Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “CHRISTMAS”

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 1,207 records · Page 67Linked to original sources

Cytokines and acute pancreatitis.

Cytokines have been shown to play a pivotal role in multiple organ dysfunction, a major cause of death in severe acute pancreatitis. Moreover, the two-hit hypothesis of the cytokine-induced systemic inflammatory response syndrome explains the variable individual response to severe acute pancreatitis and the impact of secondary events such as sepsis or therapeutic intervention. Many experimental anti-cytokine therapies have been administered following induction of experimental pancreatitis, and have proved to be therapeutic. Patients with severe pancreatitis present early because of pain. Clearly then a window for therapeutic intervention is available between onset of symptoms and peak pro-inflammatory cytokine expression. It is this fundamental observation that convinces many in the field that the treatment of AP will be one of the first clinical successes for novel drugs or therapy that seek to modulate the inflammatory response.

Acute Disease↗

Long-term follow-up of residual masses after chemotherapy in patients with non-seminomatous germ cell tumours.

This retrospective study was undertaken to determine the outcome of patients with non-seminomatous germ cell tumour who achieved a serological complete response but who had residual radiologic abnormalities upon completion of primary platinum-based chemotherapy. This was an analysis of 76 consecutive patients treated at Mount Vernon Hospital between 1983 and 1997. The patients were placed into two groups based upon whether they had surgical resection (surgery group, 48 patients) or observation (observation group, 28 patients) of residual radiologic masses on completion of initial chemotherapy (to enter the surgery group, complete surgical resection must have been achieved). The primary end-points were progression-free and overall survival. The percentage of patients alive with median follow-up 66 months was 90% for the surgery group and 80% for the observation group (P = 0.53, not significant). The percentage of patients continuously disease-free was 70% in the surgery group and 80% in the observation group (P = 0.31, not significant). In the small sub-group of patients with differentiated teratoma (TD) in the primary lesion who were observed, there was no excess risk of relapse or death. Patients who achieve a serological complete response after primary chemotherapy, but are left with </= 2 cm radiological masses that are not cystic and have responded, can be safely observed with diligent follow-up.

Adolescent↗

Undetectable ultrasensitive PSA after radical prostatectomy for prostate cancer predicts relapse-free survival.

Radical retropubic prostatectomy is considered by many centres to be the treatment of choice for men aged less than 70 years with localized prostate cancer. A rise in serum prostate-specific antigen after radical prostatectomy occurs in 10-40% of cases. This study evaluates the usefulness of novel ultrasensitive PSA assays in the early detection of biochemical relapse. 200 patients of mean age 61. 2 years underwent radical retropubic prostatectomy. Levels < or = 0.01 ng ml-1 were considered undetectable. Mean pre-operative prostate-specific antigen was 13.3 ng ml-1. Biochemical relapse was defined as 3 consecutive rises. The 2-year biochemical disease-free survival for the 134 patients with evaluable prostate-specific antigen nadir data was 61.1% (95% CI: 51.6-70.6%). Only 2 patients with an undetectable prostate-specific antigen after radical retropubic prostatectomy biochemically relapsed (3%), compared to 47 relapses out of 61 patients (75%) who did not reach this level. Cox multivariate analysis confirms prostate-specific antigen nadir < or = 0.01 ng ml-1 to be a superb independent variable predicting a favourable biochemical disease-free survival (P < 0.0001). Early diagnosis of biochemical relapse is feasible with sensitive prostate-specific antigen assays. These assays more accurately measure the prostate-specific antigen nadir, which is an excellent predictor of biochemical disease-free survival. Thus, sensitive prostate-specific antigen assays offer accurate prognostic information and expedite decision-making regarding the use of salvage prostate-bed radiotherapy or hormone therapy.

Adult↗

The membrane organization of leukotriene synthesis.

Cell signaling leading to the formation of leukotriene (LT)C(4) requires the localization of the four key biosynthetic enzymes on the outer nuclear membrane and endoplasmic reticulum. Whether any macromolecular organization of these proteins exists is unknown. By using fluorescence lifetime imaging microscopy and biochemical analysis, we demonstrate the presence of two distinct multimeric complexes that regulate the formation of LTs in RBL-2H3 cells. One complex consists of multimers of LTC(4) synthase and the 5-lipoxygenase activating protein (FLAP). The second complex consists of multimers of FLAP. Surprisingly, all LTC(4) synthase was found to be in association with FLAP. The results indicate that the formation of LTC(4) and LTB(4) may be determined by the compartmentalization of biosynthetic enzymes in discrete molecular complexes.

5-Lipoxygenase-Activating Proteins↗

Defective muscle basement membrane and lack of M-laminin in the dystrophic dy/dy mouse.

M-laminin is a major member of the laminin family of basement membrane proteins. It is prominently expressed in striated muscle and peripheral nerve. M-laminin is deficient in patients with the autosomal recessive Fukuyama congenital muscular dystrophy but is normal in patients with the sex-linked Duchenne and Becker muscular dystrophies. We have examined M-laminin expression in mice with autosomal recessive muscular dystrophy caused by the mutation dy. The heavy chain of M-laminin was undetectable in skeletal muscle, heart muscle, and peripheral nerve by immunofluorescence and immunoblotting in homozygous dystrophic dy/dy mice but was normal in heterozygous and wild-type nondystrophic mice. Immunofluorescence confirmed the presence of other major basement membrane proteins in the dystrophic mice. Very low levels of M-laminin heavy chain mRNA were detected by Northern blotting of muscle and heart tissue from dy/dy mice, suggesting that M-laminin heavy-chain mRNA may be produced at very low levels or is unstable. Information about the chromosomal localization of the M heavy-chain in human and mouse suggests that a mutation in the M-chain gene causes the muscular dystrophy in dy/dy mice. The dy mouse may provide a model for autosomal muscular dystrophies in humans and facilitate studies of functions of M-laminin.

Animals↗

Expression of the CYP4F3 gene. tissue-specific splicing and alternative promoters generate high and low K(m) forms of leukotriene B(4) omega-hydroxylase.

Cytochrome P450 4F3 (CYP4F3) catalyzes the inactivation of leukotriene B(4) by omega-oxidation in human neutrophils. To understand the regulation of CYP4F3 expression, we analyzed the CYP4F3 gene and cloned a novel isoform (CYP4F3B) that is expressed in fetal and adult liver, but not in neutrophils. The CYP4F3 gene contains 14 exons and 13 introns. The cDNAs for CYP4F3A (the neutrophil isoform) and CYP4F3B have identical coding regions, except that they contain exons 4 and 3, respectively. Both exons code for amino acids 66-114 but share only 27% identity. When expressed in COS-7 cells, the K(m) of CYP4F3B was determined to be 26-fold higher than the K(m) of CYP4F3A using leukotriene B(4) as a substrate. 5'-Rapid amplification of cDNA end studies reveal that the CYP4F3A and CYP4F3B transcripts have 5'-termini derived from different parts of the gene and are initiated from distinct transcription start sites located 519 and 71 base pairs (bp), respectively, from the ATG initiation codon. A consensus TATA box is located 27 bp upstream of the CYP4F3B transcription start site, and a TATA box-like sequence is located 23 bp upstream of the CYP4F3A transcription start site. The data indicate that the tissue-specific expression of functionally distinct CYP4F3 isoforms is regulated by alternative promoter usage and mutually exclusive exon splicing.

Adult↗

Differential localization of 5- and 15-lipoxygenases to the nuclear envelope in RAW macrophages.

Leukotriene formation is initiated in myeloid cells by an increase in intracellular calcium and translocation of 5-lipoxygenase from the cytoplasm to the nuclear envelope where it can utilize arachidonic acid. Monocyte- macrophages and eosinophils also express 15-lipoxygenase, which converts arachidonic acid to 15(S)-hydroxyeicosatetraenoic acid. Enhanced green fluorescent 5-lipoxygenase (5-LO) and 15-lipoxygenase (15-LO) fusion proteins were expressed in the cytoplasm of RAW 264.7 macrophages. Only 5-lipoxygenase translocated to the nuclear envelope after cell stimulation, suggesting that differential subcellular compartmentalization can regulate the generation of leukotrienes versus 15(S)-hydroxyeicosatetraenoic acid in cells that possess both lipoxygenases. A series of truncation mutants of 5-LO were created to identify putative targeting domains; none of these mutants localized to the nuclear envelope. The lack of targeting of 15-LO was then exploited to search for specific targeting motifs in 5-LO, by creating 5-LO/15-LO chimeric molecules. The only chimera that could sustain nuclear envelope translocation was one which involved replacement of the N-terminal 237 amino acids with the corresponding segment of 15-LO. Significantly, no discrete targeting domain could be identified in 5-LO, suggesting that sequences throughout the molecule are required for nuclear envelope localization.

Amino Acid Sequence↗

Alternative splicing determines the function of CYP4F3 by switching substrate specificity.

Diversity of cytochrome P450 function is determined by the expression of multiple genes, many of which have a high degree of identity. We report that the use of alternate exons, each coding for 48 amino acids, generates isoforms of human CYP4F3 that differ in substrate specificity, tissue distribution, and biological function. Both isoforms contain a total of 520 amino acids. CYP4F3A, which incorporates exon 4, inactivates LTB4 by omega-hydroxylation (Km = 0.68 microm) but has low activity for arachidonic acid (Km = 185 microm); it is the only CYP4F isoform expressed in myeloid cells in peripheral blood and bone marrow. CYP4F3B incorporates exon 3 and is selectively expressed in liver and kidney; it is also the predominant CYP4F isoform in trachea and tissues of the gastrointestinal tract. CYP4F3B has a 30-fold higher Km for LTB4 compared with CYP4F3A, but it utilizes arachidonic acid as a substrate for omega-hydroxylation (Km = 22 microm) and generates 20-HETE, an activator of protein kinase C and Ca2+/calmodulin-dependent kinase II. Homology modeling demonstrates that the alternative exon has a position in the molecule which could enable it to contribute to substrate interactions. The results establish that tissue-specific alternative splicing of pre-mRNA can be used as a mechanism for changing substrate specificity and increasing the functional diversity of cytochrome P450 genes.

Alternative Splicing↗

Membrane localization and topology of leukotriene C4 synthase.

Leukotriene C(4) (LTC(4)) synthase conjugates LTA(4) with GSH to form LTC(4). Determining the site of LTC(4) synthesis and the topology of LTC(4) synthase may uncover unappreciated intracellular roles for LTC(4), as well as how LTC(4) is transferred to its export carrier, the multidrug resistance protein-1. We have determined the membrane localization of LTC(4) synthase by immunoelectron microscopy. In contrast to the closely related five-lipoxygenase-activating protein, LTC(4) synthase is distributed in the outer nuclear membrane and peripheral endoplasmic reticulum but is excluded from the inner nuclear membrane. We have combined immunofluorescence with differential membrane permeabilization to determine the topology of LTC(4) synthase. The active site of LTC(4) synthase is localized in the lumen of the nuclear envelope and endoplasmic reticulum. These results indicate that the synthesis of LTB(4) and LTC(4) occurs in different subcellular locations and suggests that LTC(4) must be returned to the cytoplasmic side of the membrane for export by multidrug resistance protein-1. The differential localization of two very similar integral membrane proteins suggests that mechanisms other than size-dependent exclusion regulate their passage to the inner nuclear membrane.

Animals↗

Myeloid expression of cytochrome P450 4F3 is determined by a lineage-specific alternative promoter.

The cytochrome P450 4F3 (CYP4F3) gene encodes two functionally distinct enzymes that differ only by the selection of exon 4 (CYP4F3A) or exon 3 (CYP4F3B). CYP4F3A inactivates leukotriene B4, a reaction that has significance for controlling inflammation. CYP4F3B converts arachidonic acid to 20-hydroxyeicosatetraenoic acid, a potent activator of protein kinase C. We have previously shown that mRNAs coding for CYP4F3A and CYP4F3B are generated from distinct transcription start sites in neutrophils and liver. We therefore investigated mechanisms that regulate the cell-specific expression of these two isoforms. Initially, we analyzed the distribution of CYP4F3 in human leukocytes and determined a lineage-specific pattern of isoform expression. CYP4F3A is expressed in myeloid cells and is coordinate with myeloid differentiation markers such as CD11b and myeloperoxidase during development in the bone marrow. In contrast, CYP4F3B expression is restricted to a small population of CD3+ T lymphocytes. We identified distinct transcriptional features in myeloid, lymphoid, and hepatic cells that indicate the presence of multiple promoters in the CYP4F3 gene. The hepatic promoter depends on a cluster of hepatocyte nuclear factor sites 123-155 bp upstream of the initiator ATG codon. The myeloid promoter spans 400 bp in a region 468-872 bp upstream of the ATG codon; it is associated with clusters of CACCT sites and can be activated by ZEB-2, a factor primarily characterized as a transcriptional repressor in cells that include lymphocytes. ZEB-2 interacts with C-terminal binding protein and Smads, and this would provide opportunities for integrating environmental signals in myelopoiesis and inflammation.

Base Sequence↗

Cytochrome P-450 4F18 is the leukotriene B4 omega-1/omega-2 hydroxylase in mouse polymorphonuclear leukocytes: identification as the functional orthologue of human polymorphonuclear leukocyte CYP4F3A in the down-regulation of responses to LTB4.

Leukotriene B(4) (LTB(4)) is a potent chemoattractant for polymorphonuclear leukocytes (PMN) and other cells. Human PMN inactivate LTB(4) by omega-oxidation catalyzed by cytochrome P-450 (CYP) 4F3A. The contribution of the enzymatic inactivation of LTB(4) by CYP4Fs to down-regulating functional responses of cells to LTB(4) is unknown. To elucidate the role of CYP4F-mediated inactivation of LTB(4) in terminating the responses of PMN to LTB(4) and to identify a target for future genetic studies in mice, we have identified the enzyme that catalyzes the omega-1 and omega-2 oxidation of LTB(4) in mouse myeloid cells as CYP4F18. As determined by mass spectrometry, this enzyme catalyzes the conversion of LTB(4) to 19-OH LTB(4) and to a lesser extent 18-OH LTB(4). Inhibition of CYP4F18 resulted in a marked increase in calcium flux and a 220% increase in the chemotactic response of mouse PMN to LTB(4). CYP4F18 expression was induced in bone marrow-derived dendritic cells by bacterial lipopolysaccharide, a ligand for TLR4, and by poly(I.C), a ligand for TLR3. However, when bone marrow-derived myeloid dendritic cells trafficked to popliteal lymph nodes from paw pads, the expression of CYP4F18 was down-regulated. The results identify CYP4F18 as a critical protein in the regulation of LTB(4) metabolism and functional responses in mouse PMN and identify it as the functional orthologue of human PMN CYP4F3A.

Animals↗

Outbreaks of acute gastroenteritis associated with Norwalk-like viruses in campus settings.

Norwalk-like viruses (NLVs) are transmitted by fecally contaminated food, water, fomites, and person-to-person contact. They are a leading cause of acute gastroenteritis epidemics in industrialized countries. NLV outbreaks are characterized by a 12- to 48-hour incubation period; nausea, vomiting, and diarrhea for 24 to 72 hours; and high secondary attack rates. NLV infections spread rapidly on college and university campuses because of close living quarters, shared bathrooms and common rooms, many food handlers, popular self-service salad bars in dining halls, and person-to-person contact through sports and recreational activities. The illness is generally mild and self-limited but an outbreak can strain the resources of campus health services and cause high absenteeism among both students and staff. Treatment is primarily through antiemetic medication and oral rehydration. Prevention and control of NLV outbreaks rests on promoting hand washing; enforcement of strict hygiene in all food preparation areas; and prompt, rigorous cleaning of potentially contaminated areas where someone has been ill.

Acute Disease↗

College health 2050.

On May 31, 2040, Kunta Kinte Sanchez O'Shaunessey-Chan, MOND, president of the North American College Health Association (NACHA), gave the keynote address at the opening session of the annual meeting held in the Marriott Conference Center, Saskatoon, Saskatchewan. He recounted important events of the past 50 years that have shaped the college health field of today, and he predicted important trends for the next decade. Although his speech was given in Spanish, it was simultaneously translated into English, French, and 15 other languages requested by attendees. The English version follows.

Forecasting↗

The history of sections in the American College Health Association.

The founders of the American College Health Association (ACHA) recognized the importance of regional groups (affiliates) and worked actively to foster their formation and continued existence. In 1932, D. F. Smiley, MD, described the concept of establishing ACHA regions and suggested combining institutional membership in both the national and regional organizations. Significant affiliate representation in the association's governance structure finally became a reality in 1987, when regional representatives became permanent members of the board of directors. Standing committees of the association were transformed into the present ACHA sections in 1957, and a new category for individual membership established for college health professionals interested in participating in educational activities of the new sections. In many ways, the changes in the association's governance that occurred in 1987 are reminiscent of the original structure of the 1920-1970 era, when the organization was much smaller and essentially an association of college health center directors.

Governing Board↗