balb/cA mice
Authors: WANG XIN , WILLÉN ROGER , SVENSSON MARIE , LJUNGH ÅSA , WADSTRÖM TORKEL
Published: May 2003

Helicobacter pylori infection is associated with chronic gastritis, peptic ulcer disease, gastric adenocarcinoma and MALT lymphoma. We previously found high‐grade lymphoma after 13 months' H. pylori infection in C57BL/6 mice. In this study we followed H. pylori infection by three different isolates in C57BL/6 and Balb/cA mice for 23 months. Six‐week‐old C57BL/6 and Balb/cA mice were infected with H. pylori strains 119p (CagA+, VacA+), SS1 (CagA+, VacA+) and G50 (CagA‐, VacA‐). Mice were followed at 2 weeks, 10 weeks and 23 months post‐inoculation (p.i.) by culture, histopathology and serology. Strain G50 was only reisolated from mice 2 weeks p.i. There was no difference in colonization between strain 119p and SS1 at 10 weeks p.i., whereas SS1 gave 100% colonization versus 119p gave 50% 23 months p.i.. Interestingly, the inflammation score was higher in mice infected with strain 119p than with SS1 10‐week p.i., and there were lymphoepithelial lesions in mice infected with strain 119p and G50 but not with SS1 at 23 months post‐infection. Eight mice infected with strains 119p and G50 developed gastric lymphoma (grade 5 and 4). One C57BL/6 mouse infected with strain 119p developed hepatocellular carcinoma after 23 months. Immunoblot showed specific bands of 26–33 kDa against H. pylori in infected mice, and two mice infected with strain SSI reacted with antibodies to the 120 kDa CagA toxin.

Conclusion: A reproducible animal model for H. pylori‐induced lymphoma and possibly hepatocellular carcinoma is described. Strain diversity may lead to different outcomes of H. pylori infection.
Expression of heat‐shock proteins hsp27, hsp70 and hsp90 in malignant epithelial tumour of the ovaries
Authors: ELPEK GÜLSÜM ÖZLEM , KARAVELI ŞEYDA , ŞIMŞEK TAYYUP , KELEŞ NURAN , AKSOY NAZIF HIKMET
Published: May 2003

Recently, considerable attention has been focused on the role of the small heat‐shock protein group hsp27, hsp70 and hsp90 in the clinical outcome of several malignancies. However, conflicting data exist regarding the prognostic role of hsp27 expression in ovarian carcinoma, and the prognostic significance of hsp70 and hsp90 expression still remains unknown in these tumours. The purpose of this study was to investigate immunohistochemically whether hsp27, hsp70 and hsp90 expression was associated with clinicopathological parameters and survival in 52 epithelial ovarian carcinomas. Chi‐square test, Kaplan‐Meier and Cox regression analysis were used for statistical analysis. Among clinicopathological parameters, hsp27, hsp70 and hsp90 expression was only correlated with FIGO stage; hsp70 and hsp90 positivity failed to detect survival. However, the overall survival rate of patients with hsp27 expression was 13%, which was significantly worse than that of patients without hsp27 expression (47%) (p<0.01). The prognosis was also adversely affected by FIGO stage (p<0.01) and presence of ascites (p<0.01). In multivariate analysis, hsp27 expression and FIGO stage were independent prognostic variables. Our results indicate that hsp70 and hsp90 expression had no prognostic relevance in epithelial ovarian carcinomas. However, hsp27 expression and FIGO stage in these tumours could be reliable indicators of prognosis.
Photodynamic therapy (PDT) using topically applied δ‐aminolevulinic acid (ALA) for the treatment of oral leukoplakia
Authors: Sieroń Aleksander , Adamek Mariusz , Kawczyk‐Krupka Aleksandra , Mazur Sebastian , Ilewicz Leszek
Published: June 2003

Background:  Photodynamic therapy (PDT) is a non‐invasive method for topical and selective treatment of pre‐malignant lesions of oral cavity. The aim of our study was to determine therapeutic response to PDT in patients with oral leukoplakia.

Methods:  Twelve patients participated in our study. Lesions affected a variety of intraoral sites. The most common location was buccal, gingival and mandibular mucosa. Patients were treated with topically applied 10% δ‐aminolevulinic acid (ALA) and light from an argon‐pumped dye laser. Irradiation was performed in several (6–8) sessions using light at 635 nm wavelength, delivering a total dose of 100 J/cm2 per session.

Results:  A complete response was obtained in 10 out of 12 treated patients. One recurrence was observed during 6 months.

Conclusion:  Photodynamic therapy appears to be a feasible alternative to conventional therapy of pre‐malignant lesions of oral cavity.
Id proteins are overexpressed in human oral squamous cell carcinomas
Authors: Nishimine Masayoshi , Nakamura Mitsutoshi , Mishima Kenji , Kishi Munehiro , Kirita Tadaaki , Sugimura Masahito , Konishi Noboru
Published: June 2003

Background:  The helix‐loop‐helix (HLH) proteins Id‐1, Id‐2 and Id‐3 have been demonstrated to inhibit the activity of transcription factors and play an important role in regulating cell growth and tissue‐specific differentiation.

Methods:  To elucidate the involvement of Id in human oral squamous cell carcinoma (OSCC), we examined 83 surgical specimens and eight normal gingival mucosae for the expression of Id proteins by immunohistochemistry; in addition, some specimens of the OSCC and the normal gingivae were also examined for the expression of Id‐1 mRNA by in situ hybridization (ISH), while Western blots were performed on six of the tumours and on cell lysates of five OSCC cell lines. We also explored the correlation between Id expressions and cellular proliferation indicating Ki‐67 or clinical parameters.

Results:  We discovered a higher and more frequent expression of Id‐1 protein (27.7%) in human OSCC compared to that of Id‐2 and Id‐3 proteins (6.0 and 7.2%, respectively). Western blot analysis detected Id‐1 protein in four of six tumour samples and in all cell lines. ISH demonstrated strong cytoplasmic localization of Id‐1 mRNA in tumour samples at significantly higher levels compared to those of normal gingival mucosae.

Conclusion:  Id‐1 protein expression significantly correlates with lymph node status, indicating that increased Id expression may relate to the metastatic behaviour in human OSCC.
Shifts in cellular localization of moesin in normal oral epithelium, oral epithelial dysplasia, verrucous carcinoma and oral squamous cell carcinoma
Authors: Kobayashi Hiroichi , Sagara Junji , Masumoto Junya , Kurita Hiroshi , Kurashina Kenji , Taniguchi Shuníichiro
Published: June 2003

Background:  Moesin, a member of ERM (ezrin/radixin/moesin) family, links actin filaments of cell surface structure to the cell membrane. The purpose of the study is to assess the shifts in cellular distribution of moesin in normal oral epithelium, oral epithelial dysplasia (OED), verrucous carcinoma (VC), and oral squamous cell carcinoma (OSCC).

Methods:  The expression of moesin was evaluated immuohistochemically in paraffin‐embedded tissues of 59 specimens of OSCC, 35 specimens of OED, 17 specimens of VC, and five specimens of normal oral epithelium.

Results:  In the normal oral epithelia, all specimens showed a pattern of membranous expression against the anti‐moesin antibody in the basal layer cells. In the OED specimens, moesin was dominantly expressed in the cell membrane except for the cornified layer. In VC and OSCC specimens, almost the whole of the carcinoma cells were stained with anti‐moesin antibody. However, in OSCC samples, moesin was markedly expressed increasingly in the cytoplasm and decreasingly in the cell membrane, as compared with OED and VC. In addition, there was a significant correlation between the pattern of moesin expression and tumor differentiation in OSCC.

Conclusions:  Our results suggest that it is useful to detect the moesin expression as adjunct to screening mucosal lesions in the oral cavity.
Auto‐fluorescence spectra of oral submucous fibrosis
Authors: Chen Hsin‐Ming , Wang Chih‐Yu , Chen Chin‐Tin , Yang Hsiang , Kuo Ying‐Shiung , Lan Wan‐Hong , Kuo Mark Yen‐Ping , Chiang Chun‐Pin
Published: June 2003

Background:  Oral submucous fibrosis (OSF) is a chronic oral mucosal disease characterized by progressive deposition of collagen in the subepithelial connective tissue and epithelial atrophy. Previous studies have shown that at 330‐nm excitation, the 380‐ and 460‐nm emission peaks of the auto‐fluorescence spectra for oral mucosal tissues reflect the collagen content in the subepithelial connective tissue and the nicotinamide adenine dinucleotide phosphate (NADH) content in the epithelial cells, respectively. Therefore, at 330‐nm excitation OSF mucosa may have a higher 380‐nm emission peak and a lower 460‐nm emission peak than the normal oral mucosa (NOM).

Methods:  To test the above hypothesis, we measured the in vivo auto‐fluorescence spectra of 59 OSF mucosal sites and compared the measured spectra with auto‐fluorescence spectra obtained from 15 NOM samples from 15 healthy volunteers, five samples of friction hyperkeratosis (histologic diagnosis, hyperkeratosis and acanthosis) on OSF buccal mucosa (FHOSF), and 29 samples of oral leukoplakia (histologic diagnosis, hyperkeratosis and acanthosis) on OSF buccal mucosa (OLOSF).

Results:  We found that the spectrum of the OSF mucosa had a significantly higher 380‐nm emission peak and a significantly lower 460‐nm emission peak than the spectra of NOM, FHOSF, and OLOSF samples. When the mean (±SD) fluorescence intensities at 380 ± 15 nm (I380 ± 15 nm) and 460 ± 15 nm (I460 ± 15 nm) emission peaks and the mean ratio of I460 ± 15 nm/I380 ± 15 nm were compared between groups, we found that OSF group had a significantly higher mean value of I380 ± 15 nm, a significantly lower mean value of I460 ± 15 nm, and a significantly lower mean ratio of I460 ± 15 nm/I380 ± 15 nm than the NOM, FHOSF, and OLOSF groups (P < 0.001). However, no significant differences in the mean values of I380 ± 15 nm, I460 ± 15 nm, and ratio of I460 ± 15 nm/I380 ± 15 nm were found between NOM and FHOSF or OLOSF samples as well as between FHOSF and OLOSF samples (P > 0.05).

Conclusion:  Because OSF mucosa has a very unique pattern of auto‐fluorescence spectrum, we conclude that auto‐fluorescence spectroscopy is a good method for real‐time diagnosis of OSF.
Multinucleated giant cells in various forms of giant cell containing lesions of the jaws express features of osteoclasts
Authors: Liu Bo , Yu Shi‐Feng , Li Tie‐Jun
Published: June 2003

Background:  The nature and the mechanism involved in the formation of the multinucleated giant cells (MGCs) in various giant cell‐containing lesions of the jaws are not fully understood. The aim of this study is to clarify the osteoclastic features of the MGCs in central giant cell granuloma (CGCG), peripheral giant cell granuloma (PGCG), cherubism, and aneurysmal bone cyst (ABC), and the mechanism underlying the interrelations between cellular components in the formation of the MGCs.

Methods:  Immunohistochemical study with a panel of antibodies including vacuolar H+‐ATPase (V‐ATPase), carbonic anhydrase II (CA II), Cathepsin K, matrix metalloproteinases‐9 (MMP‐9), CD68, and proliferating cell nuclear antigen (PCNA), and enzyme histochemical staining for tartarate‐resistant acid phosphatase (TRAP) were applied on a total number of 53 cases of giant cell‐containing lesions including CGCG (n = 34), PGCG (n = 6), cherubism (n = 7), and ABC (n = 6). In situ hybridization was also carried out to detect the mRNA expression of the receptor activator of NF‐kappaB ligand (RANKL), a newly identified cytokine that is shown to be essential in the osteoclastogenesis, its receptor RANK (receptor activator of NF‐kappaB ligand), and its decoy receptor OPG (osteoprotegerin) in these four types of lesions.

Results:  Immunohistochemical and enzyme histochemical studies showed that both the MGCs and a fraction of mononuclear cells in these lesions were strongly positive for TRAP, V‐ATPase, CA II, Cathepsin K, MMP‐9, and CD68, while the spindle‐shaped mononuclear cells were positive for PCNA. The results with in situ hybridization indicated that RANKL mRNA was mainly expressed in the spindle mononuclear cells while OPG was extensively distributed in both the MGCs and the mononuclear cells. RANK mRNA was expressed in the MGCs and some round mononuclear cells.

Conclusions:  These results suggest that MGCs in the four types of giant cell‐containing lesions of the jaws show characteristics of the osteoclast phenotype. The mononuclear stromal cells, which show TRAP positively, may be the precursors of the MGCs. RANKL, OPG, and RANK expressed in these lesions may play important roles in the formation of the MGCs. The similar characteristics and mechanisms in the differentiation of MGCs in these lesions also suggest that there might be a similar kind of pathogenesis involved in the formation of the MGCs in these lesions
Ameloblastomatous calcifying odontogenic cyst: a rare histologic variant
Authors: Aithal D. , Reddy B. S. , Mahajan S. , Boaz K. , Kamboj M.
Published: June 2003

Calcifying odontogenic cyst (COC) is an uncommon developmental odontogenic cyst first described by Gorlin in 1962. It is considered as extremely rare and accounts for only 1% of jaw cysts reported. Because of its diverse histopathology, there has always been confusion about its nature as a cyst, neoplasm or hamartoma. Several subclassifications have been proposed. Here, we present a case of calcifying odontogenic cyst with ameloblastic proliferation – an extremely rare histologic variant. The classical histologic features of the lining epithelium in the form of cords and presence of characteristic ghost cells were seen along with ameloblastomatous proliferations. Ameloblastomatous COC microscopically resembles unicystic ameloblastoma except for the ghost cells and calcifications within the proliferative epithelium. The nature of the COC is controversial. The case is presented here for its rarity, and difference between ameloblastomatous COC and ameloblastoma ex COC has been emphasized.
Systemic and topical corticosteroid treatment of oral lichen planus: a comparative study with long‐term follow‐up
Authors: Carbone M. , Goss E. , Carrozzo M. , Castellano S. , Conrotto D. , Broccoletti R. , Gandolfo S.
Published: June 2003

Background:  Topical corticosteroids are the mainstay treatment for oral lichen planus (OLP), but some authors suggest that systemic corticosteroid therapy is the only way to control acute presentation of OLP.

Methods:  Forty‐nine patients with histologically proven atrophic–erosive OLP were divided into two groups matched for age and sex. The test group (26 patients) was treated systemically with prednisone (50 mg/day), and afterwards with clobetasol ointment in an adhesive medium plus antimicotics, whereas the control group (23 patients) was only treated topically with clobetasol plus antimycotics.

Results:  Complete remission of signs was obtained in 68.2% of the test group and 69.6% of the control group, respectively (P = 0.94). Similar results were obtained for symptoms. Follow‐up showed no significant differences between the two groups. One‐third of the patients of the test group versus none in the control group experienced systemic side‐effects (P = 0.003).

Conclusions:  The most suitable corticosteroid therapy in the management of OLP is the topical therapy, which is easier and more cost‐effective than the systemic therapy followed by topical therapy.
Basic fibroblast growth factor and epidermal growth factor reverse impaired ulcer healing of the rabbit oral mucosa
Authors: Fujisawa Kenji , Miyamoto Youji , Nagayama Masaru
Published: June 2003

Background:  The therapies for refractory ulcers on the oral mucosa are symptomatic and very unsatisfactory. We hypothesized that application of growth factors might be able to achieve successful remission of the lesion. We evaluated the effects of systemic administration and topical application of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) on impaired wound healing of ulcers in the rabbit gingiva.

Methods:  Almost uniform round ulcers could be created on the gingiva of the rabbits by chemical injury with acetic acid. When the submandibular glands were removed or i.v. injection of cisplatin (CDDP) and peplomycin sulfate was performed before ulcer formation, healing of the ulcers took longer than in untreated rabbits. To ascertain whether or not human EGF and bFGF affect rabbit cells, we first examined the effects of EGF and bFGF on the proliferation of the cells derived from rabbit gingiva. We then applied EGF or bFGF in these impaired healing models.

Results:  EGF and bFGF promoted proliferation of the fibroblasts, and EGF also promoted proliferation of the keratinocytes isolated from gingival tissue of rabbits in vitro. Systemic injections of EGF and bFGF in rabbits, which had their submandibular glands removed, and topical application of bFGF accelerated healing of ulcers created in rabbits injected with CDDP and peplomycin sulfate. The ability of bFGF to promote the healing of ulcers was much greater than that of EGF.

Conclusion:  Basic FGF may be effective for refractory oral mucosal lesions.
Peduncular hallucinosis due to brain metastases from cervix cancer: a case report
Authors: Gokce Mustafa , Adanali Seval
Published: May 2003

Background:

Brain metastases from cervical carcinoma are rare. Accompanying symptoms depend on the location of the metastatic lesions. Penduncular hallucinosis is a vivid form of hallucination with clinical findings indicating a lesion of the upper midbrain. We hereby report a probable first case of peduncular hallucinosis associated with brain metastases from cervical cancer.

Case:

A 42-year-old woman had been diagnosed with adenocarcinoma of cervix. On admission for her increasing pelvic pain, she had complex visual hallucinations comprising cartoon children, figurative people and a foggy room. Magnetic resonance imaging of the head revealed a lesion in the left mesencephalothalamic area.

Conclusion:

Peduncular hallucinosis is well known for its vivid and life-like characteristics associated with a mesencephalic area lesion, and recognition of this may be useful of its diagnosis and differential diagnosis from confusion and other hallucinations.
Hypothalamic digoxin-mediated model for epileptogenesis
Authors: Kurup Ravi Kumar , Kurup Parameswara Achutha
Published: May 2003

Background/aims:

This study assessed the changes in the isoprenoid pathway and its metabolites in seizure disorder (ILAE classification – I generalized – idiopathic generalized epilepsy with age-related onset – epilepsy with generalized tonic clonic seizures on awakening) and the metabolic cascade produced by isoprenoid pathway dysregulation.

Methods:

The following parameters were assessed in seizure disorder: isoprenoid pathway metabolites, tyrosine and tryptophan catabolites, glycoconjugates metabolism and red blood cell (RBC) membrane composition.

Results:

There was elevation in plasma HMG-CoA reductase activity, serum digoxin and dolichol and a reduction in RBC membrane Na-K+ATPase activity, serum magnesium and ubiquinone levels. Serum tryptophan, serotonin, strychnine, nicotine and quinolinic acid were elevated while tyrosine, dopamine, morphine and norepinephrine were decreased. The total serum glycosaminoglycans and glycosaminoglycan fractions (except dermatan sulfate), the activity of glycosaminoglycans (GAG) degrading enzymes and glycohydrolases, carbohydrate residues of glycoproteins and serum glycolipids were elevated. Total serum cholesterol, LDL cholesterol and free fatty acids were increased while HDL cholesterol and triglycerides were unaltered. The concentration of membrane hexose, fucose, cholesterol and phospholipids in the RBC membrane decreased significantly but the total RBC membrane GAG was unaltered.

Conclusions:

Epileptogenesis could be due to a dysfunctional isoprenoidal pathway and paroxysmal hypothalamic digoxin hypersecretion.
Influence of whole body cryotherapy on depressive symptoms – preliminary report
Authors: Rymaszewska Joanna , Tulczynski Adam , Zagrobelny Zdzislaw , Kiejna Andrzej , Hadrys Tomasz
Published: May 2003

Background:

Cryotherapy has a long tradition in somatic medicine. Yet we know very little about its impact on psyche and mood disturbances in particular. Therefore there is a real need for scientific investigations into this problem.

Objective:

The study reported here was an initial approach to whole-body cryotherapy (WBCT) as a potential treatment modality for depression and was expected to provide rough data helping to design a future project with extended methodology, larger sample groups and longer follow-up.

Methods:

Twenty-three patients aged 37–70 years gave informed consent to participate in the study. Ten WBCT procedures (160 s, −150°C) were applied within 2 weeks. Participants were recruited from depressed day hospital patients. Antidepressive medication was not ceased. Symptoms were rated at the beginning and end of this intervention using the 21-item Hamilton Depression Rating Scale (HDRS). Changes in scores were analyzed in the group of patients for every item separately as well as for the sum of all items for each patient.

Results:

Almost for each individual HDRS item, the overall score for all patients together was significantly lower after WBCT. This means that all symptoms, except for day–night mood fluctuations, were presumably positively influenced by cryotherapy. The HDRS sum-score for each patient after WBCT was lower than that of the baseline and reached statistical significance in a paired samples t-test. Every patient was therefore considerably relieved after WBCT.

Conclusions:

It appears that WBCT helps in alleviating depression symptoms. Should this be confirmed in the extended study we are currently implementing, WBCT may become an auxiliary treatment in depression.
The serotonin-2A receptor polymorphism and clinical symptoms in mood disorders, schizophrenia and alcohol dependence in Japan
Authors: Terayama Hayato , Takimoto Takahiro , Fukunishi Isao , Itoh Masahiro , Iwahashi Kazuhiko
Published: May 2003

In the past, there have been many epidemiological and genetic studies of mood disorders, schizophrenia, and alcohol dependence, and in this study, the human serotonin 2A receptor (5-HTR2A) polymorphism was examined in 80 patients with mood disorders, 50 patients with schizophrenia and 41 patients with alcohol dependence. 5-HTR is related to affectivity, regulation, and pharmacologic effects of antidepressant, anti-anxiety and antipsychotic medications. The polymorphism in 5-HTR2A (102T/C, −1438 A/G) was identified by the polymerase chain reaction (PCR), followed by restriction fragment length polymorphism (RFLP). The results suggest that 5-HTR2A (102T/C, −1438G/A) polymorphism might not be associated with susceptibility to schizophrenia or mood disorders, and it might not be a risk factor contributing to alcohol dependency. We found that the 102T/C polymorphism was in linkage disequilibrium with the −1438G/A polymorphism in psychosis (mood disorder, schizophrenia, and alcohol dependence) and in health controls. Further studies are needed to determine whether or not the novel serotonin receptor (5-HTR) polymorphism reflects the pathogenesis of schizophrenia, mood disorders, and alcohol dependence.
Quetiapine in relapsing schizophrenia: clinical efficacy and effect on monoaminergic parameters
Authors: van der Heijden F. M. M. A. , Verhoeven W. M. A. , Fekkes D. , Sijben A. E. S. , Tuinier S.
Published: May 2003

Methods:

Tolerability, safety and effectiveness of quetiapine in an in-patient group with a relapse of schizophrenia and the possible role of plasma amino acid concentrations, 5-HT parameters and HVA in the prediction of response to treatment were investigated in an open-label baseline-controlled trial of 14 weeks in 21 hospitalized schizophrenic patients. Responders were defined as those patients who exhibit at least a 40% reduction of BPRS total scores. Secondary efficacy measures were the PANSS, the Clinical Global Impression (CGI)-severity scale and the MADRS. Extrapyramidal side-effects were evaluated with the AIMS. Other side-effects were monitored at regular intervals. Amino acids and the derived tryptophan and tyrosine ratios, as well as monoaminergic parameters, were assessed in plasma at baseline and at weeks 3, 6 and 14.

Results:

Treatment with quetiapine resulted in the predefined treatment effect in 10 out of the 17 patients who completed at least 4 weeks of treatment. Effect in responders was observed on all efficacy parameters, including lower MADRS scores. No extrapyramidal side-effects emerged. Clinical and biochemical parameters did not predict response to treatment.

Conclusions:

This study demonstrates the moderate antipsychotic efficacy of quetiapine on preferentially positive symptoms in a group of relatively young schizophrenics. Some observed changes in biochemical parameters are discussed.
The role of the cytokine network in psychological stress
Authors: Kim Yong-Ku , Maes Michael
Published: May 2003

Although a considerable amount of evidence has shown that psychological stress alters peripheral and brain cytokines, the physiological significance of cytokine alteration in psychological stress remains to be elucidated. The aims of this review are to analyze the influence of acute and chronic psychological stresses on the cytokine network in animals and in humans, and to explore the pathophysiological implication of the cytokine changes in psychological stress. Acute psychological stress may increase proinflammatory cytokines both in animals and in humans, and increase T-helper-1 cell cytokines in humans. Investigations into the effect of chronic psychological stress on cytokine production in animals gives mixed results. However, in humans, academic exam stress or care-giver's stress appears to induce a shift in the Th1/Th2 cytokine balance toward a Th2 response and increase proinflammatory cytokines. Psychological stress-induced cytokines stimulate the activity of indoleamine 2,3 dioxygenase (IDO) and could induce serotonin depletion-related disorders such as depression in susceptible individuals. Psychological stress-induced production of cytokines may increase the risk for human diseases, such as cardiovascular disease and exacerbation of autoimmune diseases. Proinflammatory cytokines may also play a regulatory role in glucocorticoid resistance and may be involved in wound healing and skin barrier function alterations. Finally, psychological stress-induced production of cytokines may play a role in neurodegenerative changes in the brain.
Targeting mortalin using conventional and RNA‐helicase‐coupled hammerhead ribozymes
Authors: Wadhwa Renu , Ando Hiroshi , Kawasaki Hiroaki , Taira Kazunari , Kaul Sunil C
Published: May 2003

Mortalin, also known as mot2/mthsp70/GRP75/PBP74, is a member of the heat‐shock protein 70 family that is heat‐uninducible. It is differentially distributed in cells that have normal and immortal phenotypes, has been localized to various subcellular sites, and has several binding partners and functions. Here, we describe the construction and use of mortalin‐specific conventional and hybrid ribozymes to elucidate its crucial role in cell proliferation. Whereas conventional hammerhead ribozymes did not cause any repression of endogenous mortalin expression, RNA‐helicase‐linked hybrid ribozymes successfully suppressed the expression of mortalin, which resulted in the growth arrest of transformed human cells. We show that, first, RNA helicase‐coupled hybrid ribozymes that have a linked unwinding activity can be used to target genes for which conventional hammerhead ribozymes are ineffective; second, the targeting of mortalin by RNA‐helicase‐coupled hybrid ribozymes causes growth suppression of transformed human cells and could be used as a treatment for cancer.
MYC recruits the TIP60 histone acetyltransferase complex to chromatin
Authors: Frank Scott R , Parisi Tiziana , Taubert Stefan , Fernandez Paula , Fuchs Miriam , Chan Ho‐Man , Livingston David M , Amati Bruno
Published: May 2003

The transcription factor MYC binds specific DNA sites in cellular chromatin and induces the acetylation of histones H3 and H4. However, the histone acetyltransferases (HATs) that are responsible for these modifications have not yet been identified. MYC associates with TRRAP, a subunit of distinct macromolecular complexes that contain the HATs GCN5/PCAF or TIP60. Although the association of MYC with GCN5 has been shown, its interaction with TIP60 has never been analysed. Here, we show that MYC associates with TIP60 and recruits it to chromatin in vivo with four other components of the TIP60 complex: TRRAP, p400, TIP48 and TIP49. Overexpression of enzymatically inactive TIP60 delays the MYC‐induced acetylation of histone H4, and also reduces the level of MYC binding to chromatin. Thus, the TIP60 HAT complex is recruited to MYC‐target genes and, probably with other other HATs, contributes to histone acetylation in response to mitogenic signals.
Effects of ligand and thyroid hormone receptor isoforms on hepatic gene expression profiles of thyroid hormone receptor knockout mice
Authors: Yen Paul M , Feng Xu , Flamant Frederic , Chen Yidong , Walker Robert L , Weiss Roy E , Chassande Olivier , Samarut Jacques , Refetoff Samuel , Meltzer Paul S
Published: May 2003

Little is known about the overall patterns of thyroid hormone (Th)‐mediated gene regulation by the main Th receptor (Tr) isoforms, Tr‐α and Tr‐β, in vivo. We used 48 complementary DNA microarrays to examine hepatic gene expression profiles of wild‐type and Thra and Thrb knockout mice under different Th conditions: no treatment, treatment with 3,3′,5‐triiodothyronine (T3), Th‐deprivation using propylthiouracil (PTU), and treatment with a combination of PTU and T3. Hierarchical clustering analyses showed that positively regulated genes fit into three main expression patterns. In addition, only a subpopulation of target genes repressed basal transcription in the absence of ligand. Interestingly, Thra and Thrb knockout mice showed similar gene expression patterns to wild‐type mice, suggesting that these isoforms co‐regulate most hepatic target genes. Differences in the gene expression patterns of Thra/Thrb double‐knockout mice and Th‐deprived wild‐type mice show that absence of receptor and of hormone can have different effects. This large‐scale study of hormonal regulation reveals the functions of Th and of Tr isoforms in the regulation of gene expression patterns.
Interaction between the small‐nuclear‐RNA cap hypermethylase and the spinal muscular atrophy protein, survival of motor neuron
Authors: Mouaikel John , Narayanan Usha , Verheggen Céline , Matera A Gregory , Bertrand Edouard , Tazi Jamal , Bordonné Rémy
Published: May 2003

The biogenesis of spliceosomal small nuclear ribonucleoproteins (snRNPs) requires the cytoplasmic assembly of the Sm‐core complex, followed by the hypermethylation of the small nuclear RNA (snRNA) 5′ cap. Both the Sm‐core complex and the snRNA trimethylguanosine cap are required for the efficient nuclear import of snRNPs. Here, we show that trimethylguanosine synthase 1 (TGS1), the human homologue of the yeast snRNA cap hypermethylase, interacts directly with the survival of motor neuron (SMN) protein. Both proteins are similarly distributed, localizing in the cytoplasm and in nuclear Cajal bodies. The interaction between TGS1 and SMN is disrupted by a mutation in SMN that mimics the predominant isoform of the protein that is expressed in patients with the neurodegenerative disease, spinal muscular atrophy. These data indicate that, in addition to its function in cytoplasmic Sm‐core assembly, the SMN protein also functions in the recruitment of the snRNA cap hypermethylase.
O‐Mannosylation precedes and potentially controls the N‐glycosylation of a yeast cell wall glycoprotein
Authors: Ecker Margit , Mrsa Vladimir , Hagen Ilja , Deutzmann Rainer , Strahl Sabine , Tanner Widmar
Published: May 2003

Secretory proteins in yeast are N‐ and O‐glycosylated while they enter the endoplasmic reticulum. N‐glycosylation is initiated by the oligosaccharyl transferase complex and O‐mannosylation is initiated by distinct O‐mannosyltransferase complexes of the protein mannosyl transferase Pmt1/Pmt2 and Pmt4 families. Using covalently linked cell‐wall protein 5 (Ccw5) as a model, we show that the Pmt4 and Pmt1/Pmt2 mannosyltransferases glycosylate different domains of the Ccw5 protein, thereby mannosylating several consecutive serine and threonine residues. In addition, it is shown that O‐mannosylation by Pmt4 prevents N‐glycosylation by blocking the hydroxy amino acid of the single N‐glycosylation site present in Ccw5. These data prove that the O‐ and N‐glycosylation machineries compete for Ccw5; therefore O‐mannosylation by Pmt4 precedes N‐glycosylation.
Specific inhibition of gene expression using a stably integrated, inducible small‐interfering‐RNA vector
Authors: van de Wetering Marc , Oving Irma , Muncan Vanesa , Pon Fong Menno Tjon , Brantjes Helen , van Leenen Dik , Holstege Frank CP , Brummelkamp Thijn R , Agami Reuven , Clevers Hans
Published: May 2003

We have designed a doxycycline‐regulated form of the H1 promoter of RNA polymerase III that allows the inducible knockdown of gene expression by small interfering RNAs (siRNAs). As a proof‐of‐principle, we have targeted β‐catenin in colorectal cancer (CRC) cells. T‐cell factor (TCF) target‐gene expression is induced by accumulated β‐catenin, and is the main transforming event in these cells. We have shown previously that the disruption of β‐catenin/TCF4 activity in CRC cells by the overexpression of dominant‐negative TCF induces rapid G1 arrest and differentiation. Stable integration of our inducible siRNA vector allowed the rapid production of siRNAs on doxycycline induction, followed by specific downregulation of β‐catenin. In these CRC cells, TCF reporter‐gene activity was inhibited, and G1 arrest and differentiation occurred. The inhibition of two other genes using this vector system shows that it should be useful for the inducible knockdown of gene expression.
IQGAP proteins are integral components of cytoskeletal regulation
Authors: Briggs Michael W , Sacks David B
Published: May 2003

IQGAP1 is a scaffolding protein that binds to a diverse array of signalling and structural molecules. By interacting with its target proteins, human IQGAP1 participates in multiple cellular functions, including Ca2+/calmodulin signalling, cytoskeletal architecture, CDC42 and Rac signalling, E‐cadherin‐mediated cell–cell adhesion and β‐catenin‐mediated transcription. Yeast IQGAP homologues are important regulators of cellular morphogenesis because they are required for budding and cytokinesis. Here we discuss the structure and function of IQGAP1 as a member of the family of IQGAP proteins and summarize the current knowledge about IQGAP1 and IQGAP2. Collectively, these data reveal that IQGAP1 is a fundamental regulator of cytoskeletal function.
Runx3 knockouts and stomach cancer
Authors: Levanon Ditsa , Brenner Ori , Otto Florian , Groner Yoram
Published: May 2003

Gene targeting often results in knockout mice that show several phenotypes, some of which may not directly relate to the intrinsic function of the disrupted gene. Hence, to study the biological function of genes using knockout mice, one must identify the defects that are directly due to the loss of the targeted gene. Runx3 is a transcription factor that regulates lineage‐specific gene expression in developmental processes. Recently, two groups produced Runx3 knockout mice. Two comparable defects were identified in both knockout strains, one involved neurogenesis and the other thymopoiesis. In addition, a stomach defect pertaining to gastric cancer was observed in one of the mutant strains, but not in the other. Here, we assess the differences between the two Runx3 mutant strains and discuss further studies that could reconcile these discrepancies. This article highlights the difficulties of inferring gene function through the interpretation of knockout phenotypes.
Getting a grip on non‐native proteins
Authors: Stirling Peter C , Lundin Victor F , Leroux Michel R
Published: May 2003

It is an underappreciated fact that non‐native polypeptides are prevalent in the cellular environment. Native proteins have the folded structure, assembled state and cellular localization required for activity. By contrast, non‐native proteins lack function and are particularly prone to aggregation because hydrophobic residues that are normally buried are exposed on their surfaces. These unstable entities include polypeptides that are undergoing synthesis, transport to and translocation across membranes, and those that are unfolded before degradation. Non‐native proteins are normal, biologically relevant components of a healthy cell, except in cases in which their misfolding results from disease‐causing mutations or adverse extrinsic factors. Here, we explore the nature and occurrence of non‐native proteins, and describe the diverse families of molecular chaperones and coordinated cellular responses that have evolved to prevent their misfolding and aggregation, thereby maintaining quality control over these potentially damaging protein species.
Molecular basis of gastric carcinogenesis
Authors: Nardone G.
Published: June 2003

Gastric cancer is constituted by two histomorphological entities ‘intestinal’ and ‘diffuse’, however lesions with similar morphologies may differ in biological aggressiveness and response to therapy. Two distinct molecular pathways have been identified in gastric carcinogenesis: the microsatellite mutator phenotype and a phenotype associated with chromosomal and intrachromosomal instability.

Mounting evidence suggests that microsatellite mutator phenotype alterations and expression of the products of cancer‐related genes are early markers of cell transformation, and may serve to identify the gastric carcinoma histotypes. The lack of a clear genetic basis, lends weight to the notion that gastric cancer is not a monomorphic entity but may be affected by environmental factors. Helicobacter pylori is the most important environmental risk factor associated with sporadic gastric cancer. Exposure of gastric epithelial cells to bacterium results in the generation of reactive oxygen species and inducible nitric oxide synthase that in turn may cause genetic alterations leading to cancer in a subset of subjects. Thus, gastric cancer may be considered the result of an interplay between host genetic profile and environmental toxic agents. The new technologies of molecular analysis will help to establish an individual's risk of developing gastric cancer and will lead to novel biological therapeutic strategies.
Natural history and prognostic prediction of patients with hepatocellular carcinoma
Authors: Varela M. , Sala M. , Llovet J. M. , Bruix J.
Published: June 2003

The knowledge of the natural history of patients with hepatocellular carcinoma is important to estimate the prognosis at diagnosis and indicate the best therapy. Prognosis is related to tumour stage at diagnosis, degree of liver function impairment induced either by the tumour itself or by the underlying cirrhosis, general physical condition of the patients, and potential impact of therapy. Prognostic estimation should take into account all four aspects. Treatment is very relevant to be considered in patients with early stage tumours since surgical resection, transplantation or percutaneous ablation provide a high rate of complete responses and thus, improve survival. This might be as high as 50–75% at 5 years. Patients diagnosed at an intermediate/advanced stage will receive palliative treatment and prospective studies have recently redefined the outcome predictors of this stratum. Asymptomatic patients in whom the tumour has not invaded vessels or disseminated may reach a 50% survival at 3 years, while those with adverse predictors do not reach this time point. These data have to be taken into account not only in the conventional clinical practice, but also in the design and evaluation of prospective investigations that should be properly powered to reach an informative sample size. To achieve both aims, within the Barcelona Clinic Liver Cancer Group we have developed a staging system that combines prognosis prediction with decision making, thus becoming a useful tool both for practice and research.
Prevention of postsurgical relapse and recurrence in Crohn's disease
Authors: Cottone M. , Orlando A. , Viscido A. , Calabrese E. , Cammà C , Casà A.
Published: June 2003

After first resection in Crohn's disease at 1 year 60–80% of patients have endoscopic recurrence, 10–20% have clinical relapse, and 5% have surgical recurrence.1, 2 This review focuses on the actual evidence on the prevention of recurrence and relapse dealing with risk factors and with drugs. Smoking is the only risk factor for Crohn's disease, that has been shown to be related to both endoscopic and surgical recurrence and relapse. Among the different drugs evaluated, some (Mesalamine and Metronidazole) have been shown to be effective, whereas others (immunosuppressive) need to be evaluated in further, new trials.
New developments in the pathophysiology of gastro‐oesophageal reflux disease (GERD): implications for patient management
Authors: Quigley E. M. M.
Published: June 2003

The spectrum of gastro‐oesophageal reflux disease (GERD) has expanded; indeed the majority of individuals with symptomatic GERD do not have erosive reflux disease (ERD); this group has been referred to as nonerosive or negative‐endoscopy reflux disease (NERD). There may be important differences between NERD and ERD in terms of pathophysiology and management. Thus, NERD patients appear relatively resistant to proton pump inhibitors and may not be good surgical candidates. The clinician caring for patients with GERD must therefore be aware of the full spectrum of GERD and of the pathophysiological and therapeutic implications of NERD. Recent twin studies have revealed that genetic factors play a role in GERD and form the basis for future studies on the role of inheritance in the various manifestations of GERD. Several recent investigations have reaffirmed the primacy of acid reflux in the pathogenesis of GERD and have also provided insights into the pathophysiology of postprandial heartburn. Transient lower oesophageal sphincter relaxations and hiatal hernias have emerged as major and interacting factors in the genesis of reflux events and in the potentiation of acid exposure; the former are attracting considerable attention as a potential therapeutic target. Nocturnal acid breakthrough, which has been implicated in the failure of some patients to respond to high doses of proton pump inhibitors, appears, on further examination, to be a gastric rather than an oesophageal phenomenon, and may not be of clinical or therapeutic importance.
What have we learnt from gastric biopsy?
Authors: Rugge M. , Russo V. M. , Guido M.
Published: June 2003

Pathologists would claim that the most reliable information obtained on gastric diseases is pathology‐based. This manuscript summarizes the four major biopsy‐based contributions to the current knowledge of non‐neoplastic gastric diseases: (i) the in vivo definition of gastritis; (ii) the recognition of the clinicopathological patterns of gastritis; (iii) the morphological links between gastritis and stomach cancer; and finally (iv) the recent information on the possible reversibility of early or advanced precancerous gastric lesions.
Intra‐arterial treatments in patients with hepatocellular carcinoma
Authors: Trinchet J. C. , Ganne‐Carrie N. , Beaugrand M.
Published: June 2003

In Western countries, most of the patients with hepatocellular carcinoma (HCC) are not eligible for curative treatments. Intra‐arterial treatments have a palliative effect that could lead to extensive tumour necrosis and therefore have been widely used. Arterial embolization, Lipiodol‐targeted chemoembolization and intra‐arterial injection of radioactive iodine mixed with Lipiodol provided promising results in terms of tumoral growth, but were also responsible for severe side‐effects, particularly in patients with cirrhosis. Their influence on survival has been assessed by randomized trials with contradictory results. In patients with advanced cases, embolization alone has limited or no influence on survival, and chemoembolization provided a beneficial effect mostly in patients with viral liver diseases, without liver failure, and with an adequate portal flux. The effects of radioactive iodine either in the treatment of advanced cases or the prevention of recurrences after a curative treatment must be investigated further.