Core beliefs: the basis for school nursing practice.
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Humans↗
Biomedical subjects
P Anderson
Publications and source records attributed to P Anderson.
Looking at the road ahead for nurse prescribing.
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Community Health Nursing↗
The 72-kDa component of signal recognition particle is cleaved during apoptosis.
Proteins cleaved by apoptotic caspases are commonly recognized by autoantibodies found in the serum of patients with rheumatic disease. We report that the 72-kDa signal recognition particle (SRP) protein, a rare target of autoantibodies found in the serum of patients with dermatomyositis and systemic lupus erythematosus, is rapidly cleaved in Jurkat T cells treated with apoptotic (i.e. Fas ligation, treatment with gamma or ultraviolet radiation, or co-culture with anisomycin or staurosporine) but not proliferative (CD3 cross-linking) stimuli. Cleavage of SRP 72 produces a 66-kDa amino-terminal fragment and a 6-kDa carboxyl-terminal fragment that is selectively phosphorylated on serine residues. Cleavage of SRP 72 is prevented by chemical and peptide caspase inhibitors, and by overexpression of bcl-2, an inhibitor of apoptotic cell death. Analysis of the carboxyl terminus of SRP 72 has identified a putative cleavage site (SELD/A) for group III caspases, and carboxyl-terminal serine residues that are highly conserved in phylogeny. Both serine phosphorylation and caspase cleavage of SRP 72 are observed in cells derived from human, dog, rat, and mouse. Canine SRP 72 is cleaved in vitro by recombinant caspase 3 but retains the ability to mediate transport of a signal peptide-containing protein into the endoplasmic reticulum lumen. The 72-kDa component of the SRP joins a growing list of autoantigens that undergo post-translational modifications during programmed cell death.
Amino Acid Sequence↗
Perturbation of fuel homeostasis caused by overexpression of the glucose-6-phosphatase catalytic subunit in liver of normal rats.
The terminal step in hepatic gluconeogenesis is catalyzed by glucose-6-phosphatase, an enzyme activity residing in the endoplasmic reticulum and consisting of a catalytic subunit (glucose-6-phosphatase (G6Pase)) and putative accessory transport proteins. We show that Zucker diabetic fatty rats (fa/fa), which are known to exhibit impaired suppression of hepatic glucose output, have 2.4-fold more glucose-6-phosphatase activity in liver than lean controls. To define the potential contribution of increased hepatic G6Pase to development of diabetes, we infused recombinant adenoviruses containing the G6Pase cDNA (AdCMV-G6Pase) or the beta-galactosidase gene into normal rats. Animals were studied by one of three protocols as follows: protocol 1, fed ad libitum for 7 days; protocol 2, fed ad libitum for 5 days, fasted overnight, and subjected to an oral glucose tolerance test; protocol 3, fed ad libitum for 4 days, fasted for 48 h, subjected to oral glucose tolerance test, and then allowed to refeed overnight. Hepatic glucose-6-phosphatase enzymatic activity was increased by 1.6-3-fold in microsomes isolated from AdCMV-G6Pase-treated animals in all three protocols, and the resultant metabolic profile was similar in each case. AdCMV-G6Pase-treated animals exhibited several of the abnormalities associated with early stage non-insulin-dependent diabetes mellitus, including glucose intolerance, hyperinsulinemia, decreased hepatic glycogen content, and increased peripheral (muscle) triglyceride stores. These animals also exhibited significant decreases in circulating free fatty acids and triglycerides, changes not normally associated with the disease. Our studies show that overexpression of G6Pase in liver is sufficient to perturb whole animal glucose and lipid homeostasis, possibly contributing to the development of metabolic abnormalities associated with diabetes.
Animals↗
Overexpression of protein targeting to glycogen (PTG) in rat hepatocytes causes profound activation of glycogen synthesis independent of normal hormone- and substrate-mediated regulatory mechanisms.
Protein targeting to glycogen (PTG), also known as PPP1R5, is a widely expressed member of a growing family of proteins that target protein phosphatase-1 (PP-1) to glycogen particles. Because PTG also binds to glycogen synthase and phosphorylase kinase, it has been suggested that it serves as a "scaffold" for efficient activation of glycogen synthesis. However, very little is known about the metabolic effects of PTG. In this study, we have used recombinant adenovirus to overexpress PTG in primary rat hepatocytes, a cell type with high glycogenic capacity. We find that overexpression of PTG potently activates glycogen synthesis in cultured hepatocytes. Surprisingly, the glycogenic effect of PTG is observed even in the complete absence of carbohydrates or insulin in the culture medium. Furthermore, glycogenolytic agents such as forskolin or glucagon are largely ineffective at activating glycogen degradation in PTG overexpressing hepatocytes, even though large increases in cAMP levels are demonstrated. These metabolic effects of PTG overexpression are accompanied by a 3.6-fold increase in glycogen synthase activation state and a 40% decrease in glycogen phosphorylase activity. Our results are consistent with a model in which PTG overexpression "locks" the hepatocyte in a glycogenic mode, presumably via its ability to promote interaction of enzymes of glycogen metabolism with PP-1.
3T3 Cells↗
Positive margins after cervical conization as an indicator of residual dysplasia.
Objective: To determine the significance of positive margins of resection after cervical conization as an indicator of residual dysplasia.Materials and Methods: A retrospective analysis for patients who underwent cervical conization either by loop electrosurgical excision procedure or cold knife conization between 1986 and 1997 at Montefiore Medical Center and North Central Bronx Hospital. The factors evaluated included grade of dysplasia with respect to positive or negative margins and post-procedure follow-up. Differences among groups were evaluated using the chi(2) and Fisher's Exact test.Results: Of a total of 179 patients, 99 had positive margins of resection and 80 had negative margins of resection. Twenty-six patients had CIN I, of which 10 had positive margins of resection and 16 had negative margins of resection. There were 30 patients with CIN II, of which 13 had positive margins and 17 had negative margins. One hundred fourteen patients had CIN III/carcinoma in situ (CIS), of which 68 had positive margins of resection while 46 had negative margins of resection. Nine patients had microinvasive disease (MIC), of which 8 had positive margins of resection and 1 had negative margin of resection. The correlation between higher grades of dysplasia and the likelihood of having positive margins was noted to be statistically significant (P =.02). Patients were followed up from a period of 6 weeks to 5 years.Of the patients with CIN I and positive margins, 5 had a normal post-cone Papanicolaou smear while 2 had an abnormal post-cone Papanicolaou smear. Seven of 9 patients with CIN II and positive margins had normal initial post-procedure Papanicolaou smear while only 2 had abnormal initial post follow-up Papanicolaou smear. Twenty-five patients with CIN III/CIS and positive margins had normal Papanicolaou smears at their initial post-procedure follow-up while 36 patients had an abnormal initial follow-up. Six of 8 patients with MIC and positive margins had documented follow-up. Of these 6, 2 had normal post-procedure Papanicolaou smears while 4 had abnormal post-procedure Papanicolaou smears. This approaches statistical significance. Additionally, the incidence of residual disease was analyzed in hysterectomy specimens with respect to grade of dysplasia. No patients with CIN I and positive margins were treated with hysterectomy. Of the 3 patients with CIN II treated with hysterectomy, 2 had residual dysplasia. Of the 21 patients with CIN II/CIS who underwent hysterectomy, 10 had residual disease. Of the 5 patients with MIC who underwent hysterectomy, 3 had residual disease.Conclusion: The likelihood of positive margins of resection increases with higher dysplasia. The incidence of abnormal initial post-procedure Papanicolaou smear appears to be increased with increasing grade of dysplasia. Interestingly, there does not appear to be an increase in the incidence of residual dysplasia when hysterectomy is performed for positive margin of resection after conization for high grade dysplasia.
Journal Article↗
Modification of Ran GTPase-activating protein by the small ubiquitin-related modifier SUMO-1 requires Ubc9, an E2-type ubiquitin-conjugating enzyme homologue.
Covalent modification of the Ran GTPase-activating protein RanGAP1 with the ubiquitin-related protein SUMO-1 promotes its association with Nup358, a component of the cytoplasmic fibrils emanating from the nuclear pore complex (1,2). In Xenopus egg extracts, Nup358 can be found in a complex with Ubc9 (3), a structural homologue of the E2-type ubiquitin-conjugating enzymes (UBCs). Here we show that a subset of the human homologue of Ubc9 (HsUbc9) colocalizes with RanGAP1 at the nuclear envelope. HsUbc9 forms thiolester conjugates with recombinant SUMO-1, but not with recombinant ubiquitin, indicating that it is functionally distinct from E2-type UBCs. Finally, HsUbc9 is required for the modification of RanGAP1 by SUMO-1. These results suggest that HsUbc9 is a component of a novel enzymatic cascade that modifies RanGAP1, and possibly other substrates, with SUMO-1.
Adenosine Triphosphate↗
RNA-binding protein TIAR is essential for primordial germ cell development.
Primordial germ cells (PGCs) give rise to both eggs and sperm via complex maturational processes that require both cell migration and proliferation. However, little is known about the genes controlling gamete formation during the early stages of PGC development. Although several mutations are known to severely reduce the number of PGCs reaching and populating the genital ridges, the molecular identity of only two of these genes is known: the c-kit receptor protein tyrosine kinase and the c-kit ligand (the steel factor). Herein, we report that mutant mice lacking TIAR, an RNA recognition motif/ribonucleoprotein-type RNA-binding protein highly expressed in PGCs, fail to develop spermatogonia or oogonia. This developmental defect is a consequence of reduced survival of PGCs that migrate to the genital ridge around embryonic day 11.5 (E11.5). The numbers of PGCs populating the genital ridge in TIAR-deficient embryos are severely reduced compared to wild-type embryos by E11.5 and in the mutants PGCs are completely absent at E13.5. Furthermore, TIAR-deficient embryonic stem cells do not proliferate in the absence of exogenous leukemia inhibitory factor in an in vitro methylcellulose culture assay, supporting a role for TIAR in regulating cell proliferation. Because the development of PGCs relies on the action of several growth factors, these results are consistent with a role for TIAR in the expression of a survival factor or survival factor receptor that is essential for PGC development. TIAR-deficient mice thus provide a model system to study molecular mechanisms of PGC development and possibly the basis for some forms of idiopathic infertility.
Aging↗
Association of phosphorylated serine/arginine (SR) splicing factors with the U1-small ribonucleoprotein (snRNP) autoantigen complex accompanies apoptotic cell death.
Proteins subject to proteolysis or phosphorylation during apoptosis are commonly precipitated by autoantibodies found in the serum of patients with systemic lupus erythematosus (SLE). We screened a panel of murine monoclonal and human monospecific sera reactive with known autoantigens for their ability to selectively precipitate phosphoproteins from apoptotic Jurkat T cell lysates. Sera known to recognize the U1-small nuclear ribonucleoprotein (snRNP) complex (confirmed by their ability to precipitate U1-snRNA) selectively precipitated a phosphoprotein complex (pp54, pp42, pp34, and pp23) from apoptotic lysates. Monoclonal antibodies reactive with U1-snRNP proteins precipitated the same phosphoprotein complex from apoptotic lysates. The phosphorylation and/or recruitment of these proteins to the U1-snRNP complex is induced by multiple apoptotic stimuli (e.g., Fas ligation, gamma irradiation, or UV irradiation), and is blocked by overexpression of bcl-2. The U1-snRNP-associated phosphoprotein complex is immunoprecipitated by monoclonal antibodies reactive with serine/arginine (SR) proteins that comprise a structurally related family of splicing factors. The association of phosphorylated SR proteins with the U1-snRNP complex in cells undergoing apoptosis suggests a mechanism for regulation of alternative splicing of apoptotic effector molecules.
Animals↗
Activation-induced NK cell death triggered by CD2 stimulation.
Both T cells and natural killer (NK) cells express CD2, the target of an alternative activation pathway that induces the proliferation of both cell types. The mitogenic response to CD2 ligation requires the co-expression of CD3:TCR in T cells and FcgammaRIII in NK cells, suggesting that these receptors are involved in transducing the response initiated by CD2. The ability of FcgammaRIII to trigger the activation-induced death of IL-2-primed NK cells led us to investigate the potential for CD2 to trigger activation-induced NK cell death. Our results reveal that the same anti-CD2 monoclonal antibodies (mAb) that activate freshly isolated NK cells induce apoptosis in IL-2-primed NK cells. CD2-induced apoptosis results in chromatin condensation, DNA fragmentation and cleavage of caspase-3. Activation-induced NK cell death triggered by CD2 ligation is extremely rapid (DNA fragmentation is first observed at 90 min) and it is not inhibited by neutralizing antibodies reactive with TNF-alpha or Fas ligand. Whereas mAb reactive with distinct CD2 epitopes (i.e. T11.1, T11.2, and T11.3) are required for activation-induced T cell death, mAb reactive with a single CD2 epitope are sufficient for activation-induced NK cell death. The ability of CD2, CD16, and CD94 to induce apoptosis in IL-2-primed lymphocytes suggests that cytokine priming changes the response to a signaling cascade that is common to each of these activation receptors.
Apoptosis↗
Posttranslational protein modifications, apoptosis, and the bypass of tolerance to autoantigens.
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Animals↗
Effects of subchronic exposure to cadmium chloride on endocrine and metabolic functions in rainbow trout Oncorhynchus mykiss.
Adult and juvenile rainbow trout, Oncorhynchus mykiss, were exposed for 30 days to CdCl2 in water (10 and 25 micrograms Cd/L for adults, and 1 and 5 micrograms Cd/L for juveniles) to investigate effects of subchronic exposures to Cd on the hypothalamo-pituitary-interrenal and the hypothalamo-pituitary-thyroid axis, and on metabolic status. liver size and glycogen content and body mass gain were significantly reduced in the exposed adult fish and similar changes were detected in the juveniles. Plasma cortisol levels increased after exposure to the lower dose but decreased at the higher dose. Plasma T3 and T4 tended to decrease in the exposed adult fish. No significant differences in plasma glucose or cholesterol levels were detected between the controls and the exposed fish, plasma calcium levels were lower in the exposed fish. The results indicate that long-term exposures to Cd at sublethal doses have adverse effects on the physiological status of the fish and that these effects are mediated partly through alterations of endocrine function.
Animals↗
mRNA surveillance mitigates genetic dominance in Caenorhabditis elegans.
Nonsense mutant mRNAs are unstable in all eucaryotes tested, a phenomenon termed nonsense-mediated mRNA decay (NMD) or mRNA surveillance. Functions of the seven smg genes are required for mRNA surveillance in Caenorhabditis elegans. In Smg(+) genetic backgrounds, nonsense-mutant mRNAs are unstable, while in Smg(-) backgrounds such mRNAs are stable. Previous work has demonstrated that the elevated level of nonsense-mutant mRNAs in Smg(-) animals can influence the phenotypic effects of heterozygous nonsense mutations. Certain nonsense alleles of a muscle myosin heavy chain gene are recessive in Smg(+) backgrounds but strongly dominant in Smg(-) backgrounds. Such alleles probably express disruptive myosin polypeptide fragments whose abundance is elevated in smg mutants due to elevation of mRNA levels. We report here that mutations in a variety of C. elegans genes are strongly dominant in Smg(-), but recessive or only weakly dominant in Smg(+) backgrounds. We isolated 32 dominant visible mutations in a Smg(-) genetic background and tested whether their dominance requires a functional NMD system. The dominance of 21 of these mutations is influenced by NMD. We demonstrate, furthermore, that in the case of myosin, the dominant-negative effects of nonsense alleles are likely to be due to expression of N-terminal nonsense-fragment polypeptides, not to mistranslation of the nonsense codons. mRNA surveillance, therefore, may mitigate potentially deleterious effects of many heterozygous germline and somatic nonsense or frame-shift mutations. We also provide evidence that smg-6, a gene previously identified as being required for NMD, performs essential function(s) in addition to its role in NMD.
Animals↗
Scanning microradiographic studies of rates of in vitro demineralization in human and bovine dental enamel.
The aim was to measure frequently and with precision the local integrated mineral loss through small areas of the natural surface of human and bovine enamel during in vitro demineralization using an X-ray photon-counting system (scanning microradiography). The method used was an adaptation of photographic longitudinal microradiography in which the attenuation of X-rays through the enamel is measured in the direction of acid attack, i.e., normal to the enamel surface. The mass of mineral (assumed to be hydroxyapatite) per unit exposed area was measured over 15 microm dia. circles at a series of positions as a function of time in blocks of human and bovine enamel immersed in 0.1 mol/l acetic acid buffered to pH 4.0 with NaOH. There was an initial period (approx. 45 h for human, approx. 75 h for bovine enamel) during which the mineral loss with time was sigmoidal, followed by a nearly linear loss for the remainder of the experiment, in some cases up to 500 h. The initial sigmoidal period may be due to properties of surface enamel or be associated with the development of a surface layer overlying subsurface demineralization. The essentially constant rate of mineral loss after the surface layer has formed confirms earlier observations and is consistent with a rate-limiting process occurring at the dissolving enamel surfaces of the advancing front, and not by transport of ions within the lesion. Small perturbations from a linear loss were seen, which were approximately periodic for human enamel. The slope of the linear period was rather constant within one human or bovine block, but variable between blocks without a clear distinction between human and bovine enamel.
Animals↗
Diagnosis and treatment of prostatitis in Canada.
OBJECTIVES: There is a general consensus among physicians that the present management of chronic prostatitis is dismal. We undertook a survey of Canadian primary care physicians (PCPs) and urologists to determine the degree and source of frustration and to analyze present practice patterns in this disease. METHODS: Five thousand PCPs and all 545 Canadian urologists were asked to complete a comprehensive computer-assisted telephone survey that explored practice characteristics, attitudes, and diagnostic and treatment strategies in the management of prostatitis. Randomization of attribute banks, adherence to questionnaire routing, validation by on-site monitoring, and possible bias were addressed. RESULTS: Completed interviews were obtained from 10% of PCPs and 28% of urologists. PCPs see on average 3.5 (median 2) patients with prostatitis per month and urologists see on average 21.8 (median 11) patients with prostatitis per month. All physicians experience significantly more frustration in treating prostatitis than they do in treating patients with benign prostatic hyperplasia (BPH) and prostate cancer, and they perceive that prostatitis affects patients' quality of life significantly more than BPH and almost as much as prostate cancer. The degree of frustration and unhappiness in dealing with prostatitis is driven by a lack of confidence and comfort in their ability to accurately diagnose and subsequently rationalize treatment. Most PCPs and urologists continue to employ steps in addition to history and physical examination to establish a diagnosis but only a few PCPs and a third of urologists use specific lower urinary tract cultures. Physicians tend to use trimethoprim or trimethoprim-sulfamethoxazole (TMP-SMX) or a fluoroquinolone as their usual first line therapy for chronic prostatitis. The most commonly used therapeutic strategy (40%) for chronic prostatitis was TMP-SMX as first line therapy and a fluoroquinolone as second line therapy. CONCLUSIONS: There is widespread frustration, discomfort, and lack of confidence in both PCPs' and urologists' perceived ability to manage prostatitis. Physicians have expressed a desire for a better understanding of this disease, simpler and clearer diagnostic guidelines, and more rational treatment strategies.
Canada↗
Serum antibody responses of weanling mice and two-year-old children to pneumococcal-type 6A-protein conjugate vaccines of differing saccharide chain lengths.
Type 6A pneumococcal polysaccharide (PS) fractions having mean lengths 2, 7, or 14 repeat units were coupled to tetanus toxoid, giving conjugates T-6A-2, T-6A-7 or T-6A-14. In weanling outbred mice, type-6A serum antibody responses were minimal to T-6A-7 but significantly higher to T-6A-2 and T-6A-14. In contrast, two-year-old humans responded increasingly to T-6A-2, T-6A-7, and T-6A-14; type 6B antibody rose, but variably. Upon challenge with 6B PS at age 3 yr, conjugate-primed children made anamnestic responses. T-6A-14, containing the longest saccharide chains (and highest saccharide:protein mass ratio) excelled in priming as well as antibody induction.
Adult↗
Contact areas and pressures between native patellas and prosthetic femoral components.
Contact areas and pressures between native patellas and a prosthetic condylar design femoral component were measured at flexion angles of 30 degrees, 60 degrees, and 90 degrees. These were compared to measurements obtained with a domed all-polyethylene patellar component. Mean native patellar contact areas were found to be fourfold greater than seen with the prosthetic patellar component. Contact stresses in the native patellas were below the yield strength of articular cartilage in 80% of the contact area. By contrast, stresses measured in the prosthetic patella exceeded the yield strength of ultrahigh molecular weight polyethylene in 64% of the measured contact area. Contact areas and stresses were not significantly effected by flexion angle. Although contact areas and stresses reflect only a part of the dynamics of the patellofemoral articulation this information would support the selective retention of the native patella in total knee arthroplasty.
Aged↗
Functions of the Caenorhabditis elegans regulatory myosin light chain genes mlc-1 and mlc-2.
Caenorhabditis elegans contains two muscle regulatory myosin light chain genes, mlc-1 and mlc-2. To determine their in vivo roles, we identified deletions that eliminate each gene individually and both genes in combination. Functions of mlc-1 are redundant to those of mlc-2 in both body-wall and pharyngeal muscle. mlc-1(0) mutants are wild type, but mlc-1(0) mlc-2(0) double mutants arrest as incompletely elongated L1 larvae, having both pharyngeal and body-wall muscle defects. Transgenic copies of either mlc-1(+) or mlc-2(+) rescue all defects of mlc-1(0) mlc-2(0) double mutants. mlc-2 is redundant to mlc-1 in body-wall muscle, but mlc-2 performs a nearly essential role in the pharynx. Approximately 90% of mlc-2(0) hermaphrodites arrest as L1 larvae due to pharyngeal muscle defects. Lethality of mlc-2(0) mutants is sex specific, with mlc-2(0) males being essentially wild type. Four observations suggest that hermaphrodite-specific lethality of mlc-2(0) mutants results from insufficient expression of the X-linked mlc-1(+) gene in the pharynx. First, mlc-1(0) mlc-2(0) double mutants are fully penetrant L1 lethals in both hermaphrodites and males. Second, in situ localization of mlc mRNAs demonstrates that both mlc-1 and mlc-2 are expressed in the pharynx. Third, transgenic copies of either mlc-1(+) or mlc-2(+) rescue the pharyngeal defects of mlc-1(0) mlc-2(0) hermaphrodites. Fourth, a mutation of the dosage compensation gene sdc-3 suppresses hermaphrodite-specific lethality of mlc-2(0) mutants.
Animals↗