bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of precore and core promoter mutations on hepatic histology in patients with chronic hepatitis B
Authors: YUAN H.‐J. , YUEN M.‐F. , KA‐HO WONG D. , SUM S.‐M. , SABLON E. , OI‐LIN NG I. , LAI C.‐L.
Published: August 2005

Background:  The details of liver histology of patients with precore and core promoter mutations are still not clear.

Aim:  To determine the role of precore and core promoter mutations in liver histology in Chinese patients with chronic hepatitis B.

Patients and methods:  Intrahepatic hepatitis B virus DNA (by COBAS Amplicor hepatitis B virus Monitor test) and precore and core promoter mutations (by a line probe assay) were measured in 54 chronic hepatitis B patients. Expression of hepatitis B core antigen, hepatitis B e antigen and hepatitis B surface antigen was determined by immunohistological staining. Histological activity index was scored according to Knodell's criteria.

Results:  Compared with patients without core promoter mutations, patients with core promoter mutations had more severe intrahepatic inflammation and fibrosis, and more cytoplasmic expression of hepatitis B core antigen (P = 0.028). No such differences were found in patients with and without precore mutations. Logistic regression showed that core promoter mutations were independently associated with cytoplasmic expression of hepatitis B core antigen (P = 0.026). Intrahepatic hepatitis B virus DNA levels correlated with serum hepatitis B virus DNA levels (r = 0.71, P < 0.001) and the percentage of hepatitis B core antigen‐positive hepatocytes (r = 0.37, P = 0.047), but had no correlation with serum alanine aminotransferase levels nor the degree of inflammation and fibrosis.

Conclusions:  Patients with core promoter mutations had more severe inflammation and fibrosis, and more frequent cytoplasmic expression of hepatitis B core antigen. This suggested that core promoter mutations might cause more serious liver disease.
Is coeliac disease screening in risk groups justified? A fourteen‐year follow‐up with special focus on compliance and quality of life
Authors: VILJAMAA M. , COLLIN P. , HUHTALA H. , SIEVÄNEN H. , MÄKI M. , KAUKINEN K.
Published: August 2005

Background:  The benefits of serologic screening for coeliac disease in asymptomatic individuals are debatable.

Aim:  To investigate dietary compliance, quality of life and bone mineral density after long‐term treatment in coeliac disease patients found by screening in risk groups.

Methods:  The study comprised 53 consecutive screen‐detected coeliac patients diagnosed 14 years (median) ago. Dietary compliance was assessed by interview, 4‐day food record and serology. Quality of life was evaluated by the Psychological General Well‐Being and SF‐36 questionnaires, gastrointestinal symptoms by the Gastrointestinal Symptom Rating Scale and bone mineral density by dual‐energy x‐ray absorptiometry. Comparisons were made to 44 symptom‐detected‐treated coeliac patients, 110 non‐coeliac subjects and the general population.

Results:  A total of 96% of screen‐detected and 93% of symptom‐detected coeliac patients adhered to a strict or fairly strict gluten‐free diet. In screen‐detected patients, quality of life and gastrointestinal symptoms were similar to those in symptom‐detected patients or non‐coeliac controls and bone mineral density was similar to that in the general population.

Conclusions:  Long‐term dietary compliance in screen‐detected patients was good. Quality of life and bone mineral density were comparable with those in non‐coeliac subjects and the general population. Active screening in coeliac disease risk groups seems to be reasonable rather than harmful.
Is a long‐term ranitidine‐based triple therapy against Helicobacter pylori only a heritage of the past? A prospective, randomized clinicopharmacological study
Authors: PELLEGRINI M. , URSO R. , GIORGI G. , BAYELI P. F. , MARZOCCA G. , CERRETANI D.
Published: August 2005

Background:  Acid suppression plus two antibiotics is currently considered the gold standard anti‐Helicobacter pylori treatment, but the effective role of gastric antisecretory drugs is still poorly understood.

Aims:  To compare a 14‐day ranitidine‐based triple regimen against Helicobacter pylori with one based on omeprazole, and to study the influence of antisecretory drugs on metronidazole pharmacokinetics in human plasma.

Methods:  A total of 150 dyspeptic H. pylori‐infected patients were randomized for ranitidine 300 mg b.d. (RCM group) or omeprazole 20 mg b.d. (OCM group) 14‐day triple therapy, with clarithromycin 500 mg b.d. and metronidazole 500 mg b.d. On the eighth day of therapy, metronidazole pharmacokinetics was studied in plasma by high‐performance liquid chromatography. The pharmacokinetic parameters (terminal half‐life, area under the curve, peak‐plasma level, peak time) of metronidazole were computed using standard non‐compartmental methods. H. pylori status was monitored before and 4 weeks after the end of therapy by histology, serology and rapid urease test.

Results:  On an intention‐to‐treat basis, eradication rates were 91 and 76% for the RCM and OCM groups respectively (P < 0.02). Significantly different pharmacokinetic parameters of metronidazole were found between the groups: peak‐plasma level (P < 0.01) and area under the curve (P < 0.02).

Conclusion:  Our results show that the RCM regimen was more effective than that based on OCM and that the antisecretory drugs affected metronidazole availability, increasing the efficacy of ranitidine‐based regimens.
Clinical and genetic studies in Spanish patients with Usher syndrome type II: description of new mutations and evidence for a lack of genotype–phenotype correlation
Authors: Bernal S , Medà C , Solans T , Ayuso C , Garcia‐Sandoval B , Valverde D , Del Rio E , Baiget M
Published: August 2005

Patients with Usher syndrome type II (USH2) show moderate‐to‐severe hearing loss (HL), retinitis pigmentosa and normal vestibular function. The progression of HL remains controversial. To evaluate whether a phenotype–genotype correlation exists regarding the issue of progression of HL, only USH2 patients with a defined genotype were selected. Ophthalmologic, vestibular and audiometric examination along with a mutation analysis of the USH2A gene (exons 1–21) was performed in twenty‐eight Spanish USH2 patients. Ten different pathogenic mutations and 17 sequence variants not associated with the disease were found. Six of the 10 mutations are novel. Disease alleles were identified in 13 of the 28 families tested. Eight of these 13 families had a mutation found in both alleles. In the other five families, only one mutation was identified. The phenotypic data provide evidence for the existence of phenotypic differences between patients with the same genotype. These differences were observed at both the interfamilial and intrafamilial levels.
The prevalence, severity and seasonal variations of asthma, rhinitis and eczema in Taiwanese schoolchildren
Authors: Kao Chun‐Chieh , Huang Jing‐Long , Ou Liang‐Shiou , See Lai‐Chu
Published: August 2005

The prevalence of asthma is increasing in Taiwan but data remain limited. The aim of this study was to determine the prevalence, severity, demographic and seasonal variations of asthma, rhinitis, and eczema in Taiwan. Using a one‐stage stratified cluster random sampling, first grade (aged 6–8) and eighth grade (aged 13–15) students from Taoyuan, northern Taiwan, were invited to participate in this survey. The results showed a total of 6190 students, 3079 aged 6–8 and 3111 aged 13–15, completed this survey. In general, children aged 6–8 had significantly higher prevalence rates of diagnosed asthma, rhinitis, and eczema than children aged 13–15 (12.2%, 29.8%, and 10.2% vs. 9.6%, 18.3%, and 4.7%, respectively). Similarly, children aged 6–8 had significantly higher proportions of allergic symptoms, except for exercise‐induced wheezing (5.8% vs. 17.8%, p < 0.0001). Among those with allergic disorders, children aged 6–8 presented a greater severity of wheezing attacks in the last 12 months. As regards gender, boys aged 6–8 had a significantly higher proportion of asthma or rhinitis symptoms than girls aged 6–8 but not in children aged 13–15. In children aged 6–8, asthma and rhinitis peaked in winter, especially in December. However, children aged 13–15 had two peaks (winter and summer) for asthma or rhinitis.
Early rapid weight gain and current overweight in relation to asthma in adolescents born with very low birth weight
Authors: Mai Xiao‐Mei , Gäddlin Per‐Olof , Nilsson Lennart , Leijon Ingemar
Published: August 2005

Early catch‐up growth and subsequent overweight are suggested to be associated with later cardiovascular diseases and later type II diabetes. However, the impact of early catch‐up growth and childhood overweight on the development of asthma has been less studied, particularly in children born with very low birth weight (VLBW). A birth cohort of 74 VLBW children (birth weight ≤ 1500 g) was followed from birth and investigated on asthma at 12 yr of age. Early rapid weight gain was in one way defined as an increase of weight ≥1 standard deviation score (SDS) at 6 months of corrected postnatal age. Current overweight was defined by body mass index (BMI) exceeding 21.2 and 21.7 kg/m2, respectively, for boys and girls at 12 yr of age. Current asthma was diagnosed by a pediatrician, according to asthma ever in combination with a positive response to hypertonic saline bronchial provocation test and/or wheeze at physical examination at 12 yr old. Being overweight at 12 yr of age was associated with an increased risk for current asthma in the VLBW children [crude odds ratio (OR): 5.5, 95% confidence interval (CI): 1.3–22.2]. After adjustment for early weight gain and neonatal risk, the OR of overweight increased nearly three times (adjusted OR: 15.3, 95% CI: 2.5–90.6). Early rapid weight gain seemed to be inversely associated with current asthma (adjusted OR: 0.49 for an increase of weight equal to 1 SDS, 95% CI: 0.23–1.02, p = 0.06). In addition, early rapid weight gain was inversely associated with the magnitude of bronchial responsiveness at 12 yr (coefficient −1.15, p < 0.01). There was a strong and positive association between overweight and asthma at 12 yr of age in the VLBW children. This strong association had been reduced by early rapid weight gain, possibly via the reduction of bronchial responsiveness.
Urine leukotriene E4 and eosinophil cationic protein in nasopharyngeal aspiration from young wheezy children
Authors: Oh Jae‐Won , Shin Su‐A. , Lee Ha‐Baik
Published: August 2005

Respiratory syncytial virus (RSV) infection is a risk factor for the development of asthma. It is very hard to distinguish bronchiolitis with respiratory virus infection from allergic asthma at first wheezing attack in early childhood. To distinguish wheezing children with RSV bronchiolitis from asthmatic children, we measured leukotriene E4(LTE4) in urine and ECP in nasopharyngeal aspiration (NPA) at first day of admission with wheezing attack. Thirty‐two non‐atopic children younger than the age of 3 yr with RSV induced bronchiolitis, 35 atopic asthmatic children with/without respiratory viral infection, and 23 children who exhibited no evidence of atopy, asthma, or virus infections as controls were selected in this study. We measured urinary LTE4 and ECP level in NPA from subjects. Urinary LTE4 concentrations in children with asthma were significantly higher than urinary LTE4 in bronchiolitis and in controls (240.8 ± 129.8 vs. 162.8 ± 73.9 vs. 85.1 ± 31.6 pg/ml). Children with RSV infection demonstrated higher urinary LTE4 levels compared to children without RSV infection among asthmatic children. ECP in NPA was significantly correlated with urinary LTE4 (r = 0.57, p < 0.01) in children entered this study who had detectable levels for both LTE4 and ECP. In summary, Urinary LTE4 concentrations may be suggested to useful mediators for differential diagnosis of wheezy diseases in early childhood. RSV infection also is associated with synergizing LT biosynthesis and this study demonstrated ECP in NPA was significantly correlated with urinary LTE4 and may suggest that cysteinyl leukotriene initiate the production of ECP in early childhood, which could contribute to the development of wheeze.
Chronic urticaria and associated coeliac disease in children: A case–control study
Authors: Caminiti L. , Passalacqua G. , Magazzù G. , Comisi F. , Vita D. , Barberio G. , Sferlazzas C. , Pajno G. B.
Published: August 2005

Celiac disease (CD) and chronic urticaria (CU) are both sustained by immune mechanisms, but there are so far few data on their clinical association. We performed a case–control study to determine the occurrence of CD in urticaria and matched control children, and to assess the clinical relevance of this association. Children and adolescents were diagnosed to have severe chronic idiopathic urticaria in the presence of hives for more than 6 wk poorly or not responsive to oral antihistamines. Other known causes of urticaria had to be excluded. A matched control group without urticaria was enrolled. In both groups, the presence of CD was searched by assaying antitransglutaminase and antiedomysial antibodies, and confirmed with endoscopic intestinal biopsy. Results. CD was diagnosed and confirmed in 4/79 (5.0%) of children with CU and in 17/2545 (0.67%) of the controls (p = 0.0003). In the four children with urticaria and CD the gluten free diet (GFD) lead to complete remission of urticaria within 5–10 wk, whereas the disappearance of serological markers occurred in longer times (5–9 months). Conclusions. The presence of CD in children with CU was significantly more frequent than in controls. GFD resulted in urticaria remission. CD may be regarded in such subjects as a cause of CU.
Retrograde cerebral perfusion of oxygenated, compacted red blood cells attenuates brain damage after hypothermia circulation arrest of rat
Authors: Su D. S. , Wang X. R , Zheng Y. J. , Zhao Y. H. , Zhang T. J.
Published: August 2005

Background:  It was proved that higher haematocrit (Hct) might improve the function of brain after hypothermia circulation arrest (HCA). In the present study we established a new rat HCA model and investigated whether retrograde cerebral perfusion of oxygenated, compacted red blood cells (RBC) could attenuate brain injury after HCA.

Methods:  A new rat HCA model was developed and rats were randomly distributed into three groups: HCA group, HCA combined with retrograde cerebral perfusion of oxygenated, compacted red blood cell group (HCArcp group), and sham operation group (sham op. group). Animals both in the HCA group and in the HCArcp group underwent HCA 90 min at 18°C. Brain damage after HCA was evaluated with light microscopy and electron microscopy. Immunohistochemistry and RT‐PCR techniques were used to measured the different expressions of the C‐Fos, Bcl‐2, Bax mRNA and protein among the groups. Additionally we measured the wet/dry ratio of the brain in order to evaluate the oedema degree after HCA.

Results:  The new HCA model of rat we developed was comparable to the clinical setting not only in terms of the intubation, anaesthesia method and materials employed but also in terms of the priming volume in relation to body weight. The number of injured neurones in the hippocampus CA1 and parietal cortex, but not in the thalamus of the HCA group, was significantly greater than that of the HCArcp group (P < 0.05). The mean score of mitochondrion of the hippocampus CA1 in the HCA group was significantly higher than in the HCArcp group (P < 0.05). The expression of C‐Fos, Bax mRNA and protein in the hippocampus CA1 and/or parietal cortex area was higher in the HCA group than in the HCArcp group (P < 0.05). Expression of the mRNA and protein of Bcl‐2 was higher in the HCArcp group than in the HCA group (P < 0.05). The degree of oedema after HCA between the HCA group and HCArcp group had no significant difference (P > 0.05).

Conclusions:  We established a new rat model of HCA comparable to the clinical setting. Retrograde cerebral perfusion of oxygenated, compacted RBC is a simple, effective, and safe method to protect the brain during HCA. Adjusting the gene expression in relation to apoptosis might contribute to the neuroprotective effects of a retrograde cerebral infusion of oxygenated, compacted RBC.
Glycine – an important neurotransmitter and cytoprotective agent
Authors: Gundersen R. Y. , Vaagenes P. , Breivik T. , Fonnum F. , Opstad P. K.
Published: August 2005

Background:  Glycine, the simplest of the amino acids, is an essential component of important biological molecules, a key substance in many metabolic reactions, the major inhibitory neurotransmitter in the spinal cord and brain stem, and an anti‐inflammatory, cytoprotective, and immune modulating substance.

Material and methods:  Based on available literature, we discuss some of the important biological properties of glycine. In addition, we describe some clinical disorders where glycine plays a central role, either as an essential structural element, or through its metabolism or receptors.

Results:  The past few years have witnessed a broadening of glycine research. The traditional prime interest in aspects related to its role as an inhibitory neurotransmitter in the central nervous system has been expanded to equally emphasize other organs and tissues. With the demonstration of glycine‐gated chloride channels on neurons in the central nervous system, on most leukocytes, and subsequently on other cells as well, a unifying mechanism of action accounting for many of the widespread effects of glycine has been found.

Conclusions:  Glycine is a simple, easily available, and inexpensive substance with few and innocuous side‐effects. The diversity of biological activities is well documented in the literature. Despite this, glycine has only gained a modest place in clinical medicine.
Tracheal intubation using a new CCD camera‐equipped device: a report of two cases with a difficult intubation
Authors: Sehata H. , Kohase H. , Takahashi M. , Miyamoto T. , Umino M.
Published: August 2005

In two patients, one with Klippel–Feil syndrome and one with fibrous dysplasia of the maxilla, no part of the larynx could be visualized by direct laryngoscopy. In both cases, the use of an intubation device equipped with a charge‐coupled device camera, the endotracheal intubation device (EID), allowed smooth tracheal intubation.
Loss of connexin36 increases retinal cell vulnerability to secondary cell loss
Authors: Striedinger Katharine , Petrasch‐Parwez Elisabeth , Zoidl Georg , Napirei Markus , Meier Carola , Eysel Ulf T. , Dermietzel Rolf
Published: August 2005

Accruing evidence indicates that gap junctions are involved in neuronal survival after brain injury. The present study was aimed at clarifying the contribution of the neuronal gap‐junction protein connexin36 (Cx36) to secondary cell loss after injury in the mouse retina. A focal retinal lesion was induced by infrared laser photocoagulation. Remarkably, this model allowed spatial and temporal definition of the lesion with high reproducibility. Moreover, Cx36 is abundantly expressed in the retina and plays an essential role in the visual transmission process. Taking advantage of these features, cell death was assessed using TUNEL assay and light and electron microscopy, and the extent of Cx36 expression was studied by immunohistochemistry, Western blot, in situ hybridization and real‐time RT‐PCR. Secondary cell loss was most prominent between 24 and 48 h after lesioning. This peak was accompanied by an increase in Cx36 expression. When cultured explanted retinas were subjected to gap‐junction blockers a significant increase in the extent of secondary cell loss after laser photocoagulation became evident. Using the same experimental paradigm we compared the incidence of cell death in wild‐type and Cx36–/– mice. A significant increase in total number of TUNEL‐positive cells occurred in the Cx36–/– mice compared to controls. From these data we conclude that Cx36 contributes to the survival and resistance against damage of retinal cells and thus constitutes a protective factor after traumatic injury of the retina.
The unilateral 6‐OHDA rat model of Parkinson's disease revisited: an electromyographic and behavioural analysis
Authors: Metz Gerlinde A. , Tse Arthur , Ballermann Mark , Smith Lori K. , Fouad Karim
Published: August 2005

The characteristic locomotor disturbances of Parkinson's disease (PD) include shuffling gait, short steps and low walking velocity. In this study we investigated features of walking and turning in a rat model of PD caused by unilateral infusion of the neurotoxin 6‐hydroxydopamine (6‐OHDA). We assessed gait and electromyographic (EMG) patterns of the ankle flexor tibialis anterior and the knee extensor vastus lateralis of the hindlimb, and triceps brachii of the forelimb, during overgound locomotion, spontaneous rotation (turning) and apomorphine‐induced rotation. When compared with control rats, rats with unilateral dopamine depletion displayed a shuffling gait and short stride lengths. This locomotor pattern was accompanied by prolonged ankle flexor activity on the ipsilateral side, and prolonged activity of knee extensors on the contralateral side. The dopamine depletion also led to enhanced contraversive rotations after an apomorphine challenge. The EMG recordings during drug‐induced rotation suggested that hindlimb stepping was a reflective response to an active drive produced by forelimbs. The EMG recordings of the contralateral side during rotation were marked by reduced ankle flexor activity and increased knee extensor activity. Furthermore, EMG recordings indicated that dopamine‐agonists induce rotational bias by altering the coupling between ipsi‐ and contralateral hindlimbs, and between forelimbs. In straight walking, however, the gait of 6‐OHDA lesion animals reflected normal, coupled hindlimb stepping as controlled by spinal pattern generators. The data suggest that the unilateral rat model of PD resembles key features of human parkinsonian gait, and that asymmetric descending input may underlie the observed changes in gait patterns.
Transient maternal hypothyroxinemia at onset of corticogenesis alters tangential migration of medial ganglionic eminence‐derived neurons
Authors: Cuevas Estela , Ausó Eva , Telefont Martin , De Escobar Gabriella Morreale , Sotelo Constantino , Berbel Pere
Published: August 2005

Correct positioning of cortical neurons during development depends on the radial migration of the projection neurons and on the coordinated tangential and radial migrations of the subcortically generated interneurons. As previously shown, a transient and moderate maternal deficiency in thyroxin during early corticogenesis alters the radial migration of projection neurons. To determine if a similar effect might also affect tangential migration of medial ganglionic eminence (MGE)‐derived neurons at the origin of cortical interneurons, explants of MGE from green fluorescent protein (GFP)‐transgenic embryos were implanted into flat cortical mounts from wild‐type embryos. The distances covered and the preferential migration (medially) of GFP‐MGE neurons from embryos of hypothyroxinemic dams are not affected in their tangential migration into wild‐type control cortices. In contrast, when GFP‐MGE neurons from embryos of control or hypothyroxinemic dams migrate within cortices from embryos of hypothyroxinemic dams, the GFP‐MGE‐derived neurons lose their preferential direction of migration, although they still migrate for long distances throughout the cortex. Our results show that maternal hypothyroxinemia alters the tangential migration of GFP‐MGE‐derived neurons in the neocortex of the progeny and suggest that this alteration is not derived from the migratory neurons themselves but through undefined short‐ and long‐range cues responsible for the guidance of their migration.
Transcriptional involvement of protein kinase C‐alpha isozyme in amphetamine‐mediated appetite suppression
Authors: Hsieh Yih‐Shou , Yang Shun‐Fa , Chiou Hui‐Ling , Kuo Dong‐Yih
Published: August 2005

Amphetamine (AMPH) is known as an anorectic agent. The anorectic action of AMPH has been attributed to its inhibitory action on hypothalamic neuropeptide Y (NPY), an appetite stimulant in the brain. The molecular mechanisms behind this anorectic action of AMPH are still unclear. This study investigated the possible role of protein kinase C (PKC) isotypes in this anorectic action. Results revealed that most PKC isotypes (α, βII, γ, δ, η, λ and ζ), except βI and ε isotypes, were stimulated during a repeated treatment of AMPH. Among these stimulated isotypes, three isotypes (α, δ, λ) were activated and expressed in a similar manner, while the other isotypes were expressed differently and specifically. To determine if PKCα was involved in the anorectic response of AMPH, the infusions of antisense oligonucleotide into the brain were performed 1 h before daily AMPH treatment in freely moving rats, and the results showed that PKCα knock down could block the anorectic response and restore NPY mRNA levels in AMPH‐treated rats. These results suggest that PKC isotypes‐ (at least the α isotype), related modification of NPY gene expression in hypothalamus might play an essential role in the central regulation of AMPH‐mediated feeding suppression.
Individual differences in male rat ejaculatory behaviour: searching for models to study ejaculation disorders
Authors: Pattij Tommy , De Jong Trynke R. , Uitterdijk Andre , Waldinger Marcel D. , Veening Jan G. , Cools Alexander R. , Van Der Graaf Piet Hein , Olivier Berend
Published: August 2005

In addition to investigating sexual function in rats that display normal ejaculatory behaviour, studying rats that are either ‘hyposexual’ or ‘hypersexual’ may provide important insights into the aetiology of ejaculatory dysfunctions in men, such as premature and retarded ejaculation. To this end, rats were matched into groups of ‘sluggish’, ‘normal’ and ‘rapid’ ejaculators based on their ejaculation frequencies displayed in a series of weekly sexual behaviour tests. Selecting rats on this parameter revealed large and stable differences in other parameters of sexual behaviour as well, including ejaculation latency and mount frequency but not intromission frequency and mount latency, putative indices of sexual motivation. Neuroanatomically, Fos immunoreactivity as a measure of neuronal activation was increased in rapid ejaculators compared with sluggish ejaculators in ejaculation‐related brain areas, presumably associated with the differences in ejaculatory behaviour. Although the total number of oxytocin neurones within subregions of the hypothalamus did not differ between groups, in the supraoptic nucleus of the hypothalamus more oxytocin neurones were activated in rapid ejaculators compared with the other groups. Apart from the differences observed in ejaculatory behaviour, groups did not differ with respect to their locomotor activity and approach‐avoidance behaviour as measured in the elevated plus‐maze. Finally, apomorphine‐induced stereotypy was similar in sluggish and rapid ejaculators, suggesting no large differences in dopamine susceptibility. Altogether, the present results suggest stable differences in male rat ejaculatory behaviour. Further exploring the neurobiological mechanisms underlying these differences may be a promising approach to gain insights into the aetiology of sexual dysfunctions such as premature, retarded or an‐ejaculation.
Dietary n‐3 polyunsaturated fatty acid depletion activates caspases and decreases NMDA receptors in the brain of a transgenic mouse model of Alzheimer's disease
Authors: Calon Frédéric , Lim Giselle P. , Morihara Takashi , Yang Fusheng , Ubeda Oliver , Salem Norman , Frautschy Sally A. , Cole Greg M.
Published: August 2005

Epidemiological data indicate that low n‐3 polyunsaturated fatty acids (PFA) intake is a readily manipulated dietary risk factor for Alzheimer's disease (AD). Studies in animals confirm the deleterious effect of n‐3 PFA depletion on cognition and on dendritic scaffold proteins. Here, we show that in transgenic mice overexpressing the human AD gene APPswe (Tg2576), safflower oil‐induced n‐3 PFA deficiency caused a decrease in N‐methyl‐d‐aspartate (NMDA) receptor subunits, NR2A and NR2B, in the cortex and hippocampus with no loss of the presynaptic markers, synaptophysin and synaptosomal‐associated protein 25 (SNAP‐25). n‐3 PFA depletion also decreased the NR1 subunit in the hippocampus and Ca(2+)/calmodulin‐dependent protein kinase (CaMKII) in the cortex of Tg2576 mice. These effects of dietary n‐3 PFA deficiency were greatly amplified in Tg2576 mice compared to nontransgenic mice. Loss of the NR2B receptor subunit was not explained by changes in mRNA expression, but correlated with p85α phosphatidylinositol 3‐kinase levels. Most interestingly, n‐3 PFA deficiency dramatically increased levels of protein fragments, corresponding to caspase/calpain‐cleaved fodrin and gelsolin in Tg2576 mice. This effect was minimal in nontransgenic mice suggesting that n‐3 PFA depletion potentiated caspase activation in the Tg2576 mouse model of AD. Dietary supplementation with docosahexaenoic acid (DHA; 22 : 6n‐3) partly protected from NMDA receptor subunit loss and accumulation of fodrin and gelsolin fragments but fully prevented CaMKII decrease. The marked effect of dietary n‐3 PFA on NMDA receptors and caspase/calpain activation in the cortex of an animal model of AD provide new insights into how dietary essential fatty acids may influence cognition and AD risk.
Differential effects of calcineurin inhibition and protein kinase A activation on nucleus accumbens amphetamine‐produced conditioned place preference in rats
Authors: Gerdjikov Todor V. , Beninger Richard J.
Published: August 2005

The nucleus accumbens (NAc) plays a critical role in amphetamine‐produced conditioned place preference (CPP). In previous studies inhibition or activation of cyclic adenosine monophosphate‐dependent protein kinase (PKA) blocked NAc amphetamine‐produced CPP. PKA activation unrelated to ongoing DA transmission may disrupt reward‐related learning. Calcineurin (CN) down‐regulates downstream PKA targets. Unlike PKA activation, CN inhibition may preserve and enhance reward‐related learning. The PKA signalling cascade is negatively regulated by calcineurin (CN). We tested the hypothesis that post‐training CN inhibition in NAc will enhance NAc amphetamine‐produced CPP and that PKA activation will block CPP. Eight but not four or two 30‐min conditioning sessions were sufficient to establish significant CPP. Immediate post‐training, NAc injection of the calcineurin inhibitor FK506 (5.0 but not 1.0 µg in 0.5 µL per side) led to a significant amphetamine CPP in rats receiving four but not two training sessions; the 5.0‐µg dose had no effect on rats trained with eight sessions. Injections of the PKA activator Sp‐cAMPS (2.5 or 10.0 µg in 0.5 µL per side) failed to affect CPP following two or four training sessions and blocked CPP produced by a standard 8‐day conditioning schedule. Results suggest that CN acts as a negative regulator in the establishment of NAc amphetamine‐produced CPP, a form of reward‐related learning.
Requirement of NMDA receptor reactivation for consolidation and storage of nondeclarative taste memory revealed by inducible NR1 knockout
Authors: Cui Zhenzhong , Lindl Kathryn A. , Mei Bing , Zhang Shuqing , Tsien Joe Z.
Published: August 2005

We employed an inducible, reversible and region‐specific gene knockout technique to investigate the requirements for cortical NMDA receptors (NMDAR) during the various stages (acquisition, consolidation and storage, and retrieval) of nondeclarative, hippocampal‐independent memory in mice using a conditioned taste aversion memory paradigm. Here we show that temporary knockout of the cortical NMDAR during either the learning or postlearning consolidation stage, but not during the retrieval stage, causes severe performance deficits in the 1‐month taste memory retention tests. More importantly, we found that the consolidation and storage of the long‐term nondeclarative taste memories requires cortical NMDAR reactivation. Thus, the dynamic engagement of the NMDAR during the postlearning stage leads us to postulate that NMDAR reactivation‐mediated synaptic re‐entry reinforcement is crucial for overcoming the destabilizing effects intrinsic to synaptic protein turnover and for achieving consolidation and storage of nondeclarative memories in the brain.
Inhibitory glutamate receptors in spider peripheral mechanosensory neurons
Authors: Panek Izabela , Torkkeli Päivi H.
Published: August 2005

Most mechanosensory neurons are inhibited by GABAergic efferent neurons. This inhibition is often presynaptic and mediated by ionotropic GABA receptors at the axon terminals. GABA receptor activation opens Cl– channels, leading to membrane depolarization and an increase in membrane conductance. In many invertebrate preparations, efferent neurons that innervate mechanosensory afferents contain glutamate in addition to GABA, suggesting that the sensory neurons are also modulated by glutamate. However, the effects of glutamate on these neurons are not well understood. Peripheral parts of the spider (Cupiennius salei) mechanosensory neurons are surrounded by efferent fibers immunoreactive to antibodies against GABA and glutamate. GABA and its analogue muscimol were shown to effectively inhibit spider mechanosensory neurons innervating lyriform slit sensilla VS‐3 that detects cuticular strains in the leg. Here, we show that glutamate also inhibits the VS‐3 neurons, but its effects are different from those of GABA or muscimol, suggesting that it acts on a different group of receptors. GABA and muscimol always depolarized these neurons and the inhibitory effect was strongly correlated with the amount of depolarization. In contrast, glutamate inhibited the VS‐3 neurons even when it did not depolarize them. In addition, while glutamate inhibited both the axonal action potentials elicited with electrical stimulation and dendritic action potentials produced by mechanical stimulation, muscimol only inhibited the axonal action potentials. Therefore, the inhibitory glutamate receptors in the VS‐3 neurons are distinct from and differently distributed than the GABA receptors, providing a subtle control of the neurons' sensitivity in varying behavioural situations.
Methylazoxymethanol acetate does not fully block cell genesis in the young and aged dentate gyrus
Authors: Dupret David , Montaron Marie‐Françoise , Drapeau Elodie , Aurousseau Catherine , Le Moal Michel , Piazza Pier‐Vincenzo , Abrous Djoher Nora
Published: August 2005

During adulthood, new neurons are continuously added to the mammalian dentate gyrus (DG). An increasing number of studies have correlated changes in rates of dentate neurogenesis with memory abilities. One study based on subchronic treatment with the toxin methylazoxymethanol acetate (MAM) has provided causal evidence that neurogenesis is involved in hippocampal‐dependent trace conditioning. In contrast, spatial learning is not impaired following MAM treatment. We hypothesized that this was due to the small residual number of new cells produced following MAM treatment. In the present experiment, we attempted to achieve a higher level of reduction of adult‐generated cells following MAM treatment in young and aged rats. We found only a partial reduction of adult‐generated cells in the DG. More importantly, independently of the age of the animals, MAM treatment at a dose necessary to reduce neurogenesis altered the overall health of the animals. In conclusion, the behavioural results obtained following subchronic treatment with high doses of MAM in adulthood must be interpreted with extreme caution.
Viewing the body prepares the brain for touch: effects of TMS over somatosensory cortex
Authors: Fiorio Mirta , Haggard Patrick
Published: August 2005

Viewing the body can improve tactile perception. We investigated whether this could be due to a remodeling of somatosensory cortical areas during vision of the body. Single‐pulse transcranial magnetic stimulation (TMS) was delivered over the primary and secondary somatosensory areas of subjects who showed clear visual‐tactile enhancement while they performed a tactile grating discrimination task. Before the tactile stimulus, subjects viewed either their right index finger through a semisilvered mirror or an object reflected by the mirror and positioned to appear in the same location as the finger. In a first experiment we observed that TMS over primary somatosensory cortex significantly reduced subjects' accuracy whilst viewing the hand. No such reduction was found when subjects viewed a neutral object. In a second experiment, we disrupted the activity of primary and secondary somatosensory areas in different sessions. When stimulating the primary somatosensory cortex, a reduction in accuracy was again found while viewing the hand, but not a neutral object. TMS over secondary somatosensory cortex had no effect in any condition. Our results show that vision of the body may act at an early stage in stimulus elaboration and perception, allowing an anticipatory tuning of the neural circuits in primary somatosensory cortex that underlie tactile acuity.
Clinical outcomes of androgen deprivation as the sole therapy for localized and locally advanced prostate cancer
Authors: Janoff Daniel M. , Peterson Chad , Mongoue‐Tchokote Solange , Peters Laura , Beer Tomasz M. , Wersinger Emily M. , Mori Motomi , Garzotto Mark
Published: August 2005

Most papers in this section are written about various aspects of prostate cancer, and cover a wide cross‐section of subjects relating to this important topic. Interestingly there has been increasing interest by clinical oncologists in this area, and I am delighted to publish their views in this Journal. We as urologists now routinely have multidisciplinary team meetings, and find the insightful comments of the non‐urologists very helpful in the management not only of patients with prostate cancer, but also of all types of urological malignancy.

OBJECTIVE

To characterize the clinical outcomes of androgen deprivation therapy (ADT) as the sole therapy for localized prostate cancer, and to determine independent predictors of disease progression, as recent studies indicate an increasing use of ADT.

PATIENTS AND METHODS

The records of all patients with cT1–4NXM0 adenocarcinoma of the prostate treated with ADT as the primary initial therapy at the Portland Veterans Affairs Medical Center between 1993 and 2000 were reviewed. Age, race, Charlson Health Index, family history, prostate‐specific antigen (PSA) level, PSA density, digital rectal examination (DRE) findings, Gleason score, and percentage of positive biopsy cores at diagnosis were recorded for 81 patients. Patients had a median (sd, range) age of 73 (5.6, 58–84) years, a PSA level of 14.3 (34.6, 1.4–252) ng/mL and tumours were classified as Gleason score ≤ 5 in 9% of patients, 6 in 31%, 7 in 31% and 8–10 in 30%. Outcomes extracted were PSA progression, PSA nadir, bone fractures, local progression, distant progression and overall survival.

RESULTS

With a median (range) follow‐up of 54 (6–115) months, the incidence of local progression, distant progression, bone fractures, PSA progression, and death were 10%, 7%, 25%, 21% and 41% respectively. The percentage of positive biopsy cores ≥ 83%, age < 70 years, Gleason score ≥ 7, abnormal DRE, and PSA nadir ≥ 0.2 ng/mL were significantly associated with PSA progression by univariate analysis. The multivariate analysis identified age < 70 years (hazard ratio 6.52, 95% confidence interval 2.29–18.55) and Gleason score ≥ 6 (4.0, 2.0–12.0) as independent risk factors for PSA progression.

CONCLUSIONS

ADT resulted in modest control of localized prostate cancer, but younger patients and those with Gleason ≥ 6 cancers were at higher risk of treatment failure. Toxicity, principally in the form of bone fractures, was high.
ASCENT: The androgen‐independent prostate cancer study of calcitriol enhancing taxotere
Authors: Beer Tomasz M.
Published: August 2005

ASCENT, the Androgen‐Independent Prostate Cancer (AIPC) Study of Calcitriol Enhancing Taxotere, is a double‐blind, placebo‐controlled randomized clinical trial designed to determine if DN‐101, a high‐dose oral formulation of calcitriol designed for cancer therapy, significantly increases the proportion of patients who have > 50% reduction in serum prostate‐specific antigen (PSA) levels in response to docetaxel. The secondary goals of ASCENT are to evaluate the effect of DN‐101 combined with docetaxel on PSA progression‐free survival, tumour response rate in measurable disease, tumour progression‐free survival, skeletal morbidity‐free survival, clinical progression‐free survival, and overall survival, and to examine the safety and tolerability of DN‐101 combined with docetaxel. ASCENT builds on phase I work showing that weekly dosing allows substantial dose‐escalation of calcitriol, the natural ligand for the vitamin D receptor, and on phase II work that suggested that adding weekly high‐dose ‘pulse’ calcitriol may enhance the activity of weekly docetaxel in patients with AIPC. The preclinical rationale for calcitriol and its combination with docetaxel for prostate cancer therapy is reviewed, as are the key clinical trials that led to the development of ASCENT. The ASCENT design and its strengths and limitations are presented.
Long‐term sustained improvement in symptoms of benign prostatic hyperplasia with the dual 5α‐reductase inhibitor dutasteride: results of 4‐year studies
Authors: Roehrborn Claus G. , Lukkarinen Olavi , Mark Stephen , Siami Paul , Ramsdell Joe , Zinner Norman
Published: August 2005

OBJECTIVE

To report additional analyses of efficacy over the initial 2 years and during a 2‐year open‐label extension of the three pivotal phase 3 studies in which dutasteride, a dual inhibitor of type 1 and 2 5α‐reductase, was shown to be effective and well tolerated.

PATIENTS AND METHODS

All patients in the placebo and active groups were eligible for entry into the 2‐year open‐label extension, with all receiving dutasteride 0.5 mg daily. Mean changes from baseline were calculated for the American Urologic Association Symptom Index (AUA‐SI) score at each scheduled time in the double‐blind and open‐label phase. The additional analyses included a breakdown of the AUA‐SI score, including stratifying patients by symptom severity, assessment by baseline age and prostate volume, and the evaluation of symptoms responders.

RESULTS

There was a clinically meaningful improvement in AUA‐SI in patients on dutasteride in the double‐blind phase, but not in those on placebo. At 48 months, patients on dutasteride in both study phases had greater improvements in AUA‐SI score and individual question scores than those on dutasteride in the open‐label phase only. The proportion of patients with severe symptoms declined in both study groups, although these changes were more profound in those receiving dutasteride for the 4‐year duration of the study.

CONCLUSION

In men with symptomatic benign prostatic hyperplasia, long‐term (4‐year) treatment with the dual isozyme 5α‐reductase inhibitor dutasteride resulted in sustained and continued improvements in symptoms and flow rate. For 4 vs 2 years, longer dutasteride therapy resulted in greater symptom improvement.
Ease of removal of thermo‐expandable prostate stents
Authors: Barber Neil J. , Roodhouse Alison J. , Rathenborg Per , Nordling Jørgen , Ellis Brian W.
Published: August 2005

OBJECTIVE

To report the ease of removal of the Memokath 028 prostatic stent (Engineers & Doctors A/S, Hornbaek, Denmark), an important attribute of the ‘ideal’ prostatic stent.

PATIENTS AND METHODS

Data on patients who had had a Memokath 028 stent removed in three different centres in Europe over an 8‐year period were collected retrospectively. Standardized forms were used to record relevant information from each physician's patient files.

RESULTS

Ninety‐three patients had their stents removed at the three reporting centres; the mean indwelling time of their stent was 12.9 months, and most stents were inserted for symptomatic benign prostate disease. Reasons for removal included recurrent outlet or storage‐type urinary symptoms, migration of the stent, stent‐related pain, recurrent urosepsis and detrusor failure. The stents were removed on a day‐case basis in 32% of patients. Topical anaesthesia or no anaesthesia was used in 48%. Of these patients, only 9% described moderate discomfort or worse. The procedure took a mean of 11 min and was felt to be easy or fairly easy in 90% of patients.

CONCLUSIONS

These data show the ease of removal of the Memokath 028 stent, reinforce its overall success in achieving the requirements of the ideal intraprostatic stent, and further emphasize the advantages of this implant over the epithelializing, permanent intraprostatic stent.
Donor‐site morbidity in buccal mucosa urethroplasty: lower lip or inner cheek?
Authors: Kamp Stefan , Knoll Thomas , Osman Mahmoud , Häcker Axel , Michel Maurice S. , Alken Peter
Published: August 2005

Authors from Germany debate the issue as to whether the donor site for oral mucosa used in urethroplasty should be taken from the inner cheek or the lower lip, using morbidity as a deciding factor. As a result of their study they have changed their technique, now using the inner cheek as the donor site whenever possible.

OBJECTIVE

To evaluate donor‐site complications of buccal mucosa urethroplasty and whether there is a difference in morbidity between harvesting the mucosa graft from the inner cheek or the lower lip.

PATIENTS AND METHODS

Twenty‐four consecutive patients with recurrent urethral strictures were treated with buccal mucosa urethroplasty in our department between September 2002 and April 2004. In 12 patients the graft was harvested from the lower lip or cheek and lower lip (group 1), and in 12 patients from the cheek (group 2). The mean (range) age of patients was 51 (26–66) years in group 1 and 53 (32–75) years in group 2. The mean (range) graft length was 6.2 (2–16) cm in group 1 and 5.7 (2–13) cm in group 2. All patients were followed up using a mailed questionnaire that asked about pain, numbness, difficulties in mouth opening or ingestion, and satisfaction, monthly for the first 3 months and then every 6 months. The mean (range) follow‐up was 12.5 (6–23) months.

RESULTS

There were no bleeding complications or disturbances in wound healing. All of the patients reported numbness in the area of the mental and buccal nerves, and graft‐site tenderness after surgery. In group 1, the pain lasted for a mean (range) of 5.9 (0.5–22) months, compared to 1 (0.1–7) months in group 2 (P = 0.022). Perioral numbness lasted for a mean (range) of 10.3 (0.5–23) months in group 1 and 0.85 (0.1–3) months (P = 0.0027) in group 2. There were no statistically significant differences in problems with mouth opening or food intake between the two groups, but the patients in group 1 seemed to be less satisfied (6/12 patients satisfied) than those in group 2 (11/12 patients satisfied).

CONCLUSIONS

Buccal mucosa graft harvesting from the lower lip and the inner cheek are both feasible, but harvesting from the lower lip resulted in a significantly greater long‐term morbidity, which resulted in a lower proportion of satisfied patients. This seems to be due to a long‐lasting neuropathy of the mental nerve. We therefore have changed our technique entirely from lower lip to inner cheek graft harvesting, whenever possible.