bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic Significance of Microsatellite Instability and Ki-ras Mutation Type in Stage II Colorectal Cancer
Authors: Wang Cathy , van Rijnsoever Marius , Grieu Fabienne , Bydder Sean , Elsaleh Hany , Joseph David , Harvey Jennet , Iacopetta Barry
Published: April 2003

Objectives: The survival of stage II colorectal cancer (CRC) patients is approximately 70% at 5 years. Identification of the patient subgroup at high risk for tumour recurrence and death would allow more informed use of chemotherapy for this stage of disease. Several clinical and pathological factors have been reported to associate with worse survival. In the present study we investigated the prognostic significance of two major genetic alterations in CRC: microsatellite instability (MSI+) and the type of Ki-ras mutation. Methods: PCR-based molecular techniques were used to screen for MSI+ and Ki-ras mutation in 396 stage II CRC patients with an average follow-up time of 75 months. Clinicopathological information was obtained by retrospective review of pathology reports. Results: Prominent vascular invasion was identified in 19% of cases and was found to be an independent prognostic factor for poor outcome (relative risk = 2.08, 95% confidence interval: 1.22–3.57, p = 0.008). The MSI+ phenotype was found in 23% of proximal tumours and Ki-ras mutations in 38% of the overall series. Neither MSI+ nor the type of Ki-ras mutation showed prognostic significance in this cohort of stage II CRC. Conclusions: MSI+ and Ki-ras mutation type are not useful markers for the identification of high-risk stage II CRC patients. Further prospective and/or cohort studies are required to determine whether these molecular changes have predictive value for survival benefit from 5-fluorouracil-based adjuvant chemotherapy.
A Pilot Phase II Study of Capecitabine in Advanced or Recurrent Gastric Cancer
Authors: Koizumi Wasaburo , Saigenji Katsunori , Ujiie Shigeki , Terashima Masanori , Sakata Yu , Taguchi Tetsuo
Published: April 2003

Objectives: To evaluate the efficacy and safety of capecitabine in patients with advanced or recurrent gastric cancer, we conducted a pilot phase II study in Japan. Methods: Patients with advanced or recurrent gastric cancer were given oral capecitabine 828 mg/m2 twice daily for 3 weeks, followed by 1 week of no treatment. Two or more cycles were administered. From July 1996 to December 1997, 32 patients were enrolled in the study. The response to capecitabine was evaluated in 31 patients, excluding 1 found to be ineligible. Results: The overall response rate was 19.4% (6/31, 95% confidence interval: 7.5–37.5%). The median duration of response was 124.5 days, the median time to disease progression 85.0 days, and the median survival time 247.5 days. Drug-related adverse events of grade 3 or higher were infrequent: in 2 patients (6.3%) total bilirubin concentration increased, and 1 patient (3.1%) each had elevation of GOT, anemia, lymphopenia, increased creatinine, and hand-foot syndrome. No patient had gastrointestinal toxicity of grade 3 or higher. Conclusion: Capecitabine was suggested to be safe and effective in the treatment of advanced or recurrent gastric cancer. Further phase II studies of capecitabine on a large scale are warranted.
Role of Gemcitabine in the Treatment of Advanced and Metastatic Breast Cancer
Authors: Heinemann Volker
Published: April 2003

Gemcitabine is an antimetabolite drug with proven antitumor activity and tolerability in metastatic breast cancer. In a total of nine studies, gemcitabine monotherapy has reached response rates of up to 37% in the first-line setting, 26% in the second-line setting, and 18% or better in the third-line setting. Gemcitabine is an excellent choice for combination therapy by its unique mechanism of action and favorable toxicity profile, thus limiting the risk of pretreatment-related drug resistance and overlapping toxicity, and by its potential for synergistic interaction with some combination partners as indicated in preclinical studies. Numerous phase II clinical studies have combined gemcitabine with other active agents such as the taxanes, vinorelbine, vindesine, cisplatin, 5-fluorouracil, as well as anthracyclines across various regimens and conditions of pretreatment. Most of these two-drug combinations have consistently demonstrated higher efficacy than either single agent, particularly in pretreated patients. Even higher efficacy has been obtained with triple-drug regimens including gemcitabine, anthracyclines (epirubicin or doxorubicin), and paclitaxel; these regimens have yielded overall response rates of 58–92% as first-line treatment. In view of these results, gemcitabine may be regarded as a valuable alternative to the palliative treatment of metastatic breast cancer, and an excellent option for the development of effective combination treatment not only in first-line therapy, but also for intensively pretreated patients previously exposed to anthracyclines and/or the taxanes.
Expression of Vascular Endothelial Growth Factor and Angiogenesis in Gastrointestinal Stromal Tumor of the Stomach
Authors: Takahashi Ryoji , Tanaka Shinji , Kitadai Yasuhiko , Sumii Masaharu , Yoshihara Masaharu , Haruma Ken , Chayama Kazuaki
Published: April 2003

Vascular endothelial growth factor (VEGF) is associated with the malignant potential of several types of carcinoma. The aim of this study was to elucidate the clinical significance of VEGF expression in gastrointestinal stromal tumor (GIST). Methods: Specimens obtained from 53 patients who had underwent surgical resection for GIST of the stomach were used in this study. Specimens were examined immunohistochemically for VEGF expression and Ki-67 expression. Tumor microvessel density (MVD) was determined immunohistochemically with anti-CD31 antibody, and was estimated by averaging the counts from three high-power fields in the area showing the greatest neovascularization. Results: VEGF expression was detected in 14 (26.4%) of the 53 lesions and correlated significantly with tumor size, liver metastasis, Ki-67 labeling index, and MVD. Prognosis was significantly poorer than in patients with tumors expressing VEGF than in patients with tumors lacking VEGF expression. Multiple logistic regression analysis for 10-year survival showed VEGF expression and high mitotic rate to be independent predictor of a poor outcome. Conclusions: Angiogenesis associated with VEGF may play an important role in the progression of GIST. VEGF expression may serve as an indicator of a poor prognosis.
Microsatellite Instability Is Often Observed in Esophageal Carcinoma Patients with Allelic Loss in the FHIT/FRA3B Locus
Authors: Mimori Koshi , Inoue Hiroshi , Shiraishi Takeshi , Matsuyama Ayumi , Mafune Ken-ichi , Tanaka Yoichi , Mori Masaki
Published: April 2003

We have previously reported a significant correlation between the progression of colorectal carcinoma and the loss of Fhit and Msh2 expression. This observation led us to investigate the effect of an allelic loss of the FHIT gene on esophageal cancer when coupled with a deficient mismatch repair system. In this study, 8 of 42 patients with esophageal cancer had microsatellite instability (MSI), and 29 cases demonstrated allelic loss (loss of heterozygosity or homozygous deletion) at the FHIT/FRA3B locus. All 8 MSI-positive cases showed allelic loss, while 13 of 34 MSI-negative cases retained both alleles, and a significant correlation was found between the incidence of MSI and allelic loss (p < 0.05). On the other hand, only 1 of the 8 MSI-positive patients exhibited neither Msh2 nor Fhit protein expression in both normal and carcinoma epithelial tissues, but neither a relationship between Msh2 expression and Fhit expression nor with the incidence of MSI was noted. This result indicated that the disruption of the mismatch repair system of Msh2 does not mainly lead to allelic loss of the FHIT/FRA3B locus as well as MSI in esophageal cancer. We concluded that MSI is significantly related to the allelic loss in the FHIT/FRA3B region, but Msh2 might be unrelated to the progression or oncogenic process in esophageal cancer.
Interleukin-1 Increases Fibronectin Production by Cultured Rat Cardiac Fibroblasts
Authors: Fernández Lucas , Mosquera Jesús A.
Published: April 2003

Objectives: There is evidence of monocyte/macrophage infiltration and increased interleukin (IL)-1 expression, along with increased extracellular matrix (ECM) and fibrosis in the myocardial interstitium, during the course of parasitic, viral and idiopathic myocarditis. The aim of this study was to determine the effect of human and rat IL-1 on the production of fibronectin (FN) by rat cardiac fibroblast cultures. Methods: To test the role of IL-1 in the production of ECM, we determined the FN content in supernatants of rat myocardial fibroblast cultures incubated for 72 h with different doses of human recombinant IL-1β or with supernatants from lipopolysaccharide (LPS)-stimulated rat macrophage cultures. The content of soluble FN was determined by ELISA. In addition, IL-1β transcription was also investigated in controls and human recombinant IL-1β-treated fibroblast cultures. Results: There was a significant, dose-dependent FN-stimulatory effect of recombinant human IL-1β and LPS-stimulated macrophage-conditioned medium when they were used to stimulate fibroblast cultures. The stimulatory effect on FN production was found to be diminished after treatment of macrophage supernatants with an antibody against rat IL-1. Increased transcription of IL-1β was found in human recombinant IL-1β-treated cardiac fibroblasts. Conclusion: Our data suggest that the FN-stimulatory effect of IL-1 on cardiac fibroblasts could be responsible, in part, for interstitial ECM accumulation during the course of myocarditis.
Expression of Murine N-myc by Insertion of Retrovirus Sequences in a Murine Macrophage Cell Line (RAW264)
Authors: Liu Shu-Ying , Higuchi Yasunori , Setoguchi Mihoko , Matsuura Keiko , Hijiya Naoki , Yamamoto Shunsuke
Published: April 2003

RAW264 cells, reported to be originated from Abelson-virus-induced B lymphomas, are widely used as a murine monocyte cell line. We found that RAW264 show enhanced expression of murine N-myc. Murine cDNA clones associated with N-myc were separated from λgt11 cDNA library constructed by using mRNA from the macrophage cell line, RAW264 cells. Sequencing analysis of the longest cDNA clone N-mycL showed that the length of the coding region was 18 bases shorter than that of the predicted full length N-myc cDNA, and the 3′ untranslated region had the 5′ long terminal repeat (LTR) sequence of the Moloney-like proviral sequence, suggesting the expression of N-myc by insertion of the proviral sequence. This suggests that expression of N-myc plays a role in the establishment of macrophage cell line RAW264. Integration of LTR and overexpression of the N-myc gene might have existed in the parental lymphoma cells, playing a role in the development of lymphoma or in the establishment of macrophage cell line.
Fatty Acid Bile Acid Conjugates Inhibit Atherosclerosis in the C57BL/6 Mouse Model
Authors: Gonen A. , Shaish A. , Leikin-Frenkel A. , Gilat T. , Harats D.
Published: April 2003

Objective: The aim of the current research was to study whether fatty acid bile acid conjugates (FABACs) have a beneficial effect on atherosclerosis progression and blood lipid levels in mice. Methods: C57BL/6 female mice, fed a high-fat Paigen diet, were administered an oral dose of FABAC or DDH2O daily. Quantification of atherosclerotic fatty-streak lesions at the aortic sinus was performed. Results: The FABAC-treated mice showed a significant reduction in the atherosclerotic lesion areas as compared to the control group (p = 0.019). A significant elevation in total cholesterol levels was observed in both the FABAC and control groups. Higher FABAC levels were measured in the high-density lipoprotein fraction as compared to the very-low-density and low-density lipoprotein fractions. Conclusion: Our findings demonstrate that FABACs, given orally, reduce the development of atherosclerosis in mice fed a high-fat high-cholesterol diet, despite a lack of effect on plasma lipid levels.
Group Cohesion and Working Alliance: Prediction of Treatment Outcome in Cardiac Patients Receiving Cognitive Behavioral Group Psychotherapy
Authors: van Andel Peter , Erdman Rudolph A.M. , Karsdorp Petra A. , Appels Ad , Trijsburg Rutger W.
Published: April 2003

Background: Various definitions of both group cohesion and working alliance are used in theories on group psychotherapy, making the study of their relative contribution to the treatment outcome difficult. In this study, two different, nonoverlapping questionnaires were used to explore the relationship between group cohesion, working alliance and treatment outcome in a time-limited, structured cognitive behavioral group psychotherapy aiming at the reduction of coronary risk factors. Methods: After having undergone percutaneous transluminal coronary angioplasty, 42 patients were treated with the aim to reduce exhaustion, anxiety, hostility and depression. The newly developed Group Cohesion Questionnaire (GCQ) and the Helping Alliance Questionnaire (HAQ-II, measuring the bond between individual patients and the group psychotherapist) were administered after the fifth and tenth treatment session. Exhaustion, quality of life, anxiety, blood pressure and heart rate were measured before and after treatment. To test the relationship between the GCQ, the HAQ-II and outcome variables, Pearson Product-Moment correlations and hierarchical regression was applied. Results: Principal Component Analysis of the GCQ yielded two dimensions, the bond with the group as a whole and the bond with other group members. Hierarchical regression showed that both the bond with other group members and working alliance contributed significantly and independently to the prediction of posttreatment systolic and diastolic blood pressure as well as posttreatment quality of life (confidence). Conclusions: Conceptually and empirically, group cohesion and the working alliance may be considered to represent different relationships in a psychotherapy group, contributing in different ways to the treatment outcome in cardiac patients receiving cognitive behavioral group psychotherapy.
Distance between Patients’ Subjective Perceptions and Objectively Evaluated Disease Severity in Chronic Heart Failure
Authors: Grigioni Francesco , Carigi Samuela , Grandi Silvana , Potena Luciano , Coccolo Fabio , Bacchi-Reggiani Letizia , Magnani Gaia , Tossani Eliana , Musuraca Anna Chiara , Magelli Carlo , Branzi Angelo
Published: April 2003

Background: Chronic heart failure (CHF) is a socially relevant condition carrying an adverse prognosis. Systematic analysis is needed of the relationship between quality of life (QoL) – what patients are most interested in – and objective parameters of CHF severity – which largely determines physicians’ care. Methods: We prospectively investigated QoL, as ascertained by the Minnesota Living with Heart Failure Questionnaire, alongside all the currently used objective clinical/instrumental (electrocardiographic, echocardiographic, hemodynamic and functional capacity) indicators of disease severity in 106 consecutive CHF patients. Results: Besides persistence of sinus rhythm (p = 0.007), the only objective parameters that correlated with QoL were NYHA class (p < 0.001) and distance covered during the six minutes walking test (p < 0.001) (two indications of patients’ ability to attend to their daily needs). Presence of left bundle branch block was associated with a worse QoL only in patients with CHF due to ischemic heart disease (p = 0.032). All the other clinical/instrumental parameters showed no relation with QoL (p > 0.150 in all cases). Conclusions: Objective indicators of disease severity, which largely determine physicians’ care, appear to have little bearing on QoL, suggesting that current treatment for CHF fails to satisfy patients’ perceived needs. The possibility of cost-effective nonpharmaceutical therapeutic protocols (e.g. psychological interventions) specifically designed to improve patients’ QoL deserves investigation as a much needed new approach to the management of CHF.
Testing for the Integrity of Blinding in Clinical Trials: How Valid Are Forced Choice Paradigms?
Authors: Sharpe Louise , Ryan Bridget , Allard Simon , Sensky Tom
Published: April 2003

Background: In randomised controlled trials, an increasingly used test of the ‘blindness’ of assessors is to have them guess the group to which each participant has been allocated. Because assessors are usually aware of the trial hypotheses, we predicted that trial participants who showed the greatest improvement would be assumed by an assessor to have been in the ‘preferred intervention’ group. Methods: Data were derived from a trial in recent-onset rheumatoid arthritis comparing cognitive behavioural therapy plus routine care with routine care alone. Results: Although in this trial assessor blindness was demonstrated, patients ‘guessed’ by the assessor to be in the cognitive therapy group showed significantly greater improvements than those predicted to have received routine care alone in variables predicted to change in the study protocol. Conclusions: These results indicate that even if an assessor’s guesses about patient group allocations are more accurate than expected by chance, this would not necessarily demonstrate failure of blinding. This casts further doubt on the validity of forced choice paradigms in testing the integrity of blinding in clinical trials.
The Evidence for Prosthodontic Treatment Planning for Older, Partially Dentate Patients
Authors: Omar Ridwaan
Published: April 2003

This paper provides a review of the available evidence for traditional prosthodontic need determination and management strategies for older, partially dentate individuals, and compares it to the documented functional benefits of a more limited yet targeted approach to alleviating morphological shortfalls for this group of people, at the population level. The reasons for which the traditional total replacement strategy is not universally applicable or viable are discussed, and research is presented which tests many of the assertions made for the mandatory replacement of posterior teeth. Evidence is presented of the growing prosthodontic challenge posed by an increasing number of middle-aged and older partially dentate individuals in society: many of their remaining teeth are in poor condition, yet few such patients are willing to accept the prospect of becoming edentulous. The shortened dental arch concept is discussed and proposed as an appropriate strategy when complex intervention is to be avoided, inadvisable, or not possible. At the population level, current evidence suggests that prosthodontic strategies aimed at the restoration and/or replacement of all lost molars may be inappropriate in older, partially dentate individuals. A more limited yet targeted strategy is both more effective and more efficient, and should not be seen as compromised care.
Dental Education in Kuwait
Authors: Behbehani J.M.
Published: April 2003

For a long time there has been a need to establish a dental school in Kuwait, due to the fact that the majority of dentists working in Kuwait are expatriates from various countries. An Amiri decree in 1996 made it possible, and the first dental students were admitted to the Kuwait University Faculty of Dentistry in 1998. The mission of the Faculty of Dentistry is ‘to promote oral health in Kuwait through education, research and cooperation with other professional health care institutions as well as the community at large’. A 6.5-year dental curriculum was completed after 2 years of committee work and was accepted by the University Council in 2001. This curriculum incorporates current trends in medical and dental education, such as the evidence-based and community-based approaches, problem-solving methodology for outcome-based learning, and competency achieved through comprehensive patient care.
Tobacco and Oral Diseases
Authors: Reibel Jesper
Published: April 2003

It is well known that smoking contributes to the development of lung cancer and cardiovascular disease, and there is weighty evidence that it has a considerable influence on oral health. Smoking has many negative effects on the mouth, including staining of teeth and dental restorations, reduction of the ability to smell and taste, and the development of oral diseases such as smoker’s palate, smoker’s melanosis, coated tongue, and, possibly, oral candidosis and dental caries, periodontal disease, implant failure, oral precancer and cancer. From a qualitative point of view the latter is obviously the most serious tobacco-related effect in the mouth. Quantitatively, however, importance has been attached to periodontitis, which affects a large proportion of the population, and during recent years more attention has been given to implant survival rates. Dentists have an important role to play in preventing the harmful effects of smoking in the mouth, and consequently smoking counselling should be as much a part of the dentist’s job as plaque control and dietary advice.
An Evidence-Based Approach to the Prevention of Oral Diseases
Authors: Spencer A.J.
Published: April 2003

The evidence-based approach has become the mantra of health care and service delivery. But just what it means, whether it is feasible, how to build it and the outcome of its use are not well understood. The aims of this paper are to provide an overview of an evidence-based approach to the prevention of oral disease, to examine the assessment of clinical trial evidence, to examine emerging approaches to assessing population-wide interventions and oral health promotion, and to illustrate some principles and issues through examples from preventive dentistry. The evidence-based approach to prevention is presented using an evidence loop, which emphasizes that the evidence-base should begin with an understanding to the burden of oral disease and its determinants, rather than a consideration of the efficacy or effectiveness of interventions in clinical dental research. A systematic review of evidence from clinical dental research is compiled and assessed, after which the intervention is decided upon and implemented. The evidence loop is completed by the monitoring of outcomes and reassessment of the intervention process. Attention is also given to steps in assessing non-randomized population-wide interventions and evidence on oral health promotion based on expert opinion. The requirement for evidence creates a substantial challenge which can only be met by increased research activity, improved quality of information and the appropriate application of the outcomes of research to policy making for the prevention of oral disease.
Development of Oral Health in Africa
Authors: Thorpe Samuel J.
Published: April 2003

Around 80% of African communities can be considered to be materially deprived. The presence of widespread poverty and underdevelopment in Africa means that communities are increasingly exposed to all of the major environmental determinants of oral disease. Previous approaches to oral health in Africa have failed to recognize the epidemiological priorities of the region or identify reliable and appropriate strategies to address them. Efforts have consisted of providing unplanned, ad hoc and spasmodic curative oral health services, which in most cases are poorly distributed and only reach affluent or urban communities. Realizing the limited impact of existing strategies, the World Health Organization Regional Office for Africa (WHO/AFRO) developed a regional oral health strategy to assist African countries and their partners in identifying priorities and planning preventive-oriented programmes, particularly at the district level. The long-term objective is to provide equitable and universal access to cost-effective quality oral healthcare and thereby significantly reduce the incidence of oral diseases in Africa.
Outcome after Brain Haemorrhage
Authors: Dennis Martin S.
Published: April 2003

Between 10 and 20% of strokes are due to intracerebral haemorrhage. The 1-month case fatality is about 42% in unselected cohorts. This relatively low incidence (compared with ischaemic stroke) and high early case fatality means that relatively few patients are available for long-term follow-up and therefore the available data on prognosis are imprecise. Moreover, improvements in diagnostic methods, such as the introduction of gradient echo MRI, which is very sensitive to intracerebral haemorrhage, are altering the types of patients being entered into studies of prognosis. Despite these methodological difficulties, it does appear that the overall prognosis with respect to survival and residual disability is similar to that for ischaemic stroke of equivalent clinical severity. Greater age and stroke severity, whether graded by neurological score or extent of haemorrhage on imaging, are both associated with increased case fatality and poorer functional outcomes. There is no definite evidence of differential recovery between ischaemic and haemorrhagic stroke. Epileptic seizures occur more commonly after haemorrhagic stroke (about 8 per 100 patient-years) compared with ischaemic stroke and more commonly in lobar rather than basal ganglia haemorrhage. There is no reliable evidence to indicate that the risk of recurrent stroke after haemorrhage differs from that after ischaemic stroke. However, strokes due to haemorrhage, like those due to infarction, are heterogeneous not only in terms of severity but also in their causes. The causes (e.g. amyloid angiopathy, hypertension, coagulation deficits) are likely to influence the risk of subsequent stroke. Pooling of data from community-based studies of haemorrhagic stroke that have used consistent definitions and methods represents the only feasible way to obtain more precise data on prognosis after intracerebral haemorrhage.
Evidence with Antiplatelet Therapy and ADP-Receptor Antagonists
Authors: Easton J. Donald
Published: April 2003

Antiplatelet drugs have been shown to prevent a range of atherothrombotic events, including transient ischaemic attack (TIA) and ischaemic stroke. Clopidogrel and ticlopidine are adenosine diphosphate (ADP)-receptor antagonists that inhibit ADP-induced fibrinogen binding to platelets, a necessary step in the platelet aggregation process. The Antithrombotic Trialists’ Collaboration recently published a major meta-analysis that assessed the effect of antiplatelet therapy in patients with various manifestations of atherosclerosis. In total, this analysis included 135,000 patients in comparisons of antiplatelet agents versus control and 77,000 patients in comparisons of different antiplatelet regimens. This meta-analysis found that overall, antiplatelet therapy reduces the combined odds of stroke, myocardial infarction (MI) or vascular death by 22%, and that antiplatelet agents reduce the odds of a non-fatal stroke by 25% over a wide range of patients with or without a history of cerebrovascular disease. In the CAPRIE trial of clopidogrel versus acetylsalicylic acid (ASA), there was a 10% odds reduction for stroke, MI or vascular death in favour of clopidogrel (p = 0.03). In a meta-analysis performed by the Cochrane Stroke Group, ADP-receptor antagonist therapy significantly reduced the odds of a serious vascular event (stroke, MI or vascular death) by 9% (2p = 0.01) and of any stroke by 12%. The safety/tolerability profile of clopidogrel was superior to that of ticlopidine, and at least as good as that of ASA. In CURE, a long-term benefit was observed with the use of clopidogrel on top of standard therapy (including ASA in all patients), with a 20% relative risk reduction for the primary endpoint of cardiovascular death, MI or stroke (p < 0.001) in patients with unstable angina and non-Q-wave MI. A consistent benefit was seen across all patient subgroups, including patients with a previous history of stroke. More recently, CREDO has demonstrated the incremental benefit of prolonged use of clopidogrel on top of ASA in patients undergoing elective PCI, with a 27% reduction in the combined risk of death, MI or stroke after 12 months of therapy (p = 0.02) and a 25% reduction in stroke over the same time period. The MATCH trial is currently being conducted to test the hypothesis that long-term administration of clopidogrel on top of ASA is superior to clopidogrel alone for the reduction of major ischaemic events in patients with recent TIA or ischaemic stroke who are at high risk of atherothrombotic recurrence. Further trials of clopidogrel on top of standard therapy (including ASA) are planned in neurology; these include SPS3, in patients with small subcortical strokes, and ATARI, in patients who have recently recovered from a TIA.
Is the Arginine-Nitric Oxide Pathway Involved in the Pathogenesis of Schizophrenia?
Authors: Yanik Medaim , Vural Huseyin , Kocyigit Abdurrahim , Tutkun Hamdi , Zoroglu Süleyman Salih , Herken Hasan , Savaş Haluk Asuman , Köylü Alpay , Akyol Ömer
Published: April 2003

The reciprocal regulation of arginase and nitric oxide synthase (NOS) in L-arginine-metabolizing pathways has been demonstrated. There are various evidences of the role of the nitric oxide (NO) in several neuropsychiatric disorders including schizophrenia. However, there is no study which has investigated the role of arginase as an important part of the arginine regulatory system affecting NOS activity in schizophrenia. This study aims to investigate arginase, manganese (Mn) and total nitrite levels (a metabolite of NO) and their relationship to the arginine-NO pathway in patients with schizophrenia. Arginase activities, Mn and total nitrite levels were measured in plasma from 46 patients with schizophrenia and 32 healthy control subjects. Plasma arginase activities and Mn were found to be significantly lower and total nitrite level higher in patients with schizophrenia compared with controls. Our results suggest that the arginine-NO pathway is involved in the pathogenesis of schizophrenia.
Impaired Conditional Discrimination Learning in Social Phobia
Authors: Sachs Gabriele , Anderer Peter , Doby Dagmar , Saletu Bernd , Dantendorfer Karl
Published: April 2003

Eyelid conditional discrimination learning (ECDL) is a test of discriminative aversive conditioning. It places minimal demands on motivation and was shown to selectively test temporal lobe function. Twenty-five unmedicated social phobia (SP) patients (mean age 29.5 ± 7.0 years), diagnosed according to DSM-IV criteria, and 25 age- and gender-matched healthy controls (HC, mean age 34.0 ± 8.6 years) were examined with an ECDL paradigm. In the experiment two differently colored stimuli are randomly presented. Only one of the stimuli (reinforced trial) is followed by an aversive airpuff to the cornea, as opposed to unreinforced trials not followed by an airpuff. Conditioned responses (CRs) consist of reflex eyelid closures already upon light presentation. HC as well as SP patients showed a significant difference between reinforced and unreinforced trials. In SP patients, CR frequency did not increase during the ECDL task, while HCs showed appropriate conditional discrimination ability. Thus the results indicate an impairment of adequate behavior modification in an aversive conditioning task in SP.
Decreased Production of Reactive Oxygen Species by Blood Monocytes Caused by Clozapine Correlates with EEG Slowing in Schizophrenic Patients
Authors: Gross Andres , Joffe Grigori , Joutsiniemi Sirkka-Liisa , Nyberg Peter , Rimón Ranan , Appelberg Björn
Published: April 2003

We have earlier reported an increased theta-power value in clozapine (CLO)-treated patients with schizophrenia, nonresponsive to conventional antipsychotics. We also found that the decrease in the production of reactive oxygen species (ROS), induced by CLO, by peripheral blood monocytes (MO) of these patients correlates with clinical improvement. MO share the capability of ROS production with their more mature descendants, microglia of the brain. We hypothesized that the CLO-related changes in peripheral blood MO might be related to a parallel process in microglia and thus be reflected in brain activity. In those 8 patients for whom both QEEG and MO data were available, we explored possible relationships between these parameters. A clear-cut correlation between ROS production (R2 = 0.929, p < 0.05) for nonstimulated MO, and (R2 = 0.907, p < 0.001) for stimulated MO and theta-power values in the central frontal electrode (Fz) was found. It is intriguing to speculate that the EEG slowing is a result of the modulatory action of the activated microglial cells in the central nervous system via production of ROS or cytokines or both. However, this proposition has to be confirmed by future research.
Growth Hormone-Insulin-Like Growth Factor-1 Axis, Leptin and Sleep in Anorexia nervosa Patients
Authors: Lindberg Nina , Virkkunen Matti , Tani Pekka , Appelberg Björn , Rimón Ranan , Porkka-Heiskanen Tarja
Published: April 2003

The present study characterizes the relationships between severe malnutrition, sleep, growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis, and leptin levels in anorexia nervosa (AN) patients before and after weight gain. Eleven restricting-type anorectic females (mean age = 19.7 years) with severe starvation state [mean body mass index (BMI) = 13.3] were studied using polysomnography and spectral power analysis. The hormone levels were measured in the morning after sleep recording. Eleven normal-weight, age- and gender-matched healthy volunteers without a history of any eating disorder served as controls. After nutritional treatment for about 2 months (65.7 ± 6.4 days), sleep examinations and blood tests were repeated. At this stage, the study group consisted of 5 patients (mean BMI = 15.6). Higher IGF-1 and leptin levels were associated with longer and deeper sleep among anorectics. The sleep parameters including the percentages of stage 1 sleep and SWS as well as IGF-1 tended to normalize after only limited weight gain. Sleep disturbances in anorectics may be mediated through changes in the levels of the GH-IGF-1 axis hormones, as well as the levels of leptin.
Acute Antimanic Efficacy and Safety of Intravenous Valproate Loading Therapy: An Open-Label Study
Authors: Jagadheesan K. , Duggal Harpreet S. , Gupta Subash Chandra , Basu Somuya , Ranjan Sanjeev , Sandil Rajiv , Akhtar Sayeed , Nizamie S. Haque
Published: April 2003

This open-label study investigated whether acute antimanic effects and safety of intravenous valproate loading therapy is superior to oral valproate loading. Eighteen patients with DSM-IV diagnosis of either bipolar affective disorder or schizomania who met the study criteria were recruited (9 in the intravenous and 9 in the oral valproate group). Psychopathology was assessed with the scale for manic and mixed states on days 0 and 4. A checklist was used for the assessment of side effects. The results showed about 36% reduction in total mean manic scores with intravenous valproate loading; however, statistically, the degree of reduction in manic scores was comparable between the groups. A nonsignificant increase in the rate of adverse events was noted in the intravenous group. Despite its limitations, this study suggests that acute antimanic effects of both intravenous and oral valproate loading are comparable.
Influence of Housing Conditions on the Effects of Serotonergic Drugs on Feeding Behavior in Non-Deprived Rats
Authors: Silva R.C.B. , Santos N.R. , Brandão M.L.
Published: April 2003

Serotonin plays an important role in the regulation of food and water intake, and drugs that inhibit the uptake of this neurotransmitter have been used as appetite suppressors. As the clinical usage of anorectics necessarily involves chronic drug administration, the effects of chronic treatment in animals are likely to be of greater clinical relevance than acute drug effects. Besides, little effort has been made to examine whether these effects interact with stressful situations, such as isolation. We have therefore examined the effects of fluoxetine, a selective 5-HT reuptake inhibitor, and gepirone, a 5-HT1A agonist, on body weight in isolated and in group-housed rats during 3 weeks of daily treatment. Gepirone caused an increase in body weight only in isolated rats. On the other hand, fluoxetine caused a significant reduction in body weight in both singly- and group-housed animals. The effects of these serotonergic agents were more prominent during the first week of treatment. From the data obtained in this study, it is suggested that increased 5-HT transmission produced by fluoxetine during chronic administration seems to be crucial for the appetite-regulating action of 5-HT, and this hypophagic effect does not seem to be dependent on the activation of 5-HT1A receptors since it was not shared by gepirone. Moreover, a concomitant stressful situation, such as isolation, interferes with the action of gepirone on feeding behavior. The hyperphagic effects of chronic regimen with gepirone in isolated animals are probably due to the concurrent reduction of the 5-HT transmission caused by this anxiogenic condition at the earlier stages of treatment. On the other hand, the anorectic effects of fluoxetine do not seem to interact with the stressful situations caused by isolation.
Characteristics of Children with Permanent Mild Hearing Impairment
Authors: Kiese-Himmel Christiane , Ohlwein Silke
Published: April 2003

The report was intended to provide up-to-date information about permanent mild hearing impairment (HI) in early childhood. Altogether 33/250 children with a permanent mild HI in the better ear (average at frequencies of 0.5, 1, 2, 4 kHz ≧25–39 dB HL) were found during the 7-year period from 1994 to 2001 in the Outpatient Clinic of the Department Phoniatrics/Pedaudiology, University of Göttingen. Twenty-two of 33 children had a mild HI in one or both ears. The loss was sensorineural in 73% of the children (88% bilateral, 12% unilateral), and conductive in 27% (67% bilaterally, 33% unilaterally) because of ear malformations or a suspicion of middle ear anomalies. Clinical data and test performances were presented for these four types of mild HI. Altogether, standardized language assessment demonstrated no delays in receptive and expressive vocabulary ability development on average, although the acquisition of two-word phrases in infancy was in mean delayed. Nonverbal intelligence was within the normal range, and on average the children did not perform less well in central auditory processing than normal children. Provided that no additional handicaps were present, mild HI did not adversely affect speech/language development if the children were fitted with hearing aids after early identification of HI.
Outcome of Treatment regarding Articulation, Resonance and Voice in Flemish Adults with Unilateral and Bilateral Cleft Palate
Authors: van Lierde Kristiane M. , De Bodt Marc , Baetens Isabelle , Schrauwen Valentine , van Cauwenberge Paul
Published: April 2003

The purpose of this study was to evaluate the outcome regarding speech intelligibility, articulation, nasalance, nasality and voice in adult cleft palate patients. An additional objective of this study was to delineate the impact of a unilateral versus bilateral cleft lip and palate on speech outcome and to compare the nasalance and nasality patterns of cleft palate adults with data from non-cleft subjects. Objective (nasalance values obtained by the Nasometer, mirror-fogging test according to Glatzel and the determination of the dysphonia severity index, DSI) and subjective assessment techniques (perceptual evaluation of speech, nasality and voice, the Bzoch tests and the Gutzmann test) were used. All 14 subjects with a complete unilateral or bilateral cleft lip and palate consulted the same craniofacial team, followed an identical surgical protocol, completed the surgical cleft palate treatments and followed speech therapy. Most of the patients had a fairly satisfactory outcome with normal speech intelligibility, but three types of articulation errors seemed to predominate. More than one half of the subjects demonstrated hypernasality. In comparison with the non-cleft normative data, statistically higher nasalance values were obtained in the cleft group. The subjects had a DSI score that corresponds with a normal or slightly impaired voice quality. No significant differences regarding speech outcome were found between subjects with a unilateral or bilateral cleft lip and palate. The results provide important information for speech-language pathologists to evaluate and improve speech outcome in cleft palate patients.
Gene Therapy With Inducible Nitric Oxide Synthase Protects Against Myocardial Infarction via a Cyclooxygenase-2–Dependent Mechanism
Authors: Li Qianhong , Guo Yiru , Xuan Yu-Ting , Lowenstein Charles J. , Stevenson Susan C. , Prabhu Sumanth D. , Wu Wen-Jian , Zhu Yanqing , Bolli Roberto
Published: April 2003

Although the inducible isoform of NO synthase (iNOS) mediates late preconditioning (PC), it is unknown whether
iNOS
gene transfer can replicate the cardioprotective effects of late PC, and the role of this protein in myocardial ischemia is controversial. Thus, the cDNA for human
iNOS
was cloned behind the Rous sarcoma virus (RSV) promoter to create adenovirus (Ad) 5/iNOS lacking E1, E2a, and E3 regions. Intramyocardial injection of Ad5/iNOS in mice increased local iNOS protein expression and activity and markedly reduced infarct size. The infarct-sparing effects of Ad5/iNOS were at least as powerful as those of ischemic PC. The increased iNOS expression was associated with increased cyclooxygenase-2 (COX-2) protein expression and prostanoid levels. Pretreatment with the COX-2–selective inhibitor NS-398 completely abrogated the infarct-sparing actions of Ad5/iNOS, demonstrating that COX-2 is an obligatory downstream effector of iNOS-dependent cardioprotection. We conclude that gene transfer of iNOS (an enzyme commonly thought to be detrimental) affords powerful cardioprotection the magnitude of which is equivalent to that of late PC. This is the first report that upregulation of iNOS, in itself, is sufficient to reduce infarct size. The results provide proof-of-principle for gene therapy against ischemia/reperfusion injury, which increases local myocardial NO synthase levels without the need for continuous intravenous infusion of NO donors and without altering systemic hemodynamics. The data also reveal the existence of a close coupling between iNOS and COX-2, whereby induction of the former enzyme leads to secondary induction of the latter, which in turn mediates the cytoprotective effects of iNOS. We propose that iNOS and COX-2 form a stress-responsive functional module that mitigates ischemia/reperfusion injury.
Interstitial Flow as a Guide for Lymphangiogenesis
Authors: Boardman Kendrick C. , Swartz Melody A.
Published: April 2003

The lymphatic system is important in tissue fluid balance regulation, immune cell trafficking, edema, and cancer metastasis, yet very little is known about the sequence of events that initiate and coordinate lymphangiogenesis. Here, we characterize the process of lymphatic regeneration by uniquely correlating interstitial fluid flow and lymphatic endothelial cell migration with lymphatic function. A new model of skin regeneration using a collagen implant in a mouse tail has been developed, and it shows that (1) interstitial fluid channels form before lymphatic endothelial cell organization and (2) lymphatic cell migration, vascular endothelial growth factor-C expression, and lymphatic capillary network organization are initiated primarily in the direction of lymph flow. These data suggest that interstitial fluid channeling precedes and may even direct lymphangiogenesis (in contrast to blood angiogenesis, in which fluid flow proceeds only after the vessel develops); thus, a novel and robust model is introduced for correlating molecular events with functionality in lymphangiogenesis.
A Novel, Voltage-Dependent Nonselective Cation Current Activated by Insulin in Guinea Pig Isolated Ventricular Myocytes
Authors: Zhang Yin Hua , Hancox Jules C.
Published: April 2003

Insulin regulates cardiac metabolism and function by targeting metabolic proteins or voltage-gated ion channels. This study provides evidence for a novel, voltage-dependent, nonselective cation channel (NSCC) in the heart. Under voltage clamp at 37°C and with major known conductances blocked, insulin (1 nmol/L to 1 μmol/L) activated an outwardly rectifying current (
I
insulin
) in guinea pig ventricular myocytes.
I
insulin
could be carried by Cs
+
, K
+
, Li
+
, and Na
+
ions but not by NMDG
+
. It was inhibited by the NSCC blockers gadolinium and SKF96365 but not flufenamic acid.
I
insulin
was largely blocked by the insulin receptor tyrosine kinase inhibitor HNMPA-(AM)
3
and by the phospholipase C inhibitor U73122 but not by its inactive analogue U73433. Staurosporine, a potent blocker of protein kinase C, did not prevent the activation of
I
insulin
. Application of an analogue of diacylglycerol, 1-oleoyl-2-acetyl-sn-glycerol, mimicked the effect of insulin. This activated an outwardly rectifying NSCC that could be carried by Cs
+
, K
+
, Li
+
, or Na
+
and that was blocked by gadolinium but not by flufenamic acid or staurosporine. We conclude that the intracellular pathway leading to activation of this novel cardiac NSCC involves phospholipase C, is protein kinase C–independent, and may depend on direct channel activation by diacylglycerol.
Functional Roles of the Rho/Rho Kinase Pathway and Protein Kinase C in the Regulation of Cerebrovascular Constriction Mediated by Hemoglobin
Authors: Wickman Grant , Lan Christopher , Vollrath Bozena
Published: April 2003

Although there is evidence that the Rho/Rho kinase pathway and protein kinase C (PKC) are involved in the development of cerebral vasospasm, the mechanism by which subarachnoid hemorrhage (SAH) activates these pathways is unclear. A large body of evidence points to oxyhemoglobin (OxyHb) as a major causative component of blood clot responsible for vasospasm. Therefore, the present studies were conducted to explore whether the Rho/Rho kinase and PKC may be involved in a sustained vasoconstriction induced by OxyHb in cerebral arteries. OxyHb evoked sustained vasoconstriction in the endothelium-denuded rabbit basilar arteries, which was reversed by the selective inhibitors of Rho kinase, Y-27632, and HA-1077, with the IC
50
values of 0.26±0.02 and 0.74±0.1 μmol/L, respectively. In quiescent cerebrovascular smooth muscle (CVSM) cells, OxyHb induced Rho translocation, as assessed by immunoblotting, with a time course, which paralleled the contractile action of OxyHb. Rho translocation was also observed in intact arteries stimulated with OxyHb for 24 hours (219%) and 48 hours (160%). The increase in Rho translocation was fully inhibited by GGTI-297, an inhibitor of Rho prenylation. OxyHb also caused significant translocation of both PKCα and PKCε (
P
<0.01), which was maximal at the time corresponding to maximal tension developed in response to OxyHb. Ro-32-0432, an inhibitor of PKC, attenuated vasoconstriction mediated by OxyHb in basilar artery. These results show, for the first time, that OxyHb-mediated signaling in CVSM utilizes the Rho/Rho kinase and PKC-based mechanisms.