bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationships between insight and medication adherence in outpatients with schizophrenia and bipolar disorder: Prospective study
Authors: YEN CHENG‐FANG , CHEN CHENG‐SHENG , KO CHIH‐HUNG , YEH MING‐LI , YANG SHANG‐JU , YEN JU‐YU , HUANG CHI‐FENG , WU CHIA‐CHEN
Published: July 2005

Abstract  The aim of the present study was to explore the associations between insight and medication adherence at index interview and at 1‐year follow‐up interview in bipolar and schizophrenic outpatients. The Schedule for Assessment of Insight (SAI) and its expanded version (SAI‐E) were used to provide a baseline insight score for 65 bipolar subjects and 74 schizophrenic subjects considered to be in remission or to have minimal psychopathology. Medication adherence of subjects was assessed at index interview and at 1‐year follow‐up interview, and the association between insight and medication adherence was analyzed cross‐sectionally and prospectively. The results of the analysis reveal that in bipolar subjects, the index SAI scores for insight into treatment, mental‐health status and psychotic experiences, and total SAI‐E were positively correlated with medication adherence at both index and 1‐year follow‐up interviews. However, in schizophrenic subjects, insight into treatment and total SAI‐E correlated positively with medication adherence at index interview but not at 1‐year follow‐up interview. Medication adherence at index interview could predict medication adherence 1 year later in both bipolar and schizophrenic subjects. These results indicate that the predictive value of insight for medication adherence differs between bipolar and schizophrenic patients, and building insight is an important step for establishing medication adherence in bipolar patients.
Tripartite relationship among P300, clinical features and brain structure in neuroleptic‐naive schizophrenia
Authors: HOSHINO KEN‐YO , TAKEUCHI SATOSHI , JODO EIICHI , SUZUKI YOSHIAKI , KAYAMA YUKIHIKO , NIWA SHIN‐ICHI
Published: July 2005

Abstract  Auditory P300 abnormalities in schizophrenia patients have been repeatedly reported by many studies. However, reported relationships among P300 abnormalities, clinical features and other biological variables, such as abnormalities in structural brain imaging, are notably discrepant. This is partially due to the inclusion of patients who have had long‐term administration of neuroleptics and those from whom this treatment has been withdrawn. The present study measures event‐related potentials in 13 neuroleptic‐naive schizophrenia patients using an auditory oddball paradigm to clarify the relationships among P300 amplitude, clinical features and brain structure. All patients underwent computed tomography to estimate the area of the right and left frontal cortical sulci and Sylvian fissures. Clinical symptoms were assessed using the Positive And Negative Syndrome Scale. The high correlation coefficients were obtained between P300 amplitude and the anxiety/depression factor score (r =−0.77), the positive factor score (r =−0.58) and between P300 amplitude and the area ratios of the fronto‐temporal region (r =−0.66). These findings show that fronto‐temporal region and P300 amplitude are closely related to the earliest stage of illness even in neuroleptic‐naive patients.
Latency of auditory P300 correlates with self‐control as measured by the Sixteen Personality Factor Questionnaire
Authors: LEE HEON‐JEONG , KIM LEEN , HAN CHANG‐SU , KIM YONG‐KU , KIM SEUNG‐HYUN , LEE MIN‐SOO , JOE SOOK‐HAENG , JUNG IN‐KWA
Published: July 2005

Abstract  The reception, processing, and storage of information about experience define personality. The present study investigated the relationship between auditory event‐related potentials (AERP) and personality traits. The AERP were recorded using a standard auditory oddball paradigm, and personality was evaluated by Cattell's Sixteen Personality Factor Questionnaire (16PF) in 20 healthy young male subjects. The P300 latency was found to be significantly associated with rule consciousness (factor G in the 16PF), perfectionism (factor Q3), and self‐control (factor SC): it was negatively correlated with G score (r =−0.56, P = 0.01), Q3 score (r =−0.67, P = 0.001), and SC score (r =−0.65, P = 0.002). Moreover, the P300 amplitude and N100 amplitude were negatively correlated with reasoning (factor B; r =−0.46, P = 0.044; and r = −0.72, P = 0.002, respectively). These results indicate that the personality traits of self‐control, perfectionism, high superego, and reasoning are related to information processing in the brain.
Clinical application of single‐pulse transcranial magnetic stimulation for the treatment of depression
Authors: FUJITA KENICHI , KOGA YOSHIHIKO
Published: July 2005

Abstract  Transcranial magnetic stimulation (TMS) has been recently suggested for the treatment of patients with major depression. Based on the results of the authors’ pilot study showing a possible antidepressive effect of single‐pulse TMS, a clinical trial was conducted involving patients with major depression. For the present study single‐photon emission computed tomography (SPECT) was recorded for six of the target patients to study the effects of TMS on the local blood flow volume. Twenty‐three inpatients meeting the Diagnostic and Statistical Manual of Mental Disorders (4th edn; DSM‐IV) criteria for major depression were invited to participate in the study. Depressive symptoms were rated using the Hamilton Rating Scale for Depression (HAM‐D). Patients were given 10 stimuli over the frontal area of both sides for a total of 20 stimuli in a session. The subjects had daily TMS session for 5 days as an add‐on therapy. In addition, six patients had their quantitative 99mTc‐ethyl cysteinate dimer SPECT images measured before and after TMS treatment. Compared with the value 2 days prior to the start of TMS therapy (24.2 ± 4.9), the average HAM‐D scale dropped significantly to 15.3 ± 6.6 on the day after completion of such therapy. The results of SPECT showed that the regional cerebral blood flow (rCBF) of the bilateral frontal region had increased in four out of six patients when comparing before and after treatment. The present study shows that single‐pulse TMS, which is widely used as a neurological test method, possesses a wide range of antidepressive effects without inducing adverse reactions. The results suggest that although repetitive TMS is steadily becoming the mainstay technique today, single‐pulse TMS also possesses sufficient antidepressive effects.
Spatial working memory deficit correlates with disorganization symptoms and social functioning in schizophrenia
Authors: TAKAHASHI HIDETOSHI , IWASE MASAO , NAKAHACHI TAKAYUKI , SEKIYAMA RYUJI , TABUSHI KAORU , KAJIMOTO OSAMI , SHIMIZU AKIRA , TAKEDA MASATOSHI
Published: July 2005

Abstract  Both spatial working memory deficit and disorganization symptoms have been considered significant components of schizophrenic impairment involved with the dorsolateral prefrontal cortex. The purpose of the present study was to investigate the relationships among spatial working memory, psychiatric symptoms including disorganization symptoms, and social functioning in schizophrenia. Fifty clinically stable patients with schizophrenia and 34 healthy controls participated in the study. Patients were rated with the Brief Psychiatric Rating Scale and the Rehabilitation Evaluation Hall and Baker. The Advanced Trail Making Test was used to evaluate spatial working memory. Patients demonstrated significantly reduced spatial working memory compared to that of healthy controls. Spatial working memory in patients correlated significantly with social functioning such as self‐care skills, community skills and speech disturbance, and with disorganization symptoms. Disorganization symptoms also correlated with these aspects of social functioning. In conclusion it is suggested that both spatial working memory deficit and disorganization symptoms, which are impairments involved with the dorsolateral prefrontal cortex dysfunction, can serve as effective predictors of social functioning.
Sensory gating impairment in development of post‐concussive symptoms in mild head injury
Authors: KUMAR SANJAY , RAO SHOBINI L. , NAIR RAGESH G. , PILLAI SHIBU , CHANDRAMOULI BANGALORE A. , SUBBAKRISHNA DODBALAPUR K.
Published: July 2005

Abstract  Post‐concussive symptoms reported by mild head injury (MHI) patients have been inadequately understood. Post‐concussive symptoms reported by patients with MHI have so far been explained in terms of impairment in neurocognitive functions or deficits in modulation of flow of information. There are no studies that have looked into sensory gating impairment in MHI and its relation to post‐concussive symptoms. The purpose of the present paper was to investigate the role of sensory gating impairment in post‐concussive symptoms in mild head injury patients. Thirty MHI patients were evaluated for their neuropsychological functions, sensory gating deficits, and post‐concussive symptoms. Neuropsychological functions were in the domain of attention, executive functions, and learning and memory. Sensory gating was assessed by Structured Interview for Assessing Perceptual Anomalies and post‐concussive symptoms were assessed using the Neurobehavioral Rating Scale. Multiple regression method was used to identify predictors for post‐concussive symptoms. Post‐concussive symptoms were predicted by sensory gating deficits when sensory gating deficit was one of the predictors along with neuropsychological functions. Post‐concussive symptoms were predicted by scores of Digit Vigilance and Digit Symbol Substitution Test, when predictors were restricted to neuropsychological functions. Sensory gating deficits were correlated with performance on Digit Symbol Substitution test. Post‐concussive symptoms reported by MHI patients are the result of poor modulation of incoming sensory information.
Autism‐Spectrum Quotient–Japanese version and its short forms for screening normally intelligent persons with pervasive developmental disorders
Authors: KURITA HIROSHI , KOYAMA TOMONORI , OSADA HIROKAZU
Published: July 2005

Abstract  A Japanese version of the Autism Spectrum Quotient (AQ), AQ‐J was administered to 25 normally intelligent high‐functioning pervasive developmental disorder (HPDD) patients (mean age, 24.2 years; 24 male, one female) and 215 controls (mean age, 30.4 years; 86 male, 129 female) randomly selected from the general population. The AQ‐J had satisfactory internal consistency reliability (Cronbach's α > 0.70 in the two groups), test–retest reliability, and discriminant validity [i.e. the AQ‐J score was significantly higher in the HPDD (mean, 29.6) than controls (mean, 22.2)]. At a cut‐off of 26, the AQ‐J had satisfactory sensitivity, specificity, and negative predictive value, but it had low positive predictive value (0.24) possibly due to the facts that the 25 mild HPDD patients scored lower and the controls scored higher on the AQ‐J than British counterparts on the AQ. The AQ‐J‐21 (consisting of 21 items significantly associated with HPDD diagnosis) and the AQ‐J‐10 (consisting of 10 of the 21 items with an effect size >0.17) had higher, although not satisfactory, positive predictive values of 0.35 and 0.46 at cut‐offs of 12 and 7, respectively, than the AQ‐J. The AQ‐J and two short forms are useful not to predict but to rule out mild HPDD, the most difficult part of HPDD to be distinguished from non‐PDD conditions, in persons scoring under the cut‐offs and to consider professionals’ examination of HPDD in persons scoring over them, because their negative predictive values were satisfactory.
Mitochondrial DNA sequence analysis of patients with ‘atypical psychosis’
Authors: KAZUNO AN‐A , MUNAKATA KAE , MORI KANAKO , TANAKA MASASHI , NANKO SHINICHIRO , KUNUGI HIROSHI , UMEKAGE TADASHI , TOCHIGI MAMORU , KOHDA KAZUHISA , SASAKI TSUKASA , AKIYAMA TSUYOSHI , WASHIZUKA SHINSUKE , KATO NOBUMASA , KATO TADAFUMI
Published: July 2005

Abstract  Although classical psychopathological studies have shown the presence of an independent diagnostic category, ‘atypical psychosis’, most psychotic patients are currently classified into two major diagnostic categories, schizophrenia and bipolar disorder, by the Diagnostic and Statistical Manual of Mental Disorders (4th edn; DSM‐IV) criteria. ‘Atypical psychosis’ is characterized by acute confusion without systematic delusion, emotional instability, and psychomotor excitement or stupor. Such clinical features resemble those seen in organic mental syndrome, and differential diagnosis is often difficult. Because patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke‐like episodes (MELAS) sometimes show organic mental disorder, ‘atypical psychosis’ may be caused by mutations of mitochondrial DNA (mtDNA) in some patients. In the present study whole mtDNA was sequenced for seven patients with various psychotic disorders, who could be categorized as ‘atypical psychosis’. None of them had known mtDNA mutations pathogenic for mitochondrial encephalopathy. Two of seven patients belonged to a subhaplogroup F1b1a with low frequency. These results did not support the hypothesis that clinical presentation of some patients with ‘atypical psychosis’ is a reflection of subclinical mitochondrial encephalopathy. However, the subhaplogroup F1b1a may be a good target for association study of ‘atypical psychosis’.
Impact of AIDS on Family Composition, Welfare, and Investment: Evidence from Uganda*
Authors: Deininger Klaus , Crommelynck Anja , Kempaka Gloria
Published: July 2005

Although availability of quantitative information on the extent of HIV/AIDS in Africa is improving, the socio‐economic implications of the epidemic remain poorly understood. This paper explores this issue for Uganda focusing on households who received foster children between 1992 and 2000, a phenomenon that affected more than 15% of households. The authors find that addition of a foster child resulted in significant reductions of per capita consumption, income, and household investment which were more pronounced for the poor. Initial disadvantages in foster children's access to education for this group were overcome in the course of UPE implementation, while new inequalities have emerged in access to health services. Foster children's ability to access services will thus be affected by the broader policy environment as well as programs more specifically targeted at this group.
City CPI Convergence in Mexico
Authors: Sonora Robert J.
Published: July 2005

This paper tests the purchasing power parity hypothesis within a single developing country currency area: Mexico. This work stems from research in comparing price movements across countries and a growing literature on price dynamics within a single currency area. The author uses city Consumer Price Index data for 34 cities in Mexico over the period 1982–2000. He followed the standard procedure of testing for I(1) processes in relative city prices, or city real exchange rates, using univariate and panel unit root tests. The main results of the paper are: First, Mexican city relative prices are stationary—the data rejects the hypothesis that city real exchange rates contain a random walk, but only using panel unit root techniques. Finally, regional demand and supply homogeneity implies stronger evidence for price parity within regions, while there is considerable evidence of regional price convergence, regional homogeneity does not guarantee faster convergence.
The Government's Foreign Debt in the Argentine Crisis
Authors: Kitano Shigeto
Published: July 2005

Though the government had adopted a currency board regime since 1991, the Argentine economy suffered a currency crisis in 2002. It is shown that currency crises can arise, even under currency board systems in which the central bank has enough international reserves to respond to arbitrary withdrawals by individuals. The model implies that a government's rapid accumulation of foreign debt should be included as a major predictor of currency crises.
Start‐up Capital, Microenterprises and Technical Efficiency in Mexico
Authors: Hernández‐Trillo Fausto , Pagán José A. , Paxton Julia
Published: July 2005

Access to adequate start‐up capital has been identified as an important deterrent to microenteprise development and growth. Using firm level data from Mexico's National Survey of Microenterprises, we estimate a stochastic frontier production function with inefficiency effects related to the main sources of start‐up capital. Microenterprises utilizing bank loans, carryover business capital, moneylenders and credit from clients and suppliers are more technically efficient than those relying on family, friends and on own financial sources. Bank loans led to the highest degree of technical efficiency, indicating a well‐functioning screening process despite information asymmetries. Banks tend to offer the largest average loan size with the longest terms which are significant factors in allowing microentrepreneurs to overcome financing constraints.
Parthenolide is the Component of Tanacetum Parthenium that Inhibits Nitroglycerin-Induced Fos Activation: Studies in an Animal Model of Migraine
Authors: Tassorelli C , Greco R , Morazzoni P , Riva A , Sandrini G , Nappi G
Published: July 2005

Tanacetum parthenium (TP) is a member of the Asteracee family long used empirically as a herbal remedy for migraine. So far, however, clinical trials have failed to prove consistently the effectiveness of TP extracts in preventing migraine attacks, probably as a consequence of the uncertainty as regards the active principle. In this study, the biological effects of different TP extracts and purified parthenolide were tested in an animal model of migraine based on the quantification of neuronal activation induced by nitroglycerin. The extract enriched in parthenolide significantly reduced nitroglycerin-induced Fos expression in the nucleus trigeminalis caudalis. Purified parthenolide inhibited nitroglycerin-induced neuronal activation in additional brain nuclei and, significantly, the activity of nuclear factor-κB. These findings strongly suggest that parthenolide is the component responsible for the biological activity of TP as regards its antimigraine effect and provide important information for future controlled clinical trials.
Coupling between Visual Evoked Cerebral Blood Flow Velocity Responses and Visual Evoked Potentials in Migraneurs
Authors: Zaletel M , Strucl M , Bajrovi FF , Pogacnik T
Published: July 2005

Neurovascular coupling may be altered in migraneurs. Therefore, visual evoked potentials (VEP) and visually evoked cerebral blood flow velocity responses (VEFR) were simultaneously recorded in 30 healthy controls and 30 migraneurs interictally using a checkerboard stimulus with visual contrasts of 1%, 10% and 100%. The VEFR were measured in the posterior cerebral artery using transcranial Doppler and VEP were recorded from occipital leads. We found an increase in VEFR and VEP in both the healthy and migraneur groups ( P < 0.01). VEFR were significantly higher in migraneurs ( P < 0.01), while VEP did not significantly differ between the groups ( P > 0.05). Regression showed a significant association between VEP and VEFR in both healthy controls ( r = 0.66, P < 0.01) and migraneurs ( r = 0.63, P < 0.01). The regression coefficient of migraneurs (b = 0.88, SE = 0.08) was significantly higher than that of healthy controls (b = 0.55, SE = 0.07) ( P = 0.04). We conclude that neurovascular coupling is increased in migraneurs interictally.
History of Migraine and the Risk of Spontaneous Cervical Artery Dissection
Authors: Pezzini A , Granella F , Grassi M , Bertolino C , Del Zotto E , Immovilli P , Bazzoli E , Padovani A , Zanferrari C
Published: July 2005

The pathophysiology of spontaneous cervical artery dissection (sCAD) is largely unknown. An association with migraine has been suggested, but not definitively proven. In the setting of a hospital-based prospective case-control study we assessed personal and family history of migraine in 72 patients with sCAD, 72 patients with cerebral infarct unrelated to a CAD (non-CAD) and 72 control subjects. Personal history of migraine was significantly associated to sCAD compared to non-CAD (59.7% vs. 30.6%; OR 3.14; 95% CI 1.41-7.01) and controls (18.1%; OR 7.41; 95% CI 3.11-17.64). As opposed to migraine with aura, migraine without aura was significantly more frequent among sCAD than among non-CAD (56.9% vs. 25.0%; OR 3.91; 95% CI 1.71-8.90) and controls (12.5%; OR 9.84; 95% CI 3.85-25.16). Similar results were observed when the frequencies of family history of migraine were compared. These findings are consistent with the hypothesis that migraine may represent a predisposing condition for sCAD.
Insulin Sensitivity is Impaired in Patients with Migraine
Authors: Rainero I , Limone P , Ferrero M , Valfrè W , Pelissetto C , Rubino E , Gentile S , Lo Giudice R , Pinessi L
Published: July 2005

Several studies have shown the presence of a comorbidity between migraine and vascular diseases, like hypertension and stroke. The mechanisms of this comorbidity are unknown. Impaired insulin sensitivity has recently emerged as a risk factor for hypertension and stroke. We evaluated insulin sensitivity in 30 young, nonobese, nondiabetic, normotensive migraine patients and in 15 healthy controls. During the OGTT, glucose plasma concentrations were significantly higher in migraineurs than in controls. Insulin sensitivity, as measured by ISI-stumvoll and OGIS-180 indexes, was significantly altered in migraine. Our data show that insulin sensitivity is impaired in migraine and suggest a role for insulin resistance in the comorbidity between migraine and vascular diseases.
Migraine — New Perspectives from Chaos Theory
Authors: Kernick D
Published: July 2005

Converging from a number of disciplines, non-linear systems theory and in particular chaos theory offer new descriptive and prescriptive insights into physiological systems. This paper briefly reviews an approach to physiological systems from these perspectives and outlines how these concepts can be applied to the study of migraine. It suggests a wide range of potential applications including new approaches to classification, treatment and pathophysiological mechanisms. A hypothesis is developed that suggests that dysfunctional consequences can result from a mismatch between the complexity of the environment and the system that is seeking to regulate it and that the migraine phenomenon is caused by an incongruity between the complexity of mid brain sensory integration and cortical control networks. Chaos theory offers a new approach to the study of migraine that complements existing frameworks but may more accurately reflect underlying physiological mechanisms.
Trigeminal Cephalgias and Facial Pain Syndromes Associated with Autonomic Dysfunction
Authors: Al-Din AS , Mir R , Davey R , Lily O , Ghaus N
Published: July 2005

Trigeminal autonomic cephalgias (TACs) include a spectrum of primary headache syndromes associated with cranial autonomic dysfunction. Other types of headache and facial pain syndromes can be associated with marked localized facial or ear autonomic changes. We report on a group of patients suffering from episodic migraine with cranial autonomic features, patients with different presentations of the ‘red ear syndrome’ (RES), cluster headache with prominent lower facial involvement and crossover cases. In our experience crossover between TACs and migraine, RES and cluster headache is not uncommon. We propose that all these conditions belong to the same group and a unifying causative mechanism is proposed.
Disability is the Major Determinant of the Severity of Depressive Symptoms in Primary Headaches but not in Low Back Pain
Authors: Gesztelyi G , Bereczki D
Published: July 2005

Pain syndromes are often associated with depression. In a prospective study we analysed if determinants of depression differ among patients with different primary headaches and between headaches and non-headache pain. During a 2-year period between 1 February 2002 and 31 January 2004, 635 subjects (migraine n = 231; tension-type headache n = 176; cluster headache n = 11; patients with low back pain n = 103; and healthy subjects n = 114) seen by two neurologists filled in a questionnaire on pain characteristics, the MIDAS questionnaire and the Beck Depression Inventory. A multivariate general regression model was used to identify independent predictors of the severity of depressive symptoms. Pain was most frequent in chronic tension-type headache and most intense in the cluster subgroup (P < 0.001, Kruskal-Wallis ANOVA). In univariate tests gender, age, pain frequency, pain intensity and disability were all significantly associated with the severity of depressive symptoms. In the multivariate model disability was the most important independent determinant of the severity of depressive symptoms in the pooled headache group as well as in the migraine and tension-type headache subgroups. In contrast to patients with headache, pain frequency and pain intensity were the significant independent predictors of the severity of depressive symptoms in patients with low back pain. In a multivariate model, after controlling for other factors, determinants of the severity of depressive symptoms were different in headache and non-headache pain subjects, suggesting a different mechanism for developing depression in primary headaches and in other pain syndromes.
Gene Polymorphism Association Studies in Dialysis: The Nutrition‐Inflammation Axis
Authors: Jaber Bertrand L. , Balakrishnan Vaidyanathapuram S. , Stenvinkel Peter , Pecoits‐Filho Roberto , Lindholm Bengt ,   for the DialGene Consortium
Published: July 2005

Although traditional risk factors for cardiovascular disease are common in dialysis patients, they alone cannot explain the unacceptably high prevalence of vascular disease in this patient group. Much recent interest has therefore focused on the role of various nontraditional cardiovascular risk factors, such as inflammation, wasting, obesity, vascular calcification, and oxidative stress. In addition, genetic factors such as single nucleotide polymorphisms (SNPs) may significantly influence the immune response, the levels of inflammatory markers and body composition, as well as the prevalence of vascular calcification in this patient group. While genetic variations in the tumor necrosis factor (TNF)‐α−308 and interleukin (IL)‐10 −1082 SNPs seem to be consistently associated with adverse clinical outcome in end‐stage renal disease (ESRD) patients, the results regarding genetic variations in the IL‐6 gene have been conflicting. To elucidate the respective role of DNA polymorphisms in the IL‐6 and C‐reactive protein (CRP) genes, as well as genes that encode vascular calcification inhibitors (such as fetuin‐A, matrix Gla protein, and osteoprotegerin), sufficiently powered studies are needed in which both the protein product and the specific phenotype are determined. In addition, polymorphisms in genes related to body composition may be excellent candidates for analysis in the ESRD population, since nutritional parameters are strongly associated with adverse events in these patients. It seems conceivable that in the future, prognostic or predictive multigene DNA assays (which allow a simultaneous and rapid assessment of multiple genetic variants) will provide nephrologists with a more precise approach for the identification of “high‐risk” ESRD patients and the development of accurate individualized treatment strategies.
Sumoylation modulates transcriptional activity of MITF in a promoter‐specific manner
Authors: Murakami Hideki , Arnheiter Heinz
Published: July 2005

The microphthalmia transcription factor MITF plays important roles in several cell lineages including retinal and neural crest‐derived pigment cells. Previous reports have shown that besides its regulation at the transcriptional level, MITF is also regulated post‐translationally by phosphorylation and ubiquitination which affect the protein's activity and stability. Here we demonstrate that in addition, MITF is modified in melanoma cells by small ubiquitin‐like modifier (SUMO). In vitro assays further show that sumoylation occurs at two lysine residues, K182 and K316, and depends on SUMO E1 activating enzyme (SAE I/SAE II) and E2 conjugating enzyme (Ubc9). Interestingly, MITF with double lysine 182/316 to arginine mutations, although displaying normal DNA binding, stability and nuclear localization, shows a substantial increase in the transcriptional stimulation of promoters containing multiple but not single MITF binding sites. MITF containing the double lysine‐to‐arginine substitution also shows enhanced cooperation with Sox10 on the Dct promoter. We conclude that SUMO modification of MITF regulates the protein's transcriptional activity especially with respect to synergistic activation. The results suggest that sumoylation plays a significant role among the multiple mechanisms that regulate MITF during development and in adulthood.
Novel expression patterns of Pax3/Pax7 in early trunk neural crest and its melanocyte and non‐melanocyte lineages in amniote embryos
Authors: Lacosta Ana Ma , Muniesa Pedro , Ruberte Jesús , Sarasa Manuel , Domínguez Luis
Published: July 2005

Neural crest cells are considered a key vertebrate feature that is studied intensively because of their relevance to development and evolution. Here we report the expression of Pax7 in the dorsal non‐neural ectoderm and in the trunk neural crest of the early chick embryo. Pax7 is expressed in the trunk neural crest migrating along the ventral and dorsolateral routes. Pax7 is first downregulated in the neural crest‐derived neuronal precursors, secondly in the glial, and finally in the melanocyte precursors. Conserved developmental expression in the melanocyte lineage of both Pax3 and Pax7 was evidenced in chick and quail, but only Pax3 in mouse and rat.
Dopamine melanin‐loaded PC12 cells: a model for studies on pigmented neurons
Authors: Östergren Anna , Svensson Anne‐Lie , Lindquist Nils Gunnar , Brittebo Eva B.
Published: July 2005

The most conspicuous feature in idiopathic parkinsonism is the degeneration of pigmented neurons in the substantia nigra. A major problem for the study of the significance of neuromelanin for the development of parkinsonism is that common experimental animals lack neuromelanin in substantia nigra. The aim of this study was to develop an in vitro model that could be used to study the role of neuromelanin in chemically induced toxicity in dopaminergic cells. Cultured neuron‐like PC12 cells were exposed to synthetic dopamine melanin (0–1.0 mg/ml) for 48 h, resulting in uptake of dopamine melanin particles into the cells. The intracellular distribution of dopamine melanin granules was similar to that found in neuromelanin‐containing neurons. Dopamine melanin, up to 0.5 mg/ml, had negligible effects on ultrastructure, induction of the endoplasmic reticulum‐stress protein glucose regulating protein 78, activation of caspase‐3 and cell viability. The decreased cell viability in response to the cytotoxic peptide amyloid‐β25−35 was similar in melanin‐loaded cells and in control cells without melanin. The results of the studies suggest that melanin‐loaded PC12 cells can serve as an in vitro model for studies on the role of neuromelanin for the toxicity of chemicals, in particular neurotoxicants with melanin affinity, in pigmented neurons.
The fibroblast growth factor‐2 is not essential for melanoma formation in a transgenic mouse model
Authors: Ackermann Julien , Beermann Friedrich
Published: July 2005

Fibroblast growth factor 2 (FGF2) has been assigned a role in melanocyte proliferation and in development of human cutaneous melanoma. We have used a transgenic mouse melanoma model in combination with mice lacking mouse FGF2 to analyse the possible implication of FGF2 in melanomagenesis. Tyr::N‐rasQ61K transgenic mice which are deficient for FGF2 and the tumor suppressors p16INK4a and p19ARF are hyperpigmented and develop cutaneous metastasizing melanoma, with no difference to mice wildtype for FGF2. We conclude from our data, that FGF2 is not essential for melanoma progression and metastasis.
Melanocyte‐specific, cytotoxic T cell responses in vitiligo: the effective variant of melanoma immunity?
Authors: Garbelli Silvia , Mantovani Stefania , Palermo Belinda , Giachino Claudia
Published: July 2005

Vitiligo is a relatively common progressive depigmentary condition that is believed to be due to the autoimmune‐mediated loss of epidermal melanocytes. An interesting aspect of vitiligo is its relation to melanoma: cytotoxic T lymphocytes directed to self‐antigens shared by normal melanocytes and melanoma cells are found in both conditions and might prove important in melanocyte destruction, yet the resulting immune reactions are completely different. From this standpoint, the selective destruction of pigment cells that occurs in cases of vitiligo is the therapeutic goal sought in melanoma research. In the present article, we will address these issues by reviewing current literature on the subject as well as by posing some speculations.
Changes in responses of UVB irradiated skin of brownish guinea pigs with aging
Authors: Tobiishi Megumi , Haratake Akinori , Kaminaga Hiroko , Nakahara Michio , Komiya Aya , Koishikawa Hisa , Uchiwa Hideyo , Kawa Yoko , Mizoguchi Masako
Published: July 2005

It is known that skin often shows irregular pigmentation during aging, which is frequently associated with hyperpigmentation. Many studies have utilized brownish A1 guinea pigs to investigate the pathogenesis of ultraviolet B (UVB)‐induced skin pigmentation, however, responses associated with aging following UVB irradiation have not been elucidated. To characterize those responses, dorsal skin of A1 guinea pigs from 14‐weeks to 5‐yr old were investigated. The minimal erythema dose was found to increase with aging. Further, in pigmentation induced by UVB radiation, skin brightness (ΔL*‐value) decreased equally in both the 14‐week old (young) group and in the 3‐yr old (old) group of guinea pigs. The ΔL*‐value recovered in the young group from 21 d after UVB irradiation, whereas no such recovery was seen in the old group. In addition, the amount of melanin and the number of melanocytes returned near pre‐irradiation levels in the young group, while they remained high in the old group. Our results therefore demonstrate for the first time that skin responses following UVB irradiation change with aging in A1 guinea pigs.
Identification of critical active‐site residues in angiotensin‐converting enzyme‐2 (ACE2) by site‐directed mutagenesis
Authors: Guy Jodie L. , Jackson Richard M. , Jensen Hanne A. , Hooper Nigel M. , Turner Anthony J.
Published: July 2005

Angiotensin‐converting enzyme‐2 (ACE2) may play an important role in cardiorenal disease and it has also been implicated as a cellular receptor for the severe acute respiratory syndrome (SARS) virus. The ACE2 active‐site model and its crystal structure, which was solved recently, highlighted key differences between ACE2 and its counterpart angiotensin‐converting enzyme (ACE), which are responsible for their differing substrate and inhibitor sensitivities. In this study the role of ACE2 active‐site residues was explored by site‐directed mutagenesis. Arg273 was found to be critical for substrate binding such that its replacement causes enzyme activity to be abolished. Although both His505 and His345 are involved in catalysis, it is His345 and not His505 that acts as the hydrogen bond donor/acceptor in the formation of the tetrahedral peptide intermediate. The difference in chloride sensitivity between ACE2 and ACE was investigated, and the absence of a second chloride‐binding site (CL2) in ACE2 confirmed. Thus ACE2 has only one chloride‐binding site (CL1) whereas ACE has two sites. This is the first study to address the differences that exist between ACE2 and ACE at the molecular level. The results can be applied to future studies aimed at unravelling the role of ACE2, relative to ACE, in vivo.
Death inducer obliterator protein 1 in the context of DNA regulation
Authors: Rojas Ana M. , Sanchez‐Pulido Luis , Fütterer Agnes , van Wely Karel H. M. , Martinez‐A Carlos , Valencia Alfonso
Published: July 2005

Death inducer obliterator protein 1 [DIDO1; also termed DIO‐1 and death‐associated transcription factor 1 (DATF‐1)] is encoded by a gene thus far described only in higher vertebrates. Current gene ontology descriptions for this gene assign its function to an apoptosis‐related process. The protein presents distinct splice variants and is distributed ubiquitously. Exhaustive sequence analyses of all DIDO variants identify distant homologues in yeast and other organisms. These homologues have a role in DNA regulation and chromatin stability, and form part of higher complexes linked to active chromatin. Further domain composition analyses performed in the context of related homologues suggest that DIDO‐induced apoptosis is a secondary effect. Gene‐targeted mice show alterations that include lagging chromosomes, and overexpression of the gene generates asymmetric nuclear divisions. Here we describe the analysis of these eukaryote‐restricted proteins and propose a novel, DNA regulatory function for the DIDO protein in mammals.
Integrating signals between cAMP and the RAS/RAF/MEK/ERK signalling pathways
Authors: Dumaz Nicolas , Marais Richard
Published: July 2005

One of the hallmarks of cAMP is its ability to inhibit proliferation in many cell types, but stimulate proliferation in others. Clearly cAMP has cell type specific effects and the outcome on proliferation is largely attributed to crosstalk from cAMP to the RAS/RAF/mitogen‐activated protein kinase (MAPK) and extracellular signal‐regulated kinase (ERK) kinase (MEK)/ERK pathway. We review the crosstalk between these two ancient and conserved pathways, describing the molecular mechanisms underlying the interactions between these pathways and discussing their possible biological importance.
Origin and properties of cytoplasmic and mitochondrial isoforms of taurocyamine kinase
Authors: Uda Kouji , Saishoji Naoto , Ichinari Shuichi , Ellington W. Ross , Suzuki Tomohiko
Published: July 2005

Taurocyamine kinase (TK) is a member of the highly conserved family of phosphagen kinases that includes creatine kinase (CK) and arginine kinase. TK is found only in certain marine annelids. In this study we used PCR to amplify two cDNAs coding for TKs from the polychaete Arenicola brasiliensis, cloned these cDNAs into the pMAL plasmid and expressed the TKs as fusion proteins with the maltose‐binding protein. These are the first TK cDNA and deduced amino acid sequences to be reported. One of the two cDNA‐derived amino acid sequences of TKs shows a high amino acid identity to lombricine kinase, another phosphagen kinase unique to annelids, and appears to be a cytoplasmic isoform. The other sequence appears to be a mitochondrial isoform; it has a long N‐terminal extension that was judged to be a mitochondrial targeting peptide by several on‐line programs and shows a higher similarity in amino acid sequence to mitochondrial creatine kinases from both vertebrates and invertebrates. The recombinant cytoplasmic TK showed activity for the substrates taurocyamine and lombricine (9% of that of taurocyamine). However, the mitochondrial TK showed activity for taurocyamine, lombricine (30% of that of taurocyamine) and glycocyamine (7% of that of taurocyamine). Neither TK catalyzed the phosphorylation of creatine. Comparison of the deduced amino acid sequences of mitochondrial CK and TK indicated that several key residues required for CK activity are lacking in the mitochondrial TK sequence. Homology models for both cytoplasmic and mitochondrial TK, constructed using CK templates, provided some insight into the structural correlation of differences in substrate specificity between the two TKs. A phylogenetic analysis using amino acid sequences from a broad spectrum of phosphagen kinases showed that annelid‐specific phosphagen kinases (lombricine kinase, glycocyamine kinase and cytoplasmic and mitochondrial TKs) are grouped in one cluster, and form a sister‐group with CK sequences from vertebrate and invertebrate groups. It appears that the annelid‐specific phosphagen kinases, including cytoplasmic and mitochondrial TKs, evolved from a CK‐like ancestor(s) early in the divergence of the protostome metazoans. Furthermore, our results suggest that the cytoplasmic and mitochondrial isoforms of TK evolved independently.
Netropsin interactions in the minor groove of d(GGCCAATTGG) studied by a combination of resolution enhancement and ab initio calculations
Authors: Van Hecke Kristof , Nam Pham Cam , Nguyen Minh Tho , Van Meervelt Luc
Published: July 2005

The structure of the complex between the minor groove binder netropsin and d(GGCCAATTGG) was determined via single‐crystal X‐ray techniques. The structure was refined to completion using refmac5.1.24, resulting in a residual R‐factor of 20.0% (including 68 water molecules). Using crystal engineering and cryocooling techniques, the resolution could be enhanced to 1.75 Å, resulting in an unambiguous determination of the drug conformation and orientation. As previously noticed, bifurcated hydrogen bonds are formed between the amide nitrogen atoms of the drug and the N3 and O2 atoms of A and T base pairs, respectively, clearly cataloging the structure to class I. As the bulky NH2 group on guanine was believed to prevent binding of the drug in the minor groove, the detailed nature of several of the amidinium and guanidinium end contacts were further investigated by ab initio quantum chemical methods.
6‐Phosphofructo‐2‐kinase and fructose‐2,6‐bisphosphatase in Trypanosomatidae
Authors: Chevalier Nathalie , Bertrand Luc , Rider Mark H. , Opperdoes Fred R. , Rigden Daniel J. , Michels Paul A. M.
Published: July 2005

Fructose 2,6‐bisphosphate is a potent allosteric activator of trypanosomatid pyruvate kinase and thus represents an important regulator of energy metabolism in these protozoan parasites. A 6‐phosphofructo‐2‐kinase, responsible for the synthesis of this regulator, was highly purified from the bloodstream form of Trypanosoma brucei and kinetically characterized. By searching trypanosomatid genome databases, four genes encoding proteins homologous to the mammalian bifunctional enzyme 6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatase (PFK‐2/FBPase‐2) were found for both T. brucei and the related parasite Leishmania major and four pairs in Trypanosoma cruzi. These genes were predicted to each encode a protein in which, at most, only a single domain would be active. Two of the T. brucei proteins showed most conservation in the PFK‐2 domain, although one of them was predicted to be inactive due to substitution of residues responsible for ligating the catalytically essential divalent metal cation; the two other proteins were most conserved in the FBPase‐2 domain. The two PFK‐2‐like proteins were expressed in Escherichia coli. Indeed, the first displayed PFK‐2 activity with similar kinetic properties to that of the enzyme purified from T. brucei, whereas no activity was found for the second. Interestingly, several of the predicted trypanosomatid PFK‐2/FBPase‐2 proteins have long N‐terminal extensions. The N‐terminal domains of the two polypeptides with most similarity to mammalian PFK‐2s contain a series of tandem repeat ankyrin motifs. In other proteins such motifs are known to mediate protein–protein interactions. Phylogenetic analysis suggests that the four different PFK‐2/FBPase‐2 isoenzymes found in Trypanosoma and Leishmania evolved from a single ancestral bifunctional enzyme within the trypanosomatid lineage. A possible explanation for the evolution of multiple monofunctional enzymes and for the presence of the ankyrin‐motif repeats in the PFK‐2 isoenzymes is presented.
Inhibition of urokinase receptor gene expression and cell invasion by anti‐uPAR DNAzymes in osteosarcoma cells
Authors: de Bock Charles E. , Lin Zhen , Itoh Takashi , Morris David , Murrell George , Wang Yao
Published: July 2005

The urokinase‐type plasminogen activator (uPA) receptor (uPAR) has been implicated in signal transduction and biological processes including cancer metastasis, angiogenesis, cell migration, and wound healing. It is a specific cell surface receptor for its ligand uPA, which catalyzes the formation of plasmin from plasminogen, thereby activating the proteolytic cascade that contributes to the breakdown of extracellular matrix, a key step in cancer metastasis. We have synthesized three different DNA enzymes (Dz372, Dz483 and Dz720) targeting uPAR mRNA at three separate purine (A or G)–pyrimidine (U or C) junctions. Two of these DNAzymes, Dz483 and Dz720, cleaved uPAR transcript in vitro with high efficacy and specificity at a molar ratio (uPAR to Dz) as low as 1 : 0.2. When analyzed over 2 h with a 200‐fold molar excess of DNAzymes to uPAR transcript, Dz720 and Dz483 were able to decrease uPAR transcript in vitro by ≈ 93% and ≈ 84%, respectively. They also showed an ability to cleave uPAR mRNA in the human osteosarcoma cell line Saos‐2 after transfection. The DNAzyme Dz720 decreased uPAR mRNA within 4 h of transfection, and inhibited uPAR protein concentrations by 55% in Saos‐2 cells. The decrease in uPAR mRNA and protein concentrations caused by Dz720 significantly suppressed Saos‐2 cell invasion as assessed by an in vitro Matrigel assay. The use of DNAzyme methodology adds a new potential clinical agent for decreasing uPAR mRNA expression and inhibiting cancer invasion and metastasis.
Methylcitrate synthase from Aspergillus fumigatus
Authors: Maerker Claudia , Rohde Manfred , Brakhage Axel A. , Brock Matthias
Published: July 2005

Methylcitrate synthase is a key enzyme of the methylcitrate cycle and required for fungal propionate degradation. Propionate not only serves as a carbon source, but also acts as a food preservative (E280–283) and possesses a negative effect on polyketide synthesis. To investigate propionate metabolism from the opportunistic human pathogenic fungus Aspergillus fumigatus, methylcitrate synthase was purified to homogeneity and characterized. The purified enzyme displayed both, citrate and methylcitrate synthase activity and showed similar characteristics to the corresponding enzyme from Aspergillus nidulans. The coding region of the A. fumigatus enzyme was identified and a deletion strain was constructed for phenotypic analysis. The deletion resulted in an inability to grow on propionate as the sole carbon source. A strong reduction of growth rate and spore colour formation on media containing both, glucose and propionate was observed, which was coincident with an accumulation of propionyl‐CoA. Similarly, the use of valine, isoleucine and methionine as nitrogen sources, which yield propionyl‐CoA upon degradation, inhibited growth and polyketide production. These effects are due to a direct inhibition of the pyruvate dehydrogenase complex and blockage of polyketide synthesis by propionyl‐CoA. The surface of conidia was studied by electron scanning microscopy and revealed a correlation between spore colour and ornamentation of the conidial surface. In addition, a methylcitrate synthase deletion led to an attenuation of virulence, when tested in an insect infection model and attenuation was even more pronounced, when whitish conidia from glucose/propionate medium were applied. Therefore, an impact of methylcitrate synthase in the infection process is discussed.