Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Comprehensive analysis”

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 1,513 records · Page 84Linked to original sources
PubMed1996

Positive and negative selection invoke distinct signaling pathways.

During T cell development, interaction of the T cell receptor (TCR) with cognate ligands in the thymus may result in either maturation (positive selection) or death (negative selection). The intracellular pathways that control these opposed outcomes are not well characterized. We have generated mice expressing dominant-negative Ras (dnRas) and Mek-1 (dMek) transgenes simultaneously, either in otherwise normal animals, or in animals expressing a transgenic TCR, thereby permitting a comprehensive analysis of peptide-specific selection. In this system, thymocyte maturation beyond the CD4+8+ stage is blocked almost completely, whereas negative selection, assessed using an in vitro deletion protocol, is quantitatively intact. This suggests that activation of the mitogen-activated protein kinase (MAPK) cascade is necessary for positive selection, but irrelevant for negative selection. Generation of gamma/delta and of CD4-8- alpha/beta T cells proceeds normally despite blockade of the MAPK cascade. Hence, only cells that mature via conventional, TCR-mediated repertoire selection require activation of the MAPK pathway to complete their maturation.

Amino Acid Sequence↗
PubMed1996

Beta 2-microglobulin-dependent NK1.1+ T cells are not essential for T helper cell 2 immune responses.

A number of investigations have established the critical role of interleukin 4 (IL-4) in mediating the development of T helper (Th)2 effector cells in vitro and in vivo. Despite intensive study, the origin of the IL-4 required for Th2 priming and differentiation remains unclear. Natural killer (NK)1.1+ alpha/beta T cell receptor+ T(NT) cells, a unique lineage of cells capable of producing large amounts of IL-4 after activation in vivo, are important candidates for directing Th2 priming. These cells are selected by the nonpolymorphic major histocompatibility complex (MHC) class I molecule, CD1, and are deficient in beta 2-microglobulin (beta 2m)-null mice. We used beta 2m-deficient mice on both BALB/c and C57BL/6 backgrounds to examine their capacity to mount Th2 immune responses after challenge with a number of well-characterized antigens administered by a variety of routes. As assessed by immunization with protein antigen, infection with Leishmania major, embolization with eggs of Schistosoma mansoni, intestinal infection with Nippostrongylus brasiliensis, or induction of airway hyperreactivity to aerosolized antigen, beta 2m-deficient mice developed functional type 2 immune responses that were not substantially different than those in wild-type mice. Production of IL-4 and the generation of immunoglobulin E (IgE) and eosinophil responses were preserved as assessed by a variety of assays. Collectively, these results present a comprehensive analysis of type 2 immune responses in beta 2m-deficient mice, and indicate that beta 2m-dependent NT cells are not required for Th2 development in vivo.

Animals↗
PubMed2006

Single-channel properties of human NaV1.1 and mechanism of channel dysfunction in SCN1A-associated epilepsy.

Mutations in genes encoding neuronal voltage-gated sodium channel subunits have been linked to inherited forms of epilepsy. The majority of mutations (>100) associated with generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI) occur in SCN1A encoding the NaV1.1 neuronal sodium channel alpha-subunit. Previous studies demonstrated functional heterogeneity among mutant SCN1A channels, revealing a complex relationship between clinical and biophysical phenotypes. To further understand the mechanisms responsible for mutant SCN1A behavior, we performed a comprehensive analysis of the single-channel properties of heterologously expressed recombinant WT-SCN1A channels. Based on these data, we then determined the mechanisms for dysfunction of two GEFS+-associated mutations (R1648H, R1657C) both affecting the S4 segment of domain 4. WT-SCN1A has a slope conductance (17 pS) similar to channels found in native mammalian neurons. The mean open time is approximately 0.3 ms in the -30 to -10 mV range. The R1648H mutant, previously shown to display persistent sodium current in whole-cell recordings, exhibited similar slope conductance but had an increased probability of late reopening and a subfraction of channels with prolonged open times. We did not observe bursting behavior and found no evidence for a gating mode shift to explain the increased persistent current caused by R1648H. Cells expressing R1657C exhibited conductance, open probability, mean open time, and latency to first opening similar to WT channels but reduced whole-cell current density, suggesting decreased number of functional channels at the plasma membrane. In summary, our findings define single-channel properties for WT-SCN1A, detail the functional phenotypes for two human epilepsy-associated sodium channel mutants, and clarify the mechanism for increased persistent sodium current induced by the R1648H allele.

Alleles↗
PubMed1993

Killing, letting die, and withdrawing aid.

One of the aims of this article is to contribute to the identification of the empirical criteria governing the use of the concepts of killing and letting die. I will not attempt a comprehensive analysis of the concepts but will limit the inquiry to certain problematic cases -- namely, cases involving the removal or withdrawal of life-supporting aid or protection. The analysis of these cases will, however, shed light on the criteria for distinguishing killing and letting die in other cases as well. My overall aims in the article are partly constructive and partly skeptical. I hope to advance our understanding of the nature of the distinction between killing and letting die. This, I believe, will enable us to defend the moral relevance of the distinction against certain objections -- in particular, objections that claim that the distinction fails to coincide with commonsense moral intuitions. Yet I will suggest that, as we get clearer about the nature of the distinction and the sources of its intuitive appeal, it may seem that the intuitions it supports are not so well grounded as one could wish.

Abortion, Induced↗
PubMed2001

The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas.

A comprehensive analysis of somatic and germline mutations related to DNA mismatch-repair (MMR) genes can clarify the prevalence and mechanism of inactivation in colorectal carcinoma (CRC). In the present study, 257 unselected patients referred for CRC resection were examined for evidence of defective DNA MMR. In particular, we sought to determine the frequency of hereditary defects in DNA MMR in this cohort of patients. MMR status was assessed by testing of tumors for the presence or absence of hMLH1, hMSH2, and hMSH6 protein expression and for microsatellite instability (MSI). Of the 257 patients, 51 (20%) had evidence of defective MMR, demonstrating high levels of MSI (MSI-H) and an absence of either hMLH1 (n=48) or hMSH2 (n=3). All three patients lacking hMSH2, as well as one patient lacking hMLH1, also demonstrated an absence of hMSH6. DNA sequence analysis of the 51 patients with defective MMR revealed seven germline mutations-four in hMLH1 (two truncating and two missense) and three in hMSH2 (all truncating). A detailed family history was available for 225 of the 257 patients. Of the seven patients with germline mutations, only three had family histories consistent with hereditary nonpolyposis colorectal cancer. Of the remaining patients who had tumors with defective MMR, eight had somatic mutations in hMLH1. In addition, hypermethylation of the hMLH1 gene promoter was present in 37 (88%) of the 42 hMLH1-negative cases available for study and in all MSI-H tumors that showed loss of hMLH1 expression but no detectable hMLH1 mutations. Our results suggest that, although defective DNA MMR occurs in approximately 20% of unselected patients presenting for CRC resection, hereditary CRC due to mutations in the MMR pathway account for only a small proportion of patients. Of the 257 patients, only 5 (1.9%) appear to have unequivocal evidence of hereditary defects in MMR. The epigenetic (nonhereditary) mechanism of hMLH1 promoter hypermethylation appears to be responsible for the majority of the remaining patients whose tumors are characterized by defective DNA MMR.

Adaptor Proteins, Signal Transducing↗
PubMed2002

A comprehensive study of Candida-specific antibodies in the saliva of human immunodeficiency virus-positive individuals with oropharyngeal candidiasis.

Oropharyngeal candidiasis (OPC) is a common oral opportunistic infection among human immunodeficiency virus (HIV)-positive individuals. Although most cases of OPC correlate with reduced systemic levels of CD4(+) T cells, the role of humoral immunity in protection against mucosal candidiasis, including OPC, remains questionable. In the present study, a comprehensive analysis of saliva from 33 HIV-negative and 68 HIV-positive individuals, stratified by OPC status and peripheral CD4(+) cell count, was conducted to measure levels of total and Candida-specific immunoglobulin A(IgA) and IgG antibodies, including subclasses and secretory IgA. Despite changes in total immunoglobulin levels, when levels of Candida-specific antibodies were normalized to total protein or total immunoglobulin of the corresponding isotype, no distinct differences in IgG (including subclasses), IgA (including subclasses), or secretory IgA levels were seen, regardless of HIV status, OPC status, or CD4(+) cell count. These data suggest that when a complete repertoire of antibodies is evaluated, with appropriate normalization of data, there is no evidence of appreciable changes in levels of Candida-specific antibodies in saliva that would account for the prevalence of OPC among HIV-positive individuals.

AIDS-Related Opportunistic Infections↗
PubMed2002

Staphylococcus aureus express unique superantigens depending on the tissue source.

A comprehensive analysis of Staphylococcus aureus superantigen (SAG) genes was undertaken in isolates from a major hospital and compared with isolates from patients with toxic shock syndrome (TSS). Polymerase chain reaction (PCR) analysis included recently discovered SAGs. Staphylococcal enterotoxin (SE) G and SEI were uniquely expressed in genital isolates. Genital isolates were similar to TSS isolates, although the latter frequently expressed TSS toxin 1. Both had a high frequency of SEG/SEI and a high number of SAG genes per bacterium. Detection of an SAG gene by PCR correlated with positive results in functional assays for SAG activity. Levels of serum antibodies to SEG and SEI, but not to other superantigens, were higher in healthy women than in men and served as an independent measure of the higher frequency of exposure to SEG/SEI among women. Together, the data suggest a role for SEG/SEI or closely linked genes in the adaptation of S. aureus to the genital mucosa environment.

Adolescent↗
PubMed2003

Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-Mendelian Bardet-Biedl syndrome.

Bardet-Biedl syndrome is a genetically and clinically heterogeneous disorder caused by mutations in at least seven loci (BBS1-7), five of which are cloned (BBS1, BBS2, BBS4, BBS6, and BBS7). Genetic and mutational analyses have indicated that, in some families, a combination of three mutant alleles at two loci (triallelic inheritance) is necessary for pathogenesis. To date, four of the five known BBS loci have been implicated in this mode of oligogenic disease transmission. We present a comprehensive analysis of the spectrum, distribution, and involvement in non-Mendelian trait transmission of mutant alleles in BBS1, the most common BBS locus. Analyses of 259 independent families segregating a BBS phenotype indicate that BBS1 participates in complex inheritance and that, in different families, mutations in BBS1 can interact genetically with mutations at each of the other known BBS genes, as well as at unknown loci, to cause the phenotype. Consistent with this model, we identified homozygous M390R alleles, the most frequent BBS1 mutation, in asymptomatic individuals in two families. Moreover, our statistical analyses indicate that the prevalence of the M390R allele in the general population is consistent with an oligogenic rather than a recessive model of disease transmission. The distribution of BBS oligogenic alleles also indicates that all BBS loci might interact genetically with each other, but some genes, especially BBS2 and BBS6, are more likely to participate in triallelic inheritance, suggesting a variable ability of the BBS proteins to interact genetically with each other.

Alleles↗
PubMed2003

The challenge of implementation of preventive programs in a developing country: experiences, situations, and perspectives in Uruguay.

In recent years, Uruguay has seen an alarming increase in the percentage of persons with human immunodeficiency virus infection/acquired immunodeficiency syndrome who are injection drug users (IDUs) and their sex partners, which has consequently contributed to the rate of perinatal transmission. Development of preventive harm reduction and risk reduction strategies has become imperative. These strategies must be suitable for a developing country and focused on its population of IDUs. These strategies must include, as a preliminary step, a comprehensive analysis of the current local legal system and knowledge about the kinds of drugs used, the ways in which they are used, and their effects on public health. The conclusions of some studies and a pilot program that Institute of Social Research and Development, Instituto de Investigación y Desarrollo Social, Uruguay, implemented in 2001 have pointed to new avenues for the control of the epidemic spread among IDUs and to their social environment.

Adolescent↗
PubMed2003

An integrated haplotype map of the human major histocompatibility complex.

Numerous studies have clearly indicated a role for the major histocompatibility complex (MHC) in susceptibility to autoimmune diseases. Such studies have focused on the genetic variation of a small number of classical human-leukocyte-antigen (HLA) genes in the region. Although these genes represent good candidates, given their immunological roles, linkage disequilibrium (LD) surrounding these genes has made it difficult to rule out neighboring genes, many with immune function, as influencing disease susceptibility. It is likely that a comprehensive analysis of the patterns of LD and variation, by using a high-density map of single-nucleotide polymorphisms (SNPs), would enable a greater understanding of the nature of the observed associations, as well as lead to the identification of causal variation. We present herein an initial analysis of this region, using 201 SNPs, nine classical HLA loci, two TAP genes, and 18 microsatellites. This analysis suggests that LD and variation in the MHC, aside from the classical HLA loci, are essentially no different from those in the rest of the genome. Furthermore, these data show that multi-SNP haplotypes will likely be a valuable means for refining association signals in this region.

Chromosome Mapping↗
PubMed2004

Drug-induced liver injury associated with the use of nonnucleoside reverse-transcriptase inhibitors.

Human immunodeficiency virus (HIV)-infected patients frequently present with elevated levels of serum transaminases (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]). This has often been attributed to the hepatic effects of antiretroviral (ARV) drugs, including nonnucleoside reverse-transcriptase inhibitors (NNRTIs). A review of cohort studies investigating the incidence of hepatotoxicity among patients receiving ARV therapy suggests that the overall rate of ALT and/or AST elevations is similar among all ARVs. The rate of severe hepatotoxicity, ALT and/or ASTlevels >5 times the upper limit of normal (ULN), during therapy with NNRTIs is relatively low but may be significantly higher in patients with concurrent chronic viral hepatitis (hepatitis B or C). A comprehensive analysis of 17 randomized clinical trials of nevirapine demonstrated that 10% of all nevirapine-treated patients developed elevated levels of ALT and/or AST >5 times the ULN; however, almost two-thirds (6.3% of nevirapine-treated patients) of these elevations were asymptomatic. Symptomatic hepatic events were seen in 4.9% (3.2%-8.9%) of nevirapine-treated patients.

Adult↗
PubMed2004

How far do animals go? Determinants of day range in mammals.

Day range (daily distance traveled) is an important measure for understanding relationships between animal distributions and food resources. However, our understanding of variation in day range across species is limited. Here we present a day range model and compare predictions against a comprehensive analysis of mammalian day range. As found in previous studies, day range scales near the 1/4 power of body mass. Also, consistent with model predictions, taxonomic groups differ in the way day range scales with mass, associated with the most common diet types and foraging habitats. Faunivores have the longest day ranges and steepest body mass scaling. Frugivores and herbivores show intermediate and low scaling exponents, respectively. Day range in primates did not scale with mass, which may be consistent with the prediction that three-dimensional foraging habitats lead to lower exponents. Day ranges increase with group size in carnivores but not in other taxonomic groups.

Animals↗
PubMed2006

Intra- and interindividual epigenetic variation in human germ cells.

Epigenetics represents a secondary inheritance system that has been poorly investigated in human biology. The objective of this study was to perform a comprehensive analysis of DNA methylation variation between and within the germlines of normal males. First, methylated cytosines were mapped using bisulphite modification-based sequencing in the promoter regions of the following disease genes: presenilins (PSEN1 and PSEN2), breast cancer (BRCA1 and BRCA2), myotonic dystrophy (DM1), and Huntington disease (HD). Major epigenetic variation was detected within samples, since the majority of sperm cells of the same individual exhibited unique DNA methylation profiles. In the interindividual analysis, 41 of 61 pairwise comparisons revealed distinct DNA methylation profiles (P=.036 to 6.8 x 10(-14)). Second, a microarray-based epigenetic profiling of the same sperm samples was performed using a 12,198-feature CpG island microarray. The microarray analysis has identified numerous DNA methylation-variable positions in the germ cell genome. The largest degree of variation was detected within the promoter CpG islands and pericentromeric satellites among the single-copy DNA fragments and repetitive elements, respectively. A number of genes, such as EED, CTNNA2, CALM1, CDH13, and STMN2, exhibited age-related DNA methylation changes. Finally, allele-specific methylation patterns in CDH13 were detected. This study provides evidence for significant epigenetic variability in human germ cells, which warrants further research to determine whether such epigenetic patterns can be efficiently transmitted across generations and what impact inherited epigenetic individuality may have on phenotypic outcomes in health and disease.

Confounding Factors, Epidemiologic↗
PubMed1998

Molecular, serological, and clinical features of 16 consecutive cases of invasive streptococcal disease. Southeastern Minnesota Streptococcal Working Group.

We performed a comprehensive analysis of the molecular, serological, and clinical features of 16 consecutive cases of invasive streptococcal disease (ISD). The majority of cases were linked to two group A streptococcus (GAS) clones closely related by pulsed-field gel electrophoresis (PFGE) and designated as PFGE-1 and PFGE-1.1. These clones, serotyped as M-3, T-3/B3264, carried an allelic variant of the gene that encodes pyrogenic exotoxin A (speA3) and the gene that encodes streptococcal superantigen (SSA) but different emm alleles that encode M-protein. The characteristics and clinical features of patients were similar to those described in previous reports, regardless of the responsible GAS clone. However, worse clinical outcomes (shock and death) were more frequent when patients infected with PFGE1/1.1 clones were considered as a group and compared with all other patients as a group. One striking feature in some patients with deep tissue infection was a lack of inflammatory cells despite the presence of numerous streptococci. An evaluation of PFGE profiles of GAS isolated elsewhere demonstrated that the PFGE-1 clone has caused invasive disease in other locations in the United States and in Japan.

Adult↗
PubMed2005

Monte Carlo simulation of large electron fields.

Accurate simulation of large electron fields may lead to improved accuracy in Monte Carlo treatment planning while simplifying the commissioning procedure. We have used measurements made with wide-open jaws and no electron applicator to adjust simulation parameters. Central axis depth dose curves and profiles of 6-21 MeV electron beams measured in this geometry were used to estimate source and geometry parameters, including those that affect beam symmetry: incident beam direction and offset of the secondary scattering foil and monitor chamber from the beam axis. Parameter estimation relied on a comprehensive analysis of the sensitivity of the measured quantities, in the large field, to source and geometry parameters. Results demonstrate that the EGS4 Monte Carlo system is capable of matching dose distributions in the largest electron field to the least restrictive of 1 cGy or 1 mm, with D(max) of 100 cGy, over the full energy range. This match results in an underestimation of the bremsstrahlung dose of 10-20% at 15-21 MeV, exceeding the combined experimental and calculational uncertainty in this quantity of 3%. The simulation of electron scattering at energies of 15-21 MeV in EGS4 may be in error. The recently released EGSnrc/BEAMnrc system may provide a better match to measurement.

Computer Simulation↗
PubMed2003

Profile of gene expression in the subventricular zone after traumatic brain injury.

Neural stem cells, which reside in the subventricular zone (SVZ) and dentate gyrus (DG) of adult mammals, give rise to new neurons throughout life. However, these neural stem cells do not appear to contribute to regeneration in the damaged central nervous system. Following traumatic brain injury (TBI) in adult rats, the number of proliferating cells labeled with bromodeoxyuridine (BrdU) is significantly increased in the bilateral SVZ and DG; however, these proliferating cells do not contribute to effective regeneration in the damaged area. To gain insight into the molecular mechanisms of these biological actions, changes in gene expression in the SVZ after brain trauma were examined by cDNA microarray. Of 9,596 genes screened, 97 were upregulated and 204 were downregulated. Classifying these genes according to their function suggests that TBI affects a broad range of cellular functions. The validity of the data was confirmed by RT-PCR. The expression of some genes localized in the SVZ was confirmed by in situ hybridization. This combined strategy is effective for comprehensive analysis of the pathophysiological changes in the SVZ after brain injury and should contribute to the understanding of the molecular events that occur after injury. In the future, this may enable regeneration of the damaged central nervous system.

Animals↗
PubMed2000

Reversal of pathology in the entire brain of mucopolysaccharidosis type VII mice after lentivirus-mediated gene transfer.

Gene transfer vectors derived from human immunodeficiency virus (HIV-1) efficiently transduce nondividing cells and remain stably integrated in their genome. Long-term expression of reporter genes has been documented after intracerebral injection of these vectors. Using a HIV-based vector, we looked for a reversal of brain damage in the beta-glucuronidase-deficient mucopolysaccharidosis type VII mouse, an animal model of human lysosomal storage diseases. The vector suspension was injected stereotactically in the brain of 10-week-old animals, an age at which storage lesions are patent in glia, perivascular cells, and neurons. Either a single intrastriatal injection or multiple injections in both cerebral hemispheres and in the cerebellum were performed. Local tolerance, enzyme delivery, and correction of storage lesions were investigated by comprehensive analysis of serial sections of the entire brain of mice killed 6 or 16 weeks postinjection. Histochemical staining detected enzyme activity in widely distributed areas, the size of which increased with time. Clearance of lysosomal storage extended far beyond enzyme-positive areas. In mice receiving multiple injections of the vector, complete correction or significant reduction of the pathology was observed in every section, suggesting disease regression in the entire brain. These results may have implications for the treatment of neurological symptoms in lysosomal storage diseases.

Animals↗
PubMed2002

Thoracoscopy: the preferred approach for the resection of selected posterior mediastinal tumors.

The posterior mediastinum is a common site for neurogenic tumors. These are mostly asymptomatic and detected incidentally during radiologic investigations. However, they occasionally present with compressive or neurologic symptoms. The tumors are mostly benign but can also be malignant. Left untreated, they continue to grow. Therefore, once detected, resection is always advised. Traditionally, resection has been performed by standard posterolateral thoracotomy. More recently, such tumors have been removed thoracoscopically. We report our experience with three such cases and present a comprehensive analysis of cases of thoracoscopic resection of posterior mediastinal neurogenic tumors reported in the English literature to suggest guidelines for their current management.

Adult↗