bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early endocrine therapy versus radical prostatectomy combined with early endocrine therapy for stage D1 prostate cancer
Authors: Schmeller N. , Lubos W. 
Published: November 2003

Objective To compare disease progression and survival of patients with stage D1 adenocarcinoma after treatment with either early androgen ablation alone or combined with radical prostatectomy.Patients and methods A retrospective non‐randomized study was performed in a series of 76 consecutive patients who underwent pelvic lymphadenectomy and had pathological stage D1 (T1–3, pN1–2, M0) prostate cancer; 37 patients underwent early endocrine therapy (EET) and 39 underwent radical prostatectomy with immediate adjuvant endocrine therapy (combined therapy, COM). The median follow‐up was 3.8 years (range 0.26–13). The patients were statistically homogeneous for tumour grade, local tumour stage and nodal involvement, but not for age at lymphadenectomy (67 years and 62 years, respectively, P=0.019, a confounding factor in favour of COM).Results Twelve patients (32%) in the EET group and 11 (28%) in the COM group died; the Kaplan‐Meier actuarial overall survival curves showed no statistically significant difference between the treatment groups, but there was a trend in favour of the COM group. There was also no significant difference in the cause‐specific survival. In the EET group, 17 men (46 %) had local (five of 37, 14%) or systemic (13 of 37, 35%) progression and in the COM group 23 patients (59%) had local (eight of 39, 21%) or systemic (20 of 39, 51%) progression. Four patients had an elevated level of prostate specific antigen with no clinical recurrence. Transurethral resection of the prostate was necessary for three (8%) patients in the EET group and for two (5%) of those receiving COM. The Kaplan‐Meier actuarial disease‐free survival curves were not significantly different. Similar results were obtained when the 25 patients with early‐stage (T1 and T2) and the 51 patients with advanced primary tumours (T3 and T4) were analysed separately.Conclusion These results suggest that in patients with stage D1 prostate cancer, radical prostatectomy combined with adjuvant endocrine therapy offers no advantage over endocrine therapy alone, neither for curative nor palliative intent.
Observations on the vomeronasal organ of prenatal Tarsius bancanus borneanus with implications for ancestral morphology
Authors: Smith T. D. , Siegel M. I. , Bhatnagar K. P. 
Published: November 2003

AbstractAdult primates have at least five known phenotypes of vomeronasal organ (VNO), ranging from the typical morphology seen in most other mammals to complete absence. With such morphological disparity, the phylogenetic value and any inferences on ancestral VNO morphology of the primate VNO are left uncertain. The present study investigated the VNO of embryonic and fetal Tarsius bancanus borneanus (n = 4) in comparison with prenatal specimens from four other species of primates in an effort to clarify adult morphological variations. In all except one of the fetal primates, the VNO communicated to the nasopalatine duct. One exception occurred in the largest fetal Tarsius (25 mm crown–rump length), in which the VNO communicated with the nasal cavity alone. The vomeronasal neuroepithelium was well differentiated from a thinner, non‐sensory epithelium in all Tarsius and New World monkeys studied, as well as late embryonic and fetal Microcebus myoxinus. In anterior sections, this neuroepithelium was found in a more superior location in Tarsius and New World monkeys compared with Microcebus myoxinus. In all primates, masses of cell bodies were found superior to the VNO, intermingled with nerve fibres. These morphologically resembled luteinizing hormone‐releasing hormone neurons described in other mammals, including humans, suggesting that a primitive association of these neurons with the VNO may exist in all primate taxa. The present study revealed that prenatal similarities exist in Tarsius and New World primates in VNO epithelial morphology. However, these are transient stages of morphology. If tarsiers and anthropoids do represent a clade (Haplorhini), then the atypical morphology seen in adult tarsiers and New World monkeys probably represents the adult VNO morphology of a haplorhine common ancestor.
Histochemical analysis of lymphatic endothelial cells in the pancreas of non‐obese diabetic mice
Authors: Qu P. , Ji R. C. , Kato S. 
Published: November 2003

AbstractWe studied the relationship between insulitic development and function–structural changes of pancreatic lymphatics in non‐obese diabetic (NOD) mice using combined 5′‐nucleotidase (5′‐Nase) enzyme histochemical and secondary lymphoid tissue chemokine (SLC/CCL21) immunohistochemical methods. Interlobular lymphatic vessels were positive for 5′‐Nase throughout the pancreas, and dependent on both blood vessels and pancreatic ducts. Intralobular initial lymphatics were rare and occasionally ran in the neighbourhood of islets. During the non‐insulitic stage, the 5′‐Nase‐reactive product was evenly distributed on the surface of lymphatic endothelial cells (LECs) with weak expression of CCL21. The activity of 5′‐Nase on lymphatic vessels became slightly reduced as insulitis developed. The increasing blood glucose values appeared to be consistent with an increasing CCL21 expression by the endothelial lining, especially on the surface of LECs adjacent to the infiltrated islets and tissues. Lymphocytes and dendritic cells (DCs) were frequently located in the connective tissue, surrounding the lymphatic wall with deposition of 5′‐Nase precipitates. As the infiltration became severe, lymphocytes and DCs accumulated within lymphatic vessels and expressed high levels of CCL21. The most significant finding was that many DCs adhered to lymphatic vessels, transmigrating via the thin and indented endothelial walls. The activity of 5′‐Nase was increased on the adhesion surface between DCs (or lymphocytes) and LECs. The latter were characterized by open intercellular junctions and obvious cytoplasmic protrusions. These results suggest that LECs closely interact with DCs and lymphocytes, and play a key role in the migration of DCs and lymphocytes via lymphatic vessels during the pathological processes of insulitis in NOD mice.
Postnatal development of the basolateral complex of rabbit amygdala: a stereological and histochemical study
Authors: Jagalska‐Majewska H. , Wójcik S. , Dziewia̧tkowski J. , Łuczyńska A. , Kurlapska R. , Moryś J. 
Published: November 2003

AbstractThe aim of the study was to estimate developmental changes in the rabbit basolateral complex (BLC) by stereological and histochemical methods. Material consisted of 45 brains of New Zealand rabbits (aged from 2 to 180 days, P2 to P180) of both sexes, divided into nine groups. The following parameters were estimated: volume of the cerebral hemisphere; volume of the whole BLC and of particular BLC nuclei; neuronal density and total number of neurons in these nuclei. Developmental changes in acetylcholinesterase (AChE) activity in the BLC were also examined. The volume of the cerebral hemisphere increased until P30, whereas volumes of nuclei increased for longer – until P90. The density of neurons in all nuclei studied reached the level characteristic for an adult animal at about P30. The total number of neurons in the dorsolateral division of the lateral nucleus (Ldl) stabilized the earliest – between P30 and P60, whereas in the ventromedial division of the lateral nucleus (Lvm), basomedial (BM) and basolateral (BL) nuclei the number stabilized later – between P60 and P90. AChE activity appears minimal in the BLC on P2, reaches a maximum on P30 and then decreases to the level characteristic of an adult animal on P60. AChE activity was greater in BL than in other nuclei in all age groups. Reaching adult AChE activity 1 month earlier than the total number of neurons in the BLC may indicate a role of the cholinergic system in BLC maturation.
Changes in function and ultrastructure of striatal dopaminergic terminals that regenerate following partial lesions of the SNpc
Authors: Stanic D. , Parish C. L. , Zhu W. M. , Krstew E. V. , Lawrence A. J. , Drago J. , Finkelstein D. I. , Horne M. K. 
Published: November 2003

AbstractFollowing partial substantia nigra lesions, remaining dopaminergic neurones sprout, returning terminal density in the dorsal striatum to normal by 16 weeks. This suggests regeneration and maintenance of terminal density is regulated to release appropriate levels of dopamine. This study examined the structure and function of these reinnervated terminals, defining characteristics of dopamine uptake and release, density and affinity of the dopamine transporter (DAT) and ultrastructural morphology of dopamine terminals in the reinnervated dorsal striatum. Finally, rotational behaviour of animals in response to amphetamine was examined 4 and 16 weeks after substantia nigra pars compacta (SNpc) lesions. Dopamine transport was markedly reduced 16 weeks after lesioning along with reduced density and affinity of DAT. Rate of dopamine release and peak concentration, measured electrochemically, was similar in lesioned and control animals, while clearance was prolonged after lesioning. Ultrastructurally, terminals after lesioning were morphologically distinct, having increased bouton size, vesicle number and mitochondria, and more proximal contacts on post‐synaptic cells. After 4 weeks, tendency to rotate in response to amphetamine was proportional to lesion size. By 16 weeks, rotational behaviour returned to near normal in animals where lesions were less than 70%, although some animals demonstrated unusual rotational patterns at the beginning and end of the amphetamine effect. Together, these changes indicate that sprouted terminals are well compensated for dopamine release but that transport mechanisms are functionally impaired. We discuss these results in terms of implications for dyskinesia and other behavioural states.
Human catecholamine sulfotransferase (SULT1A3) pharmacogenetics: functional genetic polymorphism
Authors: Thomae Bianca A. , Rifki Oktay F. , Theobald Michelle A. , Eckloff Bruce W. , Wieben Eric D. , Weinshilboum Richard M. 
Published: November 2003

AbstractSulfotransferase (SULT) 1A3 catalyzes the sulfate conjugation of catecholamines and structurally related drugs. As a step toward studies of the possible contribution of inherited variation in SULT1A3 to the pathophysiology of human disease and/or variation in response to drugs related to catecholamines, we have resequenced all seven coding exons, three upstream non‐coding exons, exon–intron splice junctions and the 5′‐flanking region of SULT1A3 using DNA samples from 60 African‐American (AA) and 60 Caucasian‐American (CA) subjects. Eight single nucleotide polymorphisms (SNPs) were observed in AA and five in CA subjects, including one non‐synonymous cSNP (Lys234Asn) that was observed only in AA subjects with an allele frequency of 4.2%. This change in amino acid sequence resulted in only 28 ± 4.5% (mean ± SEM) of the enzyme activity of the wild‐type (WT) sequence after transient expression in COS‐1 cells, with a parallel decrease (54 ± 2.2% of WT) in level of SULT1A3 immunoreactive protein. Substrate kinetic studies failed to show significant differences in apparent Km values of the two allozymes for either dopamine (10.5 versus 10.2 µm for WT and variant, respectively) or the cosubstrate 3′‐phosphoadenosine 5′‐phosphosulfate (0.114 versus 0.122 µm, respectively). The decrease in level of immunoreactive protein in response to this single change in amino acid sequence was due, at least in part, to accelerated SULT1A3 degradation through a proteasome‐mediated process. These observations raise the possibility of ethnic‐specific inherited alterations in catecholamine sulfation in humans.
Aggregate formation in the spinal cord of mutant SOD1 transgenic mice is reversible and mediated by proteasomes
Authors: Puttaparthi Krishna , Wojcik Cezary , Rajendran Bhagya , DeMartino George N. , Elliott Jeffrey L. 
Published: November 2003

AbstractCu,Zn superoxide dismutase (SOD1) mutations cause one form of familial amyotrophic lateral sclerosis by a toxic gain of function that may be related to abnormal protein folding and aggregate formation. However, the processing pathways involved in SOD1 aggregate generation within spinal cord remain unclear. We have now developed an experimental system for studying SOD1 aggregate formation and clearance in intact spinal cord tissue. Here we demonstrate that the formation of SOD1‐positive aggregates in G93A SOD1 transgenic mouse spinal cord tissue involves proteasome‐mediated proteolysis. Organotypic spinal cord slices from 9‐day‐old transgenic mice expressing G93A SOD1 develop SOD1 aggregates with proteasome inhibition. In contrast, SOD1 aggregates do not form in spinal cord slices from wild type mice or transgenic mice overexpressing wild type SOD1 following proteasome inhibition. Furthermore, SOD1 aggregate formation within G93A SOD1 spinal cord is both sensitive to small changes in overall proteasome activity and reversible with the restoration of proteasome function. Our results also establish that adult mouse spinal cord exhibits a relative deficiency in proteasome activity compared with non‐CNS tissue that may help explain the propensity of spinal cord to form SOD1‐positive aggregates.
Activated Notch1 associates with a presenilin‐1/γ‐secretase docking site
Authors: Ramdya Pavan , Skoch Jesse , Bacskai Brian J. , Hyman Bradley T. , Berezovska Oksana 
Published: November 2003

AbstractPresenilin‐1 (PS1), implicated as the active component of the γ‐secretase enzymatic complex, is known to cleave the cell surface receptor Notch1 after ligand binding. Here we directly visualize Notch1–PS1 interactions using a novel fluorescence lifetime imaging microscopy assay to monitor fluorescence resonance energy transfer. We demonstrate that endogenous Notch1 and PS1 move into close proximity at the cell surface after activation of Notch1 by the Delta1 ligand. A constitutively active N‐terminally truncated form of Notch1, an immediate substrate of the γ‐secretase complex, similarly is found in close proximity to PS1. Interestingly, this interaction remains in the presence of a potent γ‐secretase active site inhibitor. Thus ligand binding to Notch1 appears to result in access of truncated Notch1 to a putative docking site on the PS1–γ‐secretase complex. These results suggest a novel mechanism of ligand binding‐mediated signal transduction of Notch1.
Cleavage of recombinant proenkephalin and blockade mutants by prohormone convertases 1 and 2: an in vitro specificity study
Authors: Peinado Juan R. , Li Hong , Johanning Karla , Lindberg Iris 
Published: November 2003

AbstractProenkephalin (PE) derived‐peptides are thought to be generated predominantly through endoproteolytic cleavage by prohormone convertases 1 and 2 (PC1 and PC2). In order to compare cleavage site preferences of these convertases, we studied the processing of recombinant wild‐type rat PE and of two mutant PEs by recombinant purified mouse PC1 and PC2. Western blot analyses of timed digestions showed that both mouse PC1 and PC2 were able to produce a variety of large and intermediate sized‐peptides from wild‐type PE as well as from the precursors mutated at initial blockade sites. PC2 exhibited a broader specificity against PE than PC1, generating a much greater number of peptide products. Mass spectrometric identification of cleavage products showed that PC2 appeared to be the principal enzyme involved in the generation of smaller active opioids. Both enzymes were able to cleave various KR‐ and KK‐containing sites, but PC2 was also able to cleave efficiently at an RR‐V site and a KK‐M site not cleaved by PC1, suggesting the exclusion of large aliphatic residues at the P1′ position in PC1 cleavage. Alternative cleavage sites were readily chosen by convertases in blockade mutants, confirming in vivo results that cleavages do not follow an obligatory order. Furthermore, glycosylated PE was less efficiently processed by PC2, indicating that glycosylation may serve as a mechanism to hinder processing.
Thel‐isomer‐selective transport of aspartic acid is mediated by ASCT2 at the blood–brain barrier
Authors: Tetsuka Kazuhiro , Takanaga Hitomi , Ohtsuki Sumio , Hosoya Ken‐ichi , Terasaki Tetsuya 
Published: November 2003

AbstractAspartic acid (Asp) undergoesl‐isomer‐selective efflux transport across the blood–brain barrier (BBB). This transport system appears to play an important role in regulatingl‐ andd‐Asp levels in the brain. The purpose of this study was to identify the responsible transporters and elucidate the mechanism forl‐isomer‐selective Asp transport at the BBB. Thel‐isomer‐selective uptake of Asp by conditionally immortalized mouse brain capillary endothelial cells used as anin vitromodel of the BBB took place in an Na+‐ and pH‐dependent manner. This process was inhibited by system ASC substrates such asl‐alanine andl‐serine, suggesting that system ASC transporters, ASCT1 and ASCT2, are involved in thel‐isomer selective transport. Indeed,l‐Asp uptake by oocytes injected with either ASCT1 or ASCT2 cRNA took place in a similar manner to that in cultured BBB cells, whereas no significantd‐Asp uptake occurred. Although both ASCT1 and ASCT2 mRNA were expressed in the cultured BBB cells, the expression of ASCT2 mRNA was 6.7‐fold greater than that of ASCT1. Moreover, immunohistochemical analysis suggests that ASCT2 is localized at the abluminal side of the mouse BBB. These results suggest that ASCT2 plays a key role inl‐isomer‐selective Asp efflux transport at the BBB.
Immunotherapy as a therapeutic treatment for neurodegenerative disorders
Authors: White Anthony R. , Hawke Simon H. 
Published: November 2003

AbstractHuman neurodegenerative illnesses such as Alzheimer's disease and Creutzfeldt‐Jakob disease exact an enormous cost on individuals, families and society. For these and related disorders, current treatment is largely symptomatic without influencing the underlying disease process. Until recently, the development of immunotherapeutic approaches to neurodegenerative disorders had been almost completely ignored despite growing successes against other non‐infectious diseases such as cancer. However, since Schenk and colleagues described the antibody‐mediated clearance of amyloid plaques in a transgenic mouse model of Alzheimer's disease, a number of studies have confirmed the feasibility of this strategy for several neurodegenerative disorders including Huntington's disease and prion diseases. These reports offer the exciting prospect that either the immune system or its derivative components can be harnessed to fight the misfolded and/or aggregated proteins that accumulate in many neurodegenerative illnesses. If the remarkable power of clonal expansion, specificity and efficiency of the immune system can successfully inactivate these abnormal proteins, real hope exists that effective immunotherapeutic treatments for neurodegenerative illnesses may be available in the near future.
Dopamine D1 receptors mediate CREB phosphorylation via phosphorylation of the NMDA receptor at Ser897–NR1
Authors: Dudman Joshua T. , Eaton Molly E. , Rajadhyaksha Anjali , Macías Wendy , Taher Muffadal , Barczak Amy , Kameyama Kimihiko , Huganir Richard , Konradi Christine 
Published: November 2003

AbstractAddictive drugs such as amphetamine and cocaine stimulate the dopaminergic system, activate dopamine receptors and induce gene expression throughout the striatum. The signal transduction pathway leading from dopamine receptor stimulation at the synapse to gene expression in the nucleus has not been fully elucidated. Here, we present evidence that D1 receptor stimulation leads to phosphorylation of the transcription factor Ca2+ and cyclic AMP response element binding protein (CREB) in the nucleus by means of NMDA receptor‐mediated Ca2+ signaling. Stimulation of D1 receptors induces the phosphorylation of Ser897 on the NR1 subunit by protein kinase A (PKA). This phosphorylation event is crucial for D1 receptor‐mediated CREB phosphorylation. Dopamine cannot induce CRE‐mediated gene expression in neurons transfected with a phosphorylation‐deficient NR1 construct. Moreover, stimulation of D1 receptors or increase in cyclic AMP levels leads to an increase in cytosolic Ca2+ in the presence of glutamate, but not in the absence of glutamate, indicating the ability of dopamine and cyclic AMP to facilitate NMDA channel activity. The recruitment of the NMDA receptor signal transduction pathway by D1 receptors may provide a general mechanism for gene regulation that is fundamental for mechanisms of drug addiction and long‐term memory.
The pesticide rotenone induces caspase‐3‐mediated apoptosis in ventral mesencephalic dopaminergic neurons
Authors: Ahmadi Ferogh A. , Linseman Daniel A. , Grammatopoulos Tom N. , Jones Susan M. , Bouchard Ron J. , Freed Curt R. , Heidenreich Kim A. , Zawada W. Michael 
Published: November 2003

Abstract In vivo, the pesticide rotenone induces degeneration of dopamine neurons and parkinsonian‐like pathology in adult rats. In the current study, we utilized primary ventral mesencephalic (VM) cultures from E15 rats as an in vitro model to examine the mechanism underlying rotenone‐induced death of dopamine neurons. After 11 h of exposure to 30 nm rotenone, the number of dopamine neurons identified by tyrosine hydroxylase (TH) immunostaining declined rapidly with only 23% of the neurons surviving. By contrast, 73% of total cells survived rotenone treatment, indicating that TH+ neurons are more sensitive to rotenone. Examination of the role of apoptosis in TH+ neuron death, revealed that 10 and 30 nm rotenone significantly increased the number of apoptotic TH+ neurons from 7% under control conditions to 38 and 55%, respectively. The increase in apoptotic TH+ neurons correlated with an increase in immunoreactivity for active caspase‐3 in TH+ neurons. The caspase‐3 inhibitor, DEVD, rescued a significant number of TH+ neurons from rotenone‐induced death. Furthermore, this protective effect lasted for at least 32 h post‐rotenone and DEVD exposure, indicating lasting neuroprotection achieved with an intervention prior to the death commitment point. Our results show for the first time in primary dopamine neurons that, at low nanomolar concentrations, rotenone induces caspase‐3‐mediated apoptosis. Understanding the mechanism of rotenone‐induced apoptosis in dopamine neurons may contribute to the development of new neuroprotective strategies against Parkinson's disease.