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PubMedDate not supplied

Familial/bilateral and sporadic testicular germ cell tumors show frequent genetic changes at loci with suggestive linkage evidence.

Testicular germ cell tumor (TGCT) is the most common tumor type among adolescent and young adult males. Familial clustering and bilateral disease are suggestive of a genetic predisposition among a subgroup of these patients, but susceptibility genes for testicular cancer have not yet been identified. However, suggestive linkage between disease and genetic markers has been reported at loci on chromosome arms 3q, 5q, 12q, 18q, and Xq. We have analyzed primary familial/bilateral (n=20) and sporadic (n=27) TGCTs, including 28 seminomas and 19 nonseminomas, for allelic imbalance (AI) within the autosomal regions. DNA from all tumors were analyzed by fluorescent polymerase chain reaction of 22 polymorphic loci at 3q27-ter, 5q13-35.1, 12q21-ter, and 18q12--ter. All tumor genotypes were evaluated against their corresponding constitutional genotypes. The percentages of TGCTs with genetic changes at 3q, 5q, 12q, and 18q, were 79%, 36%, 53% and 43%, respectively. The frequencies at 3q and 12q in nonseminomas were significantly higher than in seminomas (P=.003 and P=.004). In order to evaluate changes at hemizygous Xq loci, five loci were analyzed by co-amplification with an autosomal reference marker known to reveal retained heterozygosity in the tumor DNA. Gain of Xq sequences was seen in more than 50% of the tumors. The degree of amplification varied among the loci in each of five tumors, and based on these breakpoints, a common region of overlapping gains was found at Xq28. No significant differences were found between the frequencies of genetic changes in familial/bilateral versus sporadic tumors, an observation speaking in disfavor of the existence of a single susceptibility gene for TGCT in any of the analyzed regions. Our data suggest that gain of genetic material at distal Xq and losses at 5q and 18q contribute to establishment of seminomas, whereas imbalances at 3q as well as gain at distal part of 12q are associated with further progression into nonseminomas.

Adult↗
PubMed1998

Murine NIMA-related kinases are expressed in patterns suggesting distinct functions in gametogenesis and a role in the nervous system.

NIMA protein kinase is a major regulator of progression into mitosis in Aspergillus nidulans. Dominant negative forms of NIMA protein prevent entrance into mitosis in HeLa cells, suggesting that mammals have a similar pathway. We have reported previously the isolation of a murine NIMA-related kinase, designated Nek1, and more recently several additional NIMA-related human kinases have been cloned. The existence of several mammalian NIMA-related genes raises the questions of whether the different mammalian members have redundant, overlapping or distinct functions, and whether these functions are related to the role of NIMA in controlling mitosis. To address these questions we have studied the expression patterns of the different murine nek genes. To this end, we isolated a murine nek2 cDNA and compared its patterns of expression, during both gametogenesis and embryogenesis, to those of nek1. Both genes were highly expressed in developing germ cells, albeit in distinct patterns. In both females and males, nek1 is expressed much earlier than nek2, suggesting only limited ability for functional redundancy. Surprisingly, a striking specificity of nek1 expression was found: high levels of nek1 RNA were observed in distinct regions of the nervous system, most notably in neurons of the peripheral ganglia. These patterns suggest that the different mammalian NIMA-related kinases participate in different phases of the meiotic process and may also have functions other than cell cycle control.

Amino Acid Sequence↗
PubMed2005

Evidence suggesting that Homo neanderthalensis contributed the H2 MAPT haplotype to Homo sapiens.

The tau (MAPT) locus exists as two distinct clades, H1 and H2. The H1 clade has a normal linkage disequilibrium structure and is the only haplotype found in all populations except those derived from Caucasians. The H2 haplotype is the minor haplotype in Caucasian populations and is not found in other populations. It shows no recombination over a region of 2 Mb with the more common H1 haplotype. The distribution of the haplotype and analysis of the slippage of dinucleotide repeat markers within the haplotype suggest that it entered Homo sapiens populations between approx. 10000 and 30000 years ago. However, sequence comparison of the H2 haplotype with the H1 haplotype and with the chimp sequence suggests that the common founder of the H1 and H2 haplotypes was far earlier than this. We suggest that the H2 haplotype is derived from Homo neanderthalensis and entered H. sapiens populations during the co-existence of these species in Europe from approx. 45000 to 18000 years ago and that the H2 haplotype has been under selection pressure since that time, possibly because of the role of this H1 haplotype in neurodegenerative disease.

Animals↗
PubMed1996

Analysis of rearranged T cell receptor (TCR) V beta transcripts in livers of primary biliary cirrhosis: preferential V beta usage suggests antigen-driven selection.

The presence of autoantibodies to mitochondrial pyruvate dehydrogenase complex-E2 (PDC-E2) and self-reactive T cells to PDC suggests that autoimmune mechanisms may be involved in the pathogenesis of primary biliary cirrhosis (PBC). Molecular analysis of intrahepatic TCR repertoire may provide valuable information on a T cell mechanism for PBC immunopathogenesis. We therefore analysed the TCR V beta usage in different regions of the livers removed during transplantation from two PBC patients. Using reverse transcription and polymerase chain reaction (RT-PCR), a limited heterogeneity of rearranged TCR V beta transcripts was demonstrated in different locations of the same liver. Sequence analysis of V beta-D beta-J beta (CDR3: the third complementarity determining region) showed the presence of conserved residues, no random N additions, and a common motif within CDR3. These results suggest that T cells homing to PBC liver may be antigen-driven. To elucidate further whether an immune deviation related to T helper 1 cell (Th1) or Th2 responses may exist in PBC, intrahepatic mRNA expression of IL-2, IL-4 and interferon-gamma (IFN-gamma) was examined by the RT-PCR method. IL-2 and IFN-gamma could be amplified, whereas IL-4 was virtually undetectable in the livers from the two patients with PBC. The findings suggest that polarization of intrahepatic lymphokine expression toward the Th1-dominant pattern may be significant in the immunopathogenesis of PBC.

Amino Acid Sequence↗
PubMed2001

Risk factors suggesting malignant transformation of gastric adenoma: univariate and multivariate analysis.

BACKGROUND AND STUDY AIMS: Since gastric adenomas are precancerous lesions, polypectomy is necessary. However, there have been no reports suggesting factors capable of predicting malignant transformation of gastric adenomas removed by endoscopic snare polypectomy (ESP) or endoscopic mucosal resection (EMR) in Korea, a country in which gastric cancer is a major problem. The aim of this paper was to elucidate the risk factors suggesting malignant transformation of gastric adenomas removed by ESP or EMR at our center. PATIENTS AND METHODS: Between November 1994 and June 1999, 118 gastric adenomas diagnosed on the basis of endoscopy and histological examinations of the forceps biopsy specimens obtained were treated by ESP or EMR at our department. Factors capable of predicting malignancy were searched for in the endoscopy reports, still photographs, and histopathological findings. RESULTS: Eight of the 118 adenomas ultimately proved to have malignant foci. In the univariate analysis, four of the variables studied--location, histological type, surface redness, and degree of dysplasia--had a statistically significant relationship with malignant transformation. In the multivariate analysis, only the degree of dysplasia had a statistically significant relationship with malignant transformation. CONCLUSIONS: These results suggest that a diagnosis of high-grade dysplasia in forceps biopsy material should be considered an absolute indication for ESP or EMR.

Adenoma↗
PubMed1980

Kinetic models suggest bimolecular reaction steps in axonal Na+-channel gating.

Abstract kinetic models that can successfully simulate the ion-permeability features of axonal Na+ channels suggest the presence of bimolecular reaction steps in the activation of the channels. A chemically plausible interpretation of minimum complexity is described. The implied chemical formalism is highly suggestive of an activator-controlled gating system with strong similarities to the acetylcholine-regulated system. Conformational changes that underlie the ion-conductance changes are suggested to possess a greater sensitivity to the membrane field in axonal parts of excitable membranes than at synaptic parts. This would allow axonal permeability changes to be energetically regulated more conservatively than is observed for synaptic ion channels. Axonal K+ channels with delayed activation kinetics would serve to reverse the increase in membrane permeability to Na+ with a minimum of chemical dissipation.

Axons↗
PubMed1986

Studies on the expression of the beta nerve growth factor (NGF) gene in the central nervous system: level and regional distribution of NGF mRNA suggest that NGF functions as a trophic factor for several distinct populations of neurons.

Beta nerve growth factor (NGF), a target-derived protein necessary for survival and development of sympathetic and sensory neurons, can also affect subpopulations of neurons in the central nervous system (CNS). Using a blot hybridization assay capable of detecting 10 fg of mRNA, we measured the levels of NGF mRNA in the major brain regions, including those innervated by NGF-responsive neurons. NGF mRNA was detected unambiguously in each major region of the CNS. The levels were comparable to those in sympathetic effector organs. Discrete areas contained very different amounts of NGF mRNA. Up to 40-fold differences were seen, a range comparable to the differences between richly and sparsely innervated sympathetic effector organs. The highest concentrations of NGF mRNA were found in the cortex and hippocampus, which are the major targets of the NGF-responsive cholinergic neurons of the basal forebrain nuclei. Significant amounts of NGF mRNA were also found in areas that contain the central processes of NGF-responsive sensory neurons, such as the pons, medulla, and spinal cord. The presence of NGF mRNA in these areas suggests that brain NGF may act as a target-derived trophic factor for both populations of neurons. NGF mRNA was also found in the striatum, suggesting that locally derived NGF may act there as a trophic factor for a recently identified population of NGF-responsive cholinergic local circuit neurons. However, high levels of NGF mRNA were also found in some regions, such as the diencephalon, that have no relation to any identified population of NGF-responsive neurons. This suggests that there may be additional populations of NGF-responsive neurons in the CNS that have not yet been discovered.

Animals↗
PubMed1992

In vivo patterns of expression of urokinase and its inhibitor PAI-1 suggest a concerted role in regulating physiological angiogenesis.

To evaluate the role of plasminogen activators (PAs) in physiological angiogenesis, we have investigated the in vivo patterns of expression of urokinase-type PA (uPA) and PA-inhibitor type 1 (PAI-1) during neovascularization of ovarian follicles, the corpus luteum, and the maternal decidua. Using in situ hybridization, we detected uPA mRNA in the ovary along the route of capillary extension, originating at the existing ovarian vasculature, extending toward growing follicles, and terminating at the newly formed capillary sheaths surrounding each growing follicle. Following ovulation, uPA mRNA was expressed in capillary sprouts within the developing corpus luteum. During the process of decidual neovascularization, uPA expression was detected in endothelial cell cords traversing the maternal decidua in the direction of the newly implanted embryo. uPA mRNA was not detected in endothelial cells upon completion of neovascularization, suggesting that uPA expression is a part of the angiogenic response. During in vitro "angiogenesis" of cultured aortic explants, uPA was expressed in capillary sprouts but not in underlying endothelial cell sheets, suggesting that the expression of uPA depends on the histological context of the endothelial cell. Interestingly, during corpus luteum development and decidual neovascularization, and in aortic explants, PAI-1 expression was preferentially activated in cells in the vicinity of uPA-expressing capillary-like structures. These findings suggest a functional interplay between uPA- and PAI-1-expressing cells and support the idea that natural PA inhibitors function during angiogenesis to protect neovascularized tissues from excessive proteolysis.

Animals↗
PubMed1998

Three independent lines of evidence suggest retinoids as causal to schizophrenia.

Retinoid dysregulation may be an important factor in the etiology of schizophrenia. This hypothesis is supported by three independent lines of evidence that triangulate on retinoid involvement in schizophrenia: (i) congenital anomalies similar to those caused by retinoid dysfunction are found in schizophrenics and their relatives; (ii) those loci that have been suggestively linked to schizophrenia are also the loci of the genes of the retinoid cascade (convergent loci); and (iii) the transcriptional activation of the dopamine D2 receptor and numerous schizophrenia candidate genes is regulated by retinoic acid. These findings suggest a close causal relationship between retinoids and the underlying pathophysiological defects in schizophrenia. This leads to specific strategies for linkage analyses in schizophrenia. In view of the heterodimeric nature of the retinoid nuclear receptor transcription factors, e.g., retinoid X receptor beta at chromosome 6p21.3 and retinoic acid receptor beta at 3p24.3, two-locus linkage models incorporating genes of the retinoid cascade and their heterodimeric partners, e.g., peroxisome proliferator-activated receptor alpha at chromosome 22q12-q13 or nuclear-related receptor 1 at chromosome 2q22-q23, are proposed. New treatment modalities using retinoid analogs to alter the downstream expression of the dopamine receptors and other genes that are targets of retinoid regulation, and that are thought to be involved in schizophrenia, are suggested.

Animals↗
PubMed1996

Calreticulin interacts with newly synthesized human immunodeficiency virus type 1 envelope glycoprotein, suggesting a chaperone function similar to that of calnexin.

The ubiquitous eukaryotic protein calreticulin has been detected in a wide variety of different cell types. Recently, calreticulin was found to bind in vitro to a number of proteins isolated from the endoplasmic reticulum. In addition, calreticulin has sequence similarities with the molecular chaperone calnexin. These data suggest that calreticulin might also act as a chaperone. We found that calreticulin associated transiently with a large number of newly synthesized cellular proteins. In cells expressing recombinant human immunodeficiency virus (HIV) envelope glycoprotein, gp160 bound transiently to calreticulin with a peak at 10 min after its synthesis. Binding of gp120 to calreticulin was not detected because proteolytic cleavage of gp160 occurs in the trans-Golgi. Nonglycosylated HIV envelope protein was not associated with calreticulin, suggesting a requirement for N-linked oligosaccharides on newly synthesized proteins as has been reported for calnexin. The in vivo binding kinetics of calnexin and calreticulin to gp160 were very similar. Sequential immunoprecipitations provided evidence for the existence of ternary complexes of gp160, calreticulin, and calnexin. The data suggested that most of the gp160 associated with calreticulin was also bound to calnexin but that only a portion of the gp160 associated with calnexin was also bound to calreticulin.

Adenosine Triphosphate↗
PubMed2000

A conserved transcription motif suggesting functional parallels between Caenorhabditis elegans SKN-1 and Cap'n'Collar-related basic leucine zipper proteins.

In Caenorhabditis elegans, the predicted transcription factor SKN-1 is required for embryonic endodermal and mesodermal specification and for maintaining differentiated intestinal cells post-embryonically. The SKN-1 DNA-binding region is related to the Cap'n'Collar (CNC) family of basic leucine zipper proteins, but uniquely, SKN-1 binds DNA as a monomer. CNC proteins are absent in C. elegans, however; and their involvement in the endoderm and mesoderm suggests some functional parallels to SKN-1. Using a cell culture assay, we show that SKN-1 induces transcription and contains three potent activation domains. The functional core of one domain is a short motif, the DIDLID element, which is highly conserved in a subgroup of vertebrate CNC proteins. The DIDLID element is important for SKN-1-driven transcription, suggesting a likely significance in other CNC proteins. SKN-1 binds to and activates transcription through the p300/cAMP-responsive element-binding protein-binding protein (CBP) coactivator, supporting the genetic prediction that SKN-1 recruits the C. elegans p300/CBP ortholog, CBP-1. The DIDLID element appears to act independently of p300/CBP, however, suggesting a distinct conserved target. The evolutionarily preservation of the DIDLID transcriptional element supports the model that SKN-1 and some CNC proteins interact with analogous cofactors and may have preserved some similar functions despite having divergent DNA-binding domains.

Animals↗
PubMed2004

A cascade of 24 histatins (histatin 3 fragments) in human saliva. Suggestions for a pre-secretory sequential cleavage pathway.

The systematic search by tandem mass spectrometry of human saliva from four different subjects, of 136 possible fragments originated from histatin 3, allowed the detection of 24 different peptides. They include, with the exception of histatin 4, all the known histatin 3 fragments, namely histatins 5-12 and the peptides corresponding to 15-24, 26-32, 29-32 residues, and 13 new fragments corresponding to 1-11, 1-12, 1-13, 5-13, 6-11, 6-13, 7-11, 7-12, 7-13, 14-24, 14-25, 15-25, and 28-32 residues of histatin 3. On the contrary, none of 119 possible fragments of histatin 1, including histatin 2, was detected. The results suggest that the genesis of histatin 3-related peptides, being under the principal action of trypsin-like activities, is probably not a random process but rather follows a sequential fragmentation pathway. Lack of detection of C-terminal fragments, with the exception of 26-32, 28-32, and 29-32 fragments, suggested that arginine 25 should be the first cleavage site, generating histatin 6 and 26-32 fragments. The genesis of 28-32 and 29-32 fragments and histatin 5 should implicate a subsequent exo-protease action. Similarly, lack of detection of fragments having Lys-5 and Arg-6 at the N terminus and Arg-25 at the C terminus strongly suggested that sequences KRKF (11-14 residues) and AKR (4-6 residues) should be the second and the third cleavage sites, respectively. Lys-17 and Arg-22 are not cleaved at all.

Amino Acid Sequence↗
PubMed2005

Multiple positional nystagmus suggests multiple canal involvement in benign paroxysmal vertigo.

CONCLUSION: Video-oculography demonstrates a higher occurrence of atypical positional nystagmus in patients with benign paroxysmal positional vertigo (BPPV). This includes anterior and horizontal canal variants and multiple positional nystagmus, suggesting combined lesions affecting several canals. OBJECTIVE: To analyse the video-oculographic findings of positional tests in patients with BPPV. MATERIAL AND METHODS: Seventy individuals with symptoms of BPPV and positional nystagmus were included in this study. The diagnosis was based on a history of brief episodes of vertigo and the presence of positional nystagmus as confirmed by video-oculographic examination during the Dix-Hallpike test, the McClure test or the head-hanging manoeuvre. Patients were treated by means of different particle repositioning manoeuvres according to the affected canal (Epley's manoeuvre for the posterior or anterior canals and Lempert's manoeuvre for the lateral canal) and the effectiveness was evaluated at 7 and 30 days. RESULTS: Twenty-nine individuals (41.43%) presented an affected unilateral posterior canal. Fifteen patients (21.43%) presented a pure horizontal direction-changing positional nystagmus consistent with a diagnosis of horizontal canal BPPV. Twelve individuals (17.14%) presented a unilateral down-beating nystagmus, suggesting possible anterior canal BPPV. In addition, 14 patients (20%) showed multiple positional nystagmus during the examination corresponding to simultaneous multi-canal BPPV, 5 had bilateral posterior canal BPPV and 2 presented a positional down-beating nystagmus in both left and right Dix-Hallpike manoeuvres and the head-hanging manoeuvre, which is highly suggestive of anterior canal BPPV. However, seven individuals showed positional horizontal and vertical side-changing nystagmus that could not be explained by single-canal BPPV. These patients with multiple positional nystagmus showed changing patterns of positional nystagmus at follow-up.

Adult↗
PubMed1998

Effects on suggestibility of a new method of active-alert hypnosis: alert hand.

Research has shown that the active-alert method described by Bányai and Hilgard (1976) produces a similar increase on suggestibility as relaxation-based techniques, but it has some limitations, including the need for a stationary bicycle and a certain level of physical fitness. The authors compared that method with the new "alert hand" method, which emphasizes activity and alertness, but is simpler and less strenuous. In a repeated measures, counterbalanced design (N = 80), the authors found that (a) the alert hand method produced significantly higher objective and subjective suggestibility scores than the active-alert technique, and (b) a high percentage (23%) of volunteers discontinued participation during the active-alert method but not during the alert hand method. The alert hand method extends the benefits of active hypnosis to individuals who may have difficulties with the physical demands required by the active-alert method, and it seems to enhance suggestibility even more.

Adult↗
PubMedDate not supplied

The Duboisia genus, Australian aborigines and suggestibility.

Plant hallucinogens, such as those of the Duboisia genus called pituri, have been used by tribal elders in Australian aboriginal populations to create managed states of consciousness, to provide their youth with a fast-paced educational experience, and to inculcate values, beliefs and religious tenets. Use of the suggestible states created by such substances (particularly in pubertal initiatory rituals marking the transition to manhood) are part of this process, which contributes to cultural cohesiveness and survival; their effectiveness is due to the unique ability of the biochemical properties of the plant to evoke suggestibility in those who ingest them. This article draws on research about suggestibility as a psychological characteristic of altered states of consciousness as well as a normal human psychological phenomenon, and examines in great detail the use of the pituri plant, deriving data from a 100-item bibliography generated by the Australian Institute of Aboriginal and Torres Strait Islander Studies in Canberra. Botanical/chemical data on use of the Duboisia genus up to the end of the nineteenth century is examined, as well as the way in which this hallucinogen was utilized as a "psychotechnology."

Australia↗
PubMed2003

Smoking intervention within alcohol and other drug treatment services: a selective review with suggestions for practical management.

This selective review was undertaken in order to highlight the need for alcohol and other drug treatment services to provide intervention for tobacco smoking to their clients. The reasons for the failure of treatment services to date to deal with nicotine addiction within their programmes are discussed and positive suggestions for change are proferred. In addition to the transformation of institutional culture which will be required, managers and staff of alcohol and other drug agencies need to know how best to implement smoking intervention within the treatment setting. The paper concludes with some practical suggestions for the management of intervention for tobacco smoking within treatment settings. These suggestions include: making decisions and formulating policies and procedures with regard to how tobacco smoking will be addressed; considering the particular physical, psychological and social/environmental factors that apply to substance abuse clients; building intervention around a simple structure such as the '5 A's'; encouraging and facilitating the use of nicotine replacement therapies; and allowing flexibility to tailor intervention to the individual. A great deal of further research is required to inform us as to how to intervene most effectively for tobacco smoking among this population group.

Alcoholism↗
PubMed2006

How can we get access to the experiences of people with dementia? Suggestions and reflections.

This paper suggests and discusses a methodological approach that aims to facilitate the inclusion of people with dementia in research where the ambition is to better understand their experiences. People with dementia have commonly not been included as informants in research as their cognitive deficits have been regarded as a hindrance. Moreover, in the qualitative research tradition, most inquiries rely on data obtained from interviews, thereby requiring communication and verbal skills, which are skills that are affected early in the cause of dementia. Consequently, the considerably under-researched area of how dementia is experienced and managed from the perspective of those afflicted has long been put aside. This paper suggests that a combination of qualitative observations and adapted interviews may make it possible for people with dementia to participate as research informants. Issues concerned with creating a relationship with informants with dementia and helping them to elicit their experiences are elaborated and discussed. Some suggestions are made concerning how the context can be used for this intent, and how the observations and interviews can be adapted to the informants with dementia.

Dementia↗
PubMed2002

ARFGAP1 promotes the formation of COPI vesicles, suggesting function as a component of the coat.

The role of GTPase-activating protein (GAP) that deactivates ADP-ribosylation factor 1 (ARF1) during the formation of coat protein I (COPI) vesicles has been unclear. GAP is originally thought to antagonize vesicle formation by triggering uncoating, but later studies suggest that GAP promotes cargo sorting, a process that occurs during vesicle formation. Recent models have attempted to reconcile these seemingly contradictory roles by suggesting that cargo proteins suppress GAP activity during vesicle formation, but whether GAP truly antagonizes coat recruitment in this process has not been assessed directly. We have reconstituted the formation of COPI vesicles by incubating Golgi membrane with purified soluble components, and find that ARFGAP1 in the presence of GTP promotes vesicle formation and cargo sorting. Moreover, the presence of GTPgammaS not only blocks vesicle uncoating but also vesicle formation by preventing the proper recruitment of GAP to nascent vesicles. Elucidating how GAP functions in vesicle formation, we find that the level of GAP on the reconstituted vesicles is at least as abundant as COPI and that GAP binds directly to the dilysine motif of cargo proteins. Collectively, these findings suggest that ARFGAP1 promotes vesicle formation by functioning as a component of the COPI coat.

ADP-Ribosylation Factors↗