Helicobacter pylori (Hp) infection triggers a chronic influx of polymorphonuclear leukocyte neutrophils (PMNs) into the gastric mucosa. Although Hp reside in a neutrophil-rich environment, how these ...organisms evade phagocytic killing is largely unexplored. We now show that live Hp (strains 11637, 60190, DT61A, and 11916) are readily ingested by PMNs and induce a rapid and strong respiratory burst that is comparable to PMA. Relative to other particulate stimuli, Hp are more potent activators of PMNs than opsonized zymosan, Staphylococcus aureus, or Salmonella. Strikingly, biochemical and microscopic analyses demonstrate that Hp disrupt NADPH oxidase targeting such that superoxide anions are released into the extracellular milieu and do not accumulate inside Hp phagosomes. Specifically, nascent Hp phagosomes acquire flavocytochrome b558 but do not efficiently recruit or retain p47phox or p67phox. Superoxide release peaks at 16 min coincident with the appearance of assembled oxidase complexes in patches at the cell surface. Oxidant release is regulated by formalin-resistant and heat-sensitive bacterial surface factors distinct from urease and Hp(2-20). Following opsonization with fresh serum, Hp triggers a modest respiratory burst that is confined to the phagosome, and ingested bacteria are eliminated. We conclude that disruption of NADPH oxidase targeting allows unopsonized Hp to escape phagocytic killing, and our findings support the hypothesis that bacteria and PMNs act in concert to damage the gastric mucosa.
Mutations in the BRCA2 gene are dominantly inherited but cause cancers when the wild-type allele has loss of heterozygosity (LOH) within the cancer. Because most disease-associated BRCA2 mutations ...are protein-truncating mutations, a test for truncated BRCA2 proteins should identify most BRCA2 hereditary cancers.
We have developed a tissue truncation test to identify truncated BRCA2 proteins in breast cancer tissue biopsies in vivo that does not use amplification or genetic manipulations. N-terminal and C-terminal antibodies are used to visualize protein truncation by demonstrating that the beginning of the protein is present but the end (ie, terminus) is absent.
A quantitative C-terminal immunostaining score or a C-terminal to N-terminal truncation ratio correctly classified 20 of 21 breast cancers arising in BRCA2 mutation carriers and 57 of 58 cancers arising outside the context of a multiple-case breast cancer family. This represents a sensitivity of 95% and a specificity of 98%. Because of the presence of C-terminal BRCA2 protein and atypical clinical features of the misclassified cancer in a BRCA2 mutation carrier, we performed polymerase chain reaction and sequence analyses on this cancer. The results showed continued presence of the BRCA2 wild-type allele in the cancer, which indicated that intact BRCA2 protein was present in this cancer.
This immunohistochemistry-based test (which takes only 4 hours) appears to identify BRCA2 hereditary cancer with high accuracy. The test also appears to diagnose the biochemical loss of BRCA2 protein in cancers (ie, BRCA2-mutant genotype), which will usually but not always agree with the presence of a germline BRCA2 mutation found by susceptibility testing by DNA sequencing of blood samples.
Exposure of hematopoietic cells to DNA-damaging agents induces cell-cycle arrest at G1 and G2/M checkpoints. Previously, it was shown that DNA damage–induced growth arrest of hematopoietic cells can ...be overridden by treatment with cytokine growth factors, such as erythropoietin (EPO) or interleukin-3 (IL-3). Here, the cytokine-activated signaling pathways required to override G1 and G2/M checkpoints induced by γ-irradiation (γ-IR) are characterized. Using factor-dependent myeloid cells stably expressing EPO receptor (EPO-R) mutants, it is shown that removal of a minimal domain required for PI-3K signaling abrogated the ability of EPO to override γ-IR–induced cell-cycle arrest. Similarly, the ability of cytokines to override γ-IR–induced arrest was abolished by an inhibitor of PI-3K (LY294002) or by overexpression of dominant-negative Akt. Moreover, the ability of EPO to override these checkpoints in cells expressing defective EPO-R mutants could be restored by overexpression of a constitutively active Akt. Thus, activation of a PI-3K/Akt signaling pathway is required for cytokine-dependent suppression of DNA-damage induced checkpoints. Together, these findings suggest a novel role for PI-3K/Akt pathways in the modulation of growth arrest responses to DNA damage in hematopoietic cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This trial showed that in patients with lymphangioleiomyomatosis (LAM), a progressive, cystic lung disease in women, sirolimus therapy was associated with stabilization of lung function, reduction in ...symptoms, and improvement in qualityof-life measures.
Lymphangioleiomyomatosis (LAM) is an uncommon systemic disease that is associated with cystic destruction of the lung, chylous pleural effusions, and abdominal tumors such as renal angiomyolipomas.
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,
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LAM affects women almost exclusively and occurs sporadically, developing in about 5 persons per 1 million; it also affects 30 to 40% of women with tuberous sclerosis complex (TSC). Lung function, measured as the forced expiratory volume in 1 second (FEV
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), declines at the rate of 75 to 118 ml per year
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–
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; clinically important respiratory impairment, recurrent pneumothoraxes, and hypoxemia develop in most patients within a decade after the . . .
Studies of indoor allergen exposures are often limited by the cost and logistics of sending technicians to homes to collect dust. In this study we evaluated the feasibility of having subjects collect ...their own dust samples. The objectives were to compare allergen concentrations between subject- and technician-collected samples and to examine the sample return rate. Using a dust collection device and written instructions provided to them by mail, 102 subjects collected a combined dust sample from a bed and bedroom floor. Later the same day, a technician collected a side-by-side sample. Dust samples were weighed and analyzed for the cat allergen Fel d 1 and the dust mite allergen Der p 1. Fifty additional subjects who were enrolled by telephone were mailed dust collection packages and asked to return a dust sample and questionnaire by mail. A technician did not visit their homes. Correlations between subject- and technician-collected samples were strong for concentrations of Fel d 1 (r = 0.88) and Der p 1 (r = 0.87). With allergen concentrations dichotomized at lower limits of detection and clinically relevant thresholds, agreements between methodologies ranged from 91 to 98%. Although dust weights were correlated (r = 0.48, p < 0.001), subjects collected lighter samples. Among the group of 50 subjects, 46 returned a dust sample and completed questionnaire. The median number of days to receive a sample was 15. With some limitations, subject-collected dust sampling appears to be a valid and practical option for epidemiologic and clinical studies that report allergen concentration as a measure of exposure.
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BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This forum contrasts two perspectives regarding methodology, written by researchers with avowedly opposing epistemologies. Jeffrey Checkel represents the positivist side, with Kevin Dunn advocating ...post-positivism. To clarify the assumptions underpinning this juxtaposition, Audie Klotz & Cecelia Lynch revisit the characterization of this epistemological divide & suggest that it unduly overshadows significant agreement. Scholars such as Checkel and Dunn, they claim, should be able to see common ground once they understand each others' terminology. To probe this potential, Checkel and Dunn elaborate on how & why they conduct research in particular ways. Their exchange highlights some commonalities but also suggests abiding limits to the reconciliation between analyses based on causal mechanisms & those based on discursive practices. References. Adapted from the source document.
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BFBNIB, DOBA, INZLJ, IZUM, KILJ, NMLJ, NUK, ODKLJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK, ZRSKP
The aerobic oxidation of 5-hydroxy pentenes to trans-tetrahydrofurans (THFs), the Mukaiyama oxidation, has in recent years emerged as a powerful tool in synthetic chemistry. In this report we ...describe the first crystal structures of 2,4-dioxo-alkanoic acid dialkylamide complexes for both Co(II) and Co(III) salts. The Co(II) structures show an unprecedented arrangement of atoms, with a central Co(II)(H
2
O)
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flanked by two Co(II) atoms each coordinated with three anionic chelating ligands. The dimeric Co(III) structures show two anionic chelating ligands and bridging hydroxyl groups.Key words: aerobic oxidation, trans-tetrahydrofuran (THF), cobalt, X-ray crystallography, oxidation, coordination.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract only Background: Preoperative anemia is associated with adverse outcomes after cardiac surgery, but its association with postoperative outcomes after open and endovascular procedures is not ...well established. Elderly patients have a decreased tolerance to anemia and are at high risk for complications after vascular procedures. The objective of this study was to assess the impact of preoperative anemia (hematocrit<39%) on postoperative 30-day mortality and adverse cardiac events in patients ≥65 years of age undergoing elective vascular procedures. Methods and Results: Patients (n=31,857) were identified from the American College of Surgeons' 2007-09 National Surgical Quality Improvement Program (NSQIP) - a prospective, multicenter (>250) database maintained across the United States. The primary and secondary outcomes of interest were 30-day mortality and a composite end point of death or cardiac event (cardiac arrest or myocardial infarction), respectively. Forty-seven percent of the study population was anemic. Anemic patients had a postoperative mortality and cardiac event rate of 2.4% and 2.3% in contrast to the 1.2% and 1.2%, respectively, in patients with hematocrit within the normal range (p<0.0001). On multivariate analysis, we found a 4.2% (95% confidence interval, 1.9%-6.5%) increase in the adjusted risk of 30-day postoperative mortality for every percentage point of hematocrit decrease from the normal range. Conclusions: The presence and degree of preoperative anemia are independently associated with 30-day death and adverse cardiac events in patients ≥ 65 years undergoing elective open and endovascular procedures. Identification and treatment of anemia should be an important component of preoperative care for patients undergoing vascular operations.
Management of vertical strabismus secondary to restrictive conditions can be challenging for both the patient and practitioner. The purpose of this paper is to identify both common and uncommon ...causes of vertical restrictive strabismus, to discuss the evaluation of these conditions, and to briefly review the etiology and recommendations for surgical management.
Current literature was reviewed as well as the surgical techniques that have been found to be most useful from experience over the past twenty years of practice.
Surgical realignment and elimination of diplopia is both challenging and problematic. Surgery should be designed to relieve restriction, with attention to identifying and managing incomitance. Furthermore, it is important to establish realistic goals with patients.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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