Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “SUGGESTION”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 433 records · Page 24Linked to original sources
PubMed1993

Prognosis in men and women coming to the emergency room with chest pain or other symptoms suggestive of acute myocardial infarction.

BACKGROUND: Previous studies suggest a gender-related difference in prognosis among patients with ischaemic heart disease. In the present study, we aimed to describe the characteristics and prognosis among patients with suspected ischaemic heart disease in relation to gender. METHODS: During the 21 months of the study, all patients who came to the medical emergency room of one single hospital as a result of chest pain or other symptoms suggestive of acute myocardial infarction were prospectively followed for 1 year. RESULTS: A total of 5362 patients were admitted on 7157 occasions; men accounted for 55% of the admissions. The 1-year mortality rate was 11% for men compared with 10% for women. The women were older and had a higher prevalence of known congestive heart failure and hypertension, whereas the prevalence of previous myocardial infarction was higher in men. When correcting for the dissimilarities in age and history of cardiovascular diseases, male gender appeared as an independent predictor of death. Development of myocardial infarction occurred in 25% of the men and 16% of the women (P < 0.001) during 1 year. The symptoms that brought patients to the emergency room were interpreted as being caused by myocardial infarction or myocardial ischemia in 29% of men compared with 21% of women (P < 0.001). CONCLUSIONS: In a consecutive series of patients with chest pain or other symptoms suggesting acute myocardial infarction in the emergency room, male gender was an independent risk indicator for death during 1 year. This might be explained by a higher occurrence of coronary artery disease in men than in women in this patient population.

Aged↗
PubMed2001

Expression of fas ligand in metastatic prostatic carcinoma: suggestive of possible clonal expansion of subpopulation with metastatic potential.

Fas ligand (FasL) is a type II transmembrane tumor necrosis factor family protein, known to trigger apoptosis in cells that bear the FasL receptor, Fas. The authors found that normal prostate, benign hyperplasia, and most prostatic carcinoma cells at the primary site did not express FasL, whereas metastatic prostatic carcinoma cells in lymph nodes and bone marrow displayed almost uniform, immunohistochemically detectable, FasL expression. However, small foci of FasL-positive prostatic carcinoma cells amid a vast majority of FasL-negative tumor cells were noted at the primary sites in patients with distant metastases. Analysis of the FasL gene and its mRNA by polymerase chain reaction and reverse transcriptase-polymerase chain reaction, respectively, suggested that the expression of immunohistochemically detectable FasL in metastatic tumor cells was not due to mutation in the FasL gene with resulting overexpression. Further, FasL expression was detectable in the acinar epithelial cells of prostates with morphologic atrophic changes, suggesting that FasL also plays a role in the physiologic apoptosis process of noncancerous prostate. The current data suggest that a subpopulation of prostate carcinoma cells clonally expresses FasL, and this subpopulation may have metastatic potential. Evaluation of FasL expression in the primary tumor thus may provide a useful parameter for predicting metastatic potential of the tumor.

Bone Marrow↗
PubMed2005

Tolterodine treatment for children with symptoms of urinary urge incontinence suggestive of detrusor overactivity: results from 2 randomized, placebo controlled trials.

PURPOSE: We report the results of the first 2 large randomized controlled trials designed to evaluate the efficacy and safety of tolterodine extended release in children 5 to 10 years old with symptoms of urinary urge incontinence suggestive of detrusor overactivity. MATERIALS AND METHODS: Two double-blind, placebo controlled trials were conducted sequentially. Children 5 to 10 years old with incontinence suggestive of detrusor overactivity (1 or more diurnal incontinence episodes per 24 hours) were randomized to tolterodine (2 mg daily) or placebo for 12 weeks. The primary end point was the change from baseline to week 12 in the number of incontinence episodes per week. Changes from baseline in the number of voids per 24 hours and volume of urine per void were also evaluated. Exploratory analyses were conducted to determine whether particular subsets of patients showed differential responses to treatment. RESULTS: A total of 224 and 487 children (mean age 8 years) were randomized to placebo and tolterodine, respectively. Differences in the number of incontinence episodes per week, voids per 24 hours, and volume of urine per void between tolterodine and placebo did not reach statistical significance. This finding may be explained by a high placebo response and under dosage of tolterodine among children with greater body weight. Tolterodine was well tolerated. CONCLUSIONS: Analysis of the primary efficacy outcome did not reveal a statistically significant effect of treatment. However, secondary analyses demonstrated that tolterodine was well tolerated among 5 to 10-year-old children with diurnal incontinence. Exploratory analyses also showed that children weighing 35 kg or less with detrusor overactivity characterized by incontinence and/or frequent voiding benefited most from tolterodine treatment, suggesting that a weight adjusted dosing regimen may be required for optimal response among older and heavier children.

Benzhydryl Compounds↗
PubMed2005

Mitochondrial genomes suggest that hexapods and crustaceans are mutually paraphyletic.

For over a century the relationships between the four major groups of the phylum Arthropoda (Chelicerata, Crustacea, Hexapoda and Myriapoda) have been debated. Recent molecular evidence has confirmed a close relationship between the Crustacea and the Hexapoda, and has included the suggestion of a paraphyletic Hexapoda. To test this hypothesis we have sequenced the complete or near-complete mitochondrial genomes of three crustaceans (Parhyale hawaiensis, Squilla mantis and Triops longicaudatus), two collembolans (Onychiurus orientalis and Podura aquatica) and the insect Thermobia domestica. We observed rearrangement of transfer RNA genes only in O. orientalis, P. aquatica and P. hawaiensis. Of these, only the rearrangement in O. orientalis, an apparent autapomorphy for the collembolan family Onychiuridae, was phylogenetically informative.We aligned the nuclear and amino acid sequences from the mitochondrial protein-encoding genes of these taxa with their homologues from other arthropod taxa for phylogenetic analysis. Our dataset contains many more Crustacea than previous molecular phylogenetic analyses of the arthropods. Neighbour-joining, maximum-likelihood and Bayesian posterior probabilities all suggest that crustaceans and hexapods are mutually paraphyletic. A crustacean clade of Malacostraca and Branchiopoda emerges as sister to the Insecta sensu stricto and the Collembola group with the maxillopod crustaceans. Some, but not all, analyses strongly support this mutual paraphyly but statistical tests do not reject the null hypotheses of a monophyletic Hexapoda or a monophyletic Crustacea. The dual monophyly of the Hexapoda and Crustacea has rarely been questioned in recent years but the idea of both groups' paraphyly dates back to the nineteenth century. We suggest that the mutual paraphyly of both groups should seriously be considered.

Animals↗
PubMed1993

Fusion protein gene nucleotide sequence similarities, shared antigenic sites and phylogenetic analysis suggest that phocid distemper virus type 2 and canine distemper virus belong to the same virus entity.

Nucleotide sequencing of the fusion protein (F) gene of phocid distemper virus-2 (PDV-2), recently isolated from Baikal seals (Phoca sibirica), revealed an open reading frame (nucleotides 84 to 2075) with two potential in-frame ATG translation initiation codons. We suggest that the second in-frame ATG triplet at positions 264 to 266 initiates the translation, resulting in a protein of 537 amino acid residues with a calculated M(r) of 63,035. The putative F1/F2 cleavage site, located approximately 100 amino acid residues from the N terminus, is identical to those of the F proteins of phocid distemper virus-1 (PDV-1) isolated from European harbour seals (Phoca vitulina) and of canine distemper virus (CDV). A full scale comparison of morbillivirus F genes reveals that the conserved F0 extracellular protein-encoding region contains a large number of non-expressed mutations, suggesting that this part of the protein is under strong functional constraints. Phylogenetic analysis of morbillivirus F gene nucleotide sequences revealed a closer evolutionary relationship between PDV-2 and CDV than between PDV-1 and PDV-2. These data were supported by cross-reactivity patterns of PDV-2 and CDV obtained with monoclonal antibodies to structural proteins of PDV-1 and CDV, and suggest that PDV-2 is a strain of CDV, resulting from a trans-species infection.

Amino Acid Sequence↗
PubMed2000

Phylogenetic analysis of some large double-stranded RNA replicons from plants suggests they evolved from a defective single-stranded RNA virus.

Sequences were recently obtained from four double-stranded (ds) RNAs from different plant species. These dsRNAs are not associated with particles and as they appeared not to be horizontally transmitted, they were thought to be a kind of RNA plasmid. Here we report that the RNA-dependent RNA polymerase (RdRp) and helicase domains encoded by these dsRNAs are related to those of viruses of the alpha-like virus supergroup. Recent work on the RdRp sequences of alpha-like viruses raised doubts about their relatedness, but our analyses confirm that almost all the viruses previously assigned to the supergroup are related. Alpha-like viruses have single-stranded (ss) RNA genomes and produce particles, and they are much more diverse than the dsRNAs. This difference in diversity suggests the ssRNA alpha-like virus form is older, and we speculate that the transformation to a dsRNA form began when an ancestral ssRNA virus lost its virion protein gene. The phylogeny of the dsRNAs indicates this transformation was not recent and features of the dsRNA genome structure and translation strategy suggest it is now irreversible. Our analyses also show some dsRNAs from distantly related plants are closely related, indicating they have not strictly co-speciated with their hosts. In view of the affinities of the dsRNAs, we believe they should be classified as viruses and we suggest they be recognized as members of a new virus genus (Endornavirus) and family (Endoviridae).

Defective Viruses↗
PubMed2005

Functional characterization and expression analysis of a gene, OsENT2, encoding an equilibrative nucleoside transporter in rice suggest a function in cytokinin transport.

We identified four genes for potential equilibrative nucleoside transporters (ENTs) from rice (Oryza sativa; designated OsENT1 through OsENT4). Growth analysis of budding yeast (Saccharomyces cerevisiae) cells expressing OsENTs showed that OsENT2 transported adenosine and uridine with high affinity (adenosine, K(m) = 3.0 microm; uridine, K(m) = 0.7 microm). Purine or pyrimidine nucleosides and 2'-deoxynucleosides strongly inhibited adenosine transport via OsENT2, suggesting that OsENT2 possesses broad substrate specificity. OsENT2-mediated adenosine transport was resistant to the typical inhibitors of mammalian ENTs, nitrobenzylmercaptopurine ribonucleoside, dilazep, and dipyridamole. The transport activity was maximal at pH 5.0 and decreased slightly at lower as well as higher pH. In competition experiments with various cytokinins, adenosine transport by OsENT2 was inhibited by isopentenyladenine riboside (iPR). Direct measurements with radiolabeled cytokinins demonstrated that OsENT2 mediated uptake of iPR (K(m) = 32 microm) and trans-zeatin riboside (K(m) = 660 microm), suggesting that OsENT2 participates in iPR transport in planta. In mature plants, OsENT2 was predominantly expressed in roots. The OsENT2 promoter drove the expression of the beta-glucuronidase reporter gene in the scutellum during germination and in vascular tissues in germinated plants, suggesting a participation of OsENT2 in the retrieval of endosperm-derived nucleosides by the germinating embryo and in the long-distance transport of nucleosides in growing plants, respectively.

Adenosine↗
PubMed2004

A systematic review of the effects of estrogens for symptoms suggestive of overactive bladder.

OBJECTIVE: To perform a systematic review of the effects of estrogen therapy on symptoms suggestive of overactive bladder (OAB) in postmenopausal women. MATERIALS AND METHODS: This analysis involved a literature review of Medline, Excerpta Medica, and the Science Citation Index and a manual search of popular urology, gynecology, gerontology, and primary care medicine journals from January 1969 to December 1999. Articles had to include estrogen and placebo treatment groups, published or original data presented at a scientific meeting and report symptoms suggestive of OAB. This search identified 11 randomized trials and included a total of 430 subjects. Thirty-six subjects who participated in two crossover studies received both estrogen and placebo and thus are counted twice, therefore 236 received estrogen therapy and 230 were placebo controls. Estrogen was administered systemically or locally as estriol, estradiol, conjugated estrogen, or estradiol and estriol. A meta-analysis of these studies was performed for all estrogen therapies and then separately for systemic and local therapies. RESULTS: Overall, estrogen therapies were associated with statistically significant improvements in all outcome variables: diurnal frequency (P = 0.0011), nocturnal frequency (P = 0.0371), urgency (P = 0.0425), number of incontinence episodes (P = 0.0002), first sensation to void (P = 0.0001), and bladder capacity (P = 0.0018). Local therapies had statistically significant beneficial effects on all outcome variables. However, systemic therapies were only associated with significant improvements in incontinence episodes and first sensation to void while nocturnal frequency actually worsened. CONCLUSION: Estrogen therapy may be effective in alleviating the symptoms suggestive of OAB. Local administration may be the most beneficial route of administration.

Cross-Over Studies↗
PubMed2004

Colony structure and parentage in wild colonies of co-operatively breeding Damaraland mole-rats suggest incest avoidance alone may not maintain reproductive skew.

Colonies of co-operatively breeding African mole-rats have traditionally been thought to be composed of a single breeding female, one or two breeding males, and their offspring. In the naked mole-rat (Heterocephalus glaber), the occurrence of facultative inbreeding means incest avoidance cannot prevent reproduction in subordinate group members, and physiological suppression of reproductive function by the breeding female occurs in both sexes. In contrast, previous studies of captive colonies of the Damaraland mole-rat (Cryptomys damarensis) suggest that breeding within a colony is restricted to a single breeding pair, simply because all other colony members are highly related (first- or second-order relatives) and this species is an obligate outbreeder. Using microsatellite markers, we investigated parentage and colony composition in 18 wild Damaraland mole-rat colonies to determine whether inbreeding avoidance alone can explain the high levels of reproductive skew in this species. Multiple and unidentified paternity was widespread within colonies and immigrants of both sexes were regularly identified. Unrelated, opposite-sex nonbreeders were found coexisting in two colonies. These results suggest that, in the wild, conditions exist where nonreproductive females can come into contact with unrelated males, even when they do not disperse from their natal colony. Inbreeding avoidance alone is therefore insufficient to maintain the high levels of reproductive skew identified in this species suggesting that the breeding female somehow suppresses the reproductive function in nonbreeding females.

Animals↗
PubMed1997

Molecular and clinical studies of three cases of female pseudohermaphroditism with caudal dysplasia suggest multiple etiologies.

Female pseudohermaphroditism with caudal dysplasia is a clinical entity in which normal-appearing male genitalia may occur in the apparent absence of testosterone or the sex-determining gene (SR Y). We have extended observations of two previously reported cases, and report a third case, which strongly suggests multiple etiologies. The first case was one of identical twins. The other identical twin did not show female pseudohermaphroditism with caudal dysplasia, but both patients had the rare birth defect of neonatal cataracts. We have explored skewed X-inactivation as a possible difference between the two twins, with a negative result. The second case had a deletion at 10q25.3-->ter. This is near the location of PAX2, and we searched for mutations in PAX2 in both this and the first case, with negative results. Neither patient had a scrotal raphe, suggesting that a failure of division of the cloacal membrane was an important step in their development of female pseudohermaphroditism. The final case is newly described and differed from the above two in the presence of a scrotal raphe and an elevated testosterone level. Although no source for the testosterone was found, this case suggests that the etiology in this patient was different and that the presence of a scrotal raphe can be used to distinguish between at least two etiologies.

Abnormalities, Multiple↗
PubMed1991

The neutrophil respiratory burst. Responses to fatty acids, N-formylmethionylleucylphenylalanine and phorbol ester suggest divergent signalling mechanisms.

The oxygen-dependent respiratory burst is a key neutrophil function required for the killing of bacteria. However, despite intensive investigation, the molecular events which initiate the respiratory burst remain unclear. Recent reports have suggested the agonist-induced hydrolysis of cellular phosphatidylcholine (PtdCho) by phospholipase D may be an essential requirement for initiating or mediating the respiratory burst. We have investigated the effects of the chemotactic peptide N-formylmethionylleucylphenylalanine (fMLF), the phorbol ester 12-O-tetradecanoyl-phorbol 13-acetate (TPA) and the polyunsaturated fatty acids arachidonic [20:4 (n-6)] and docosahexaenoic [22:6 (n-3)] acids in light of this hypothesis. Ethanol-inhibited superoxide production in response to 20:4, 22:6 and fMLF, in a dose-dependent fashion, suggesting an involvement of phospholipase D. The phosphatidic-acid phosphohydrolase inhibitor DL-propranolol completely inhibited superoxide production induced by both 20:4 and 22:6, and partially inhibited the response to TPA. In contrast, superoxide production in response to fMLF was increased by propranolol. fMLF and TPA, but not the fatty acids, stimulated phospholipase D as indicated by the accumulation of phosphatidic acid and, in the presence of ethanol, phosphatidylethanol derived from PtdCho. Extracellular Ca2+ was found to be an essential requirement for fMLF-induced superoxide production. However, responses to the fatty acids were dramatically enhanced under Ca(2+)-free conditions. Responses to TPA were independent of the extracellular Ca2+ concentration. Both fatty acids and fMLF, but not TPA, mobilised Ca2+ from intracellular stores, a response insensitive to the effects of both ethanol and propranolol. These results show that, unlike fMLF and TPA, the fatty acids do not cause hydrolysis of PtdCho by phospholipase D. However, the data indirectly suggests that the fatty acids may initiate the phospholipase-D-catalysed hydrolysis of phospholipids other than PtdCho.

Calcium↗
PubMed2004

Nursing practice issues in Jordan: student-suggested causes and solutions.

BACKGROUND: The causes of the worldwide shortage of registered nurses are complex and require a multifaceted approach to the solution. It is imperative that issues of the practice environment are addressed because creating quality practice environments is essential to provide high-quality care and to persuade nurses to remain in practice. AIMS: The aims of this paper are to describe an international collaborative relationship, and to identify, describe and suggest solutions to three nursing practice issues relevant to Jordanian nursing. METHOD: Two faculty members, one from Jordan and one from Canada, collaborated via e-mail to develop a fourth-year course on nursing leadership and management, which was then jointly taught by them. A student assignment required students, working in groups, to identify a nursing practice issue in Jordan and suggest contributing causes and solutions. CONCLUSION: The issues identified by the students were: unclear role expectations, burnout and turnover, all of which were viewed as contributing to problematic practice settings. The students suggested possible solutions to the practice environment issues.

Attitude of Health Personnel↗
PubMed1990

Intrasynaptosomal sequestration of [3H]amphetamine and [3H]methylenedioxyamphetamine: characterization suggests the presence of a factor responsible for maintaining sequestration.

We examined the incorporation of [3H]methylenedioxyamphetamine ([3H]MDA) and [3H]amphetamine into rat brain synaptosomes. Saturation studies, using increasing concentrations of nonradioactive ligand, revealed that [3H]-MDA interacted with two saturable sites that were sensitive to boiling of the tissue. Eadee-Scatchard plots of [3H]MDA saturation data were curvilinear; nonlinear curve-fitting analysis of these data suggested the presence of high- and low-affinity [3H]MDA sites of association: KD high = 295 nM, Bmax high = 32 pmol/mg of protein; KD low = 45 microM, Bmax low = 5.2 nmol/mg of protein. Association of [3H]MDA to the low-affinity site was dependent on the presence of isotonic sucrose in the incubation medium. The high capacities of these sites argue against a bimolecular interaction of [3H]MDA with monovalent protein binding sites. [3H]MDA incorporation was reduced under conditions that disrupt the integrity of plasma membranes, such as sonication, incubation in hypotonic media, and incubation in the presence of the detergent digitonin. These data indicate that [3H]MDA incorporation into synaptosomes may represent an internalization and sequestration phenomenon. [3H]MDA incorporation was also reduced by preincubation of the synaptosomal preparation at 37 degrees C or in hypotonic buffer at 4 degrees C, a result suggesting that this sequestration is maintained by an intrasynaptosomal component that is lost under the preincubation conditions described above. [3H]MDA incorporation was pH dependent (maximal at pH 7.5) and temperature sensitive (maximal incorporation occurred at 21 degrees C and was substantially reduced at 37 degrees C). [3H]Amphetamine was also incorporated into synaptosomes, and this incorporation was sensitive to the same physical manipulations of the tissue preparation as [3H]MDA incorporation. The synaptosomal sequestration of both [3H]MDA and [3H]amphetamine was inhibited by permeant cations, such as sodium and potassium, a result suggesting that the proposed intrasynaptosomal component that maintains the sequestration is anionic. Preliminary pharmacological profiles of [3H]MDA and [3H]amphetamine sequestration were identical. The rank order of inhibitor potencies for the incorporation of both ligands was desipramine greater than amphetamine greater than MDA greater than methylphenidate. This order of potency does not correspond to the lipophilicity of the test drugs. The synaptosomal incorporation and sequestration of [3H]MDA, [3H]methylenedioxymethamphetamine, and [3H]amphetamine described in the present report may be important in the molecular mechanism of action of monoamine release induced by the amphetamines.

3,4-Methylenedioxyamphetamine↗
PubMedDate not supplied

Conserved expression domains for genes upstream and within the HoxA and HoxD clusters suggests a long-range enhancer existed before cluster duplication.

The posterior HoxA and HoxD genes are essential in appendicular development. Studies have demonstrated that a "distal limb enhancer," remotely located upstream of the HoxD complex, is required to drive embryonic autopod expression of the posterior Hox genes as well as the two additional non-Hox genes in the region: Evx2 and Lnp. Our work demonstrates a similar mode of regulation for Hoxa13 and four upstream genes: Evx1, Hibadh, Tax1bp, and Jaz1. These genes all show embryonic (E11.5-E13.5) distal limb and genital bud expression, suggesting the existence of a nearby enhancer influencing the expression of a domain of genes. Comparative sequence analysis between homologous human and mouse genomic sequence upstream of Hoxa13 revealed a remote 2.25-kb conserved noncoding sequence (mmA13CNS) within the fourth intron of the Hibadh gene. mmA13CNS shares a common 131-bp core identity within a conserved noncoding sequence upstream of Hoxd13, which is located within the previously identified distal limb enhancer critical region. To test the function of this conserved sequence, we created mmA13CNS-Hsp86-lacZ transgenic mice. mmA13CNS directed a wide range of tissue expression, including the central nervous system, developing olfactory tissue, limb, and genital bud. Limb and genital bud expression directed by mmA13CNS is not identical to the patterns exhibited by Hoxa13/Evx1/Hibadh/Tax1bp1/Jaz1, suggesting that mmA13CNS is not sufficient to fully recapitulate their expression in those tissues. The Evx1- and Evx2-like central nervous system expression observed in these mice suggests that the long-range regulatory element(s) for the Hox cluster existed before the cluster duplication.

Animals↗
PubMedDate not supplied

Expression of Pax group III genes suggests a single-segmental periodicity for opisthosomal segment patterning in the spider Cupiennius salei.

Pair-rule patterning forms a key step for segmentation in insects. The expression patterns of pair-rule gene orthologs in representatives of other arthropod groups imply that these genes were segmentation genes in the last common ancestor of the various arthropod groups, but almost nothing is known about the underlying mechanism in noninsect arthropods. Here, we cloned and analyzed members of the Pax group III genes from the spider Cupiennius salei. Pax group III genes comprise genes like the Drosophila genes paired, gooseberry, and gooseberry-neuro, as well as the vertebrate Pax 3 and Pax 7 genes. We recovered three Pax group III genes from the spider C. salei, Cs-pairberry-1, Cs-pairberry-2, and Cs-pairberry-3, and show that the combined expression of the three spider genes mimics the patterns in insects, suggesting an ancestral role for Pax group III genes in segmentation, neurogenesis, and appendage formation in arthropods. One of the genes, pairberry-3, is expressed in a segmental periodicity before overt morphological segmentation is visible, suggesting a single segmental periodicity for opisthosomal segment pattering in the spider. Comparisons among arthropods suggest that the underlying mechanisms for pair-rule gene orthologs are more diverged than the ones for the segment-polarity genes. We argue that there may be a correlation between the lower variation in patterns of segment-polarity genes and the phylotypic stage. The segment-polarity genes are required to define the segment borders of the embryo at the germ-band stage, the arthropod phylotypic stage. Pair-rule gene orthologs act more upstream and may display more variation in their action.

Animals↗
PubMed2001

Changes in agonist concentration dependence that are a function of duration of exposure suggest N-methyl-D-aspartate receptor nonsaturation during synaptic stimulation.

Evidence suggests that N-methyl-D-aspartate receptors (NMDARs) have a relatively high affinity for agonist compared with non-NMDA receptors. Dose-response curves constructed with sustained agonist application suggest that the 50% effective concentration (EC(50)) for peak glutamate-evoked current at NMDARs is 1 to 10 microM, whereas that of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors is approximately 500 microM. Given estimates of synaptic cleft glutamate concentration in the millimolar range, it would be expected that NMDARs would be saturated with agonist. However, studies of synaptic NMDAR responses indicate that these receptors may not be saturated during single release events at many synapses. To address this apparent contradiction, we have compared the glutamate dose-response curve for the peak NMDAR current generated by sustained glutamate application with that obtained during brief synaptic-like pulses of agonist. Our results using both recombinant and native NMDARs indicate a marked reduction in glutamate potency with reduced agonist application duration (EC(50) = 100 to 200 microM with 1 ms application). A kinetic model suggested that the reduction in potency with shorter agonist application duration could be attributed to the relatively slow activation and deactivation rates of the NMDARs. Comparison of room temperature to 37 degrees C indicated that NMDAR activation and deactivation were strongly accelerated by increased temperature. However, at 37 degrees C, we still observed a significant increase in potency with longer agonist application duration. We propose that glutamate has a relatively lower potency at NMDARs than previously thought from agonist application under equilibrium conditions. This lower potency would account for data that shows nonsaturation of NMDARs during synaptic transmission.

Cells, Cultured↗
PubMed1992

Molecular variants of human papillomavirus type 16 from four continents suggest ancient pandemic spread of the virus and its coevolution with humankind.

We have amplified by the polymerase chain reaction, cloned, and sequenced genomic segments of 118 human papillomavirus type 16 (HPV-16) isolates from 76 cervical biopsy, 14 cervical smear, 3 vulval biopsy, 2 penile biopsy, 2 anal biopsy, and 1 vaginal biopsy sample and two cell lines. The specimens were taken from patients in four countries--Singapore, Brazil, Tanzania, and Germany. The sequence of a 364-bp fragment of the long control region of the virus revealed 38 variants, most of which differed by one or several point mutations. Phylogenetic trees were constructed by distance matrix methods and a transformation series approach. The trees based on the long control region were supported by another set based on the complete E5 protein-coding region. Both sets had two main branches. Nearly all of the variants from Tanzania were assigned to one (African) branch, and all of the German and most of the Singaporean variants were assigned to the other (Eurasian) branch. While some German and Singaporean variants were identical, each group also contained variants that formed unique branches. In contrast to the group-internal homogeneity of the Singaporean, German, and Tanzanian variants, the Brazilian variants were clearly divided between the two branches. Exceptions to this were the seven Singaporean isolates with mutational patterns typical of the Tanzanian isolates. The data suggest that HPV-16 evolved separately for a long period in Africa and Eurasia. Representatives of both branches may have been transferred to Brazil via past colonial immigration. The comparable efficiencies of transfer of the African and the Eurasian variants to the New World suggest pandemic spread of HPV-16 in past centuries. Representatives of the African branch were possibly transferred to the Far East along old Arab and Indonesian sailing routes. Our data also support the view that HPV-16 is a well-defined virus type, since the variants show only a maximal genomic divergence of about 5%. The small amount of divergence in any one geographic location and the lack of marked divergence between the Tanzanian and Brazilian African genome variants two centuries after their likely introduction into the New World suggest a very slow rate of viral evolution. The phylogenetic tree therefore probably represents a minimum of several centuries of evolution, if not an age equal to that of the respective human races.

Base Sequence↗
PubMed1997

High viral burden and rapid CD4+ cell depletion in human immunodeficiency virus type 1-infected SCID-hu mice suggest direct viral killing of thymocytes in vivo.

The mechanism of CD4+ cell loss in lymphoid organs is unknown. In this study, human immunodeficiency virus (HIV) infection of human fetal thymus/liver implants in severe combined immunodeficient mice was used to investigate the mechanism of HIV-induced depletion of CD4-bearing cells in vivo. The implants were assessed for depletion of CD4+ thymocytes, apoptosis, and viral burden. We detected two phases of CD4 cell depletion, an initial rapid phase and a more gradual later phase. Compared to mock-infected implants, HIV-infected implants did not demonstrate detectable increases in the levels of apoptosis while severe depletion of CD4-bearing cells was ongoing. During peak loss of CD4+ cells, high viral burden was observed, suggesting that loss of CD4+ cells in this in vivo system is due to direct killing of infected thymocytes. Increased levels of apoptosis were observed during the later phase of thymocyte depletion; however, these apoptotic cells lacked CD4. This finding suggests that a second indirect mechanism may be responsible for the destruction of CD4- CD8+ thymocytes in vivo. Taken together, these results suggest that CD4+ and CD4- cells may die by different mechanism(s).

Animals↗