...they continue a trend endorsed by an international committee to use the term "glaucoma" only for people who have suffered injury to the optic nerve as judged by visual field abnormality, combined ...with enlargement of the cup/disc ratio outside statistical limits for the population studied. ...we might question the assumptions that ACG prevalence in Singapore may be applied to the urban People's Republic of China generally and that Mongolian prevalence of ACG may be generalised to all rural Chinese.
We constrain parity-violating interactions to the surface of last scattering using spectra from the QUaD experiment's second and third seasons of observations by searching for a possible systematic ...rotation of the polarization directions of cosmic microwave background photons. We measure the rotation angle due to such a possible "cosmological birefringence" to be 0.55 degrees +/-0.82 degrees (random) +/-0.5 degrees (systematic) using QUaD's 100 and 150 GHz temperature-curl and gradient-curl spectra over the spectra over the multipole range 200<l<2000, consistent with null, and constrain Lorentz-violating interactions to <2 x 10;{-43} GeV (68% confidence limit). This is the best constraint to date on electrodynamic parity violation on cosmological scales.
The murine Brca2 gene encodes a nuclear protein implicated in DNA repair. Brca2 behaves as a tumor suppressor, but paradoxically, its truncation causes proliferative arrest and spontaneous ...chromosomal damage. Here, we report that inactivation of cell cycle checkpoints responsive to mitotic spindle disruption, by mutant forms of p53 or Bub1, relieves growth arrest and initiates neoplastic transformation in primary cells homozygous for truncated Brca2. Tumors from Brca2-deficient animals exhibit dysfunction of the spindle assembly checkpoint, accompanied by mutations in p53, Bub1, and Mad3L. The chromosomal aberrations precipitated by Brca2 truncation can be suppressed by mutant forms of Bub1 and p53. Thus, inactivating mutations in mitotic checkpoint genes likely cooperate with BRCA2 deficiency in the pathogenesis of inherited breast cancer, with important implications for treatment.
Constitutive inflammation and hemostatic activation have been identified as key contributors to the pathophysiology of sickle cell disease (SCD), leading to clinical consequences such as ...vaso-occlusive crises and stroke. Patients with hemoglobin SS (HbSS) and hemoglobin SC (HbSC) genotypes are reported to have different symptoms, as do patients in steady-state and crisis situations. Differences among these groups remain unclear in pediatric patients.
To compare hemostatic activity in HbSS and HbSC pediatric patients during steady state, in crisis, and in clinical follow-up and compare HbSS and HbSC patients with normal healthy children.
Whole-blood coagulation assay thromboelastography (TEG) was used to assess hemostatic activity. In parallel, flow cytometry was used to assess procoagulant surface expression of platelets and red blood cells.
TEG results indicated no significant differences in clotting onset (R time), clot maximum amplitude, or maximum rate of thrombus generation among steady-state, crisis, and follow-up subgroups of HbSS and HbSC patients. TEG parameters did not differ significantly between HbSC patients and healthy children, while HbSS patients showed significantly shorter R time and greater maximum amplitude and maximum rate of thrombus generation, all indicative of a constitutive hypercoagulable state. Flow cytometry results did not detect increased platelet integrin αIIbβ3 activation or red blood cell procoagulant surface expression in SCD patients compared with unaffected children.
Our results indicate that pediatric SCD patients with the HbSS genotype have constitutively activated hemostasis relative to HbSC patients and healthy children. It remains to be determined how treatments that improve clinical outcomes in SCD patients affect this constitutively hypercoagulable state.
•Sickle cell disease patients are at risk for vaso-occlusive crises and stroke.•We assessed hemostatic activity in SCD children (HbSS and HbSC) via thromboelastography.•Children were evaluated at baseline and in crisis.•We determined that HbSS patients are in a constitutive hypercoagulable state.
BACKGROUND: Malignant cells must maintain their telomeres, but genetic mechanisms responsible for telomere maintenance in tumors have only recently been discovered. In particular, mutations of the ...telomere binding proteins alpha thalassemia/mental retardation syndrome X-linked (ATRX) or death-domain associated protein (DAXX) have been shown to underlie a telomere maintenance mechanism not involving telomerase (alternative lengthening of telomeres), and point mutations in the promoter of the telomerase reverse transcriptase (TERT) gene increase telomerase expression and have been shown to occur in melanomas. METHODS: To further define the tumor types in which TERT plays a role, we surveyed 1,230 tumors of 60 different types. We also analyzed the relationship between median overall survival (OS) of patients with IDH1/2 and TERT promoter mutations in a panel of 473 adult gliomas with the hypothesis that genetic signatures capable of distinguishing among several types of gliomas could be established providing clinically relevant information that can serve as an adjunct to histopathological diagnosis. RESULTS: We found that tumors could be divided into types with low and high frequencies of TERT promoter mutations. The nine TERT-high tumor types almost always originated in tissues with relatively low rates of self renewal, including melanomas, liposarcomas, hepatocellular carcinomas, urothelial carcinomas, squamous cell carcinomas of the tongue, medulloblastomas, and subtypes of gliomas. TERT and ATRX mutations were mutually exclusive, suggesting that these two genetic mechanisms confer equivalent selective growth advantages. We found that mutations in the TERT promoter occurred in 74.2% of glioblastomas (GBM), but occurred in a minority of Grade II-III astrocytomas (18.2%). In contrast, IDH1/2 mutations were observed in 78.4% of Grade II-III astrocytomas, but were uncommon in primary GBM. In oligodendrogliomas, TERT promoter and IDH1/2 mutations co-occurred in 79% of cases. Patients whose Grade III-IV gliomas exhibit TERT promoter mutations alone predominately have primary GBMs associated with poor median OS rates (11.5 months). Patients whose gliomas exhibit IDH1/2 mutations alone predominately have astrocytic morphologies and exhibit a median OS of 57 months while patients whose tumors exhibit both TERT promoter and IDH1/2 mutations predominately exhibit oligodendroglial morphologies and exhibit median OS of 125 months. CONCLUSIONS: In addition to their implications for understanding the relationship between telomeres and tumorigenesis, TERT mutations provide a biomarker that may aid in the classification and prognostication of brain tumors. SECONDARY CATEGORY: Tumor Biology.
The high incidence of loss of chromosome 10 alleles in glioblastoma multiforme suggests the presence on this chromosome of a tumor suppressor gene that is important in glioma tumorigenesis and ...progression. Our initial deletion mapping studies using restriction fragment length polymorphism markers indicated a common deletion region in 10q24-qter. In an attempt to localize the deleted region further, we screened a panel of 117 gliomas for loss of heterozygosity for chromosome 10 loci using 10 microsatellite markers. Seventeen tumors showed partial loss of a copy of chromosome 10 and were further analysed using 28 additional microsatellite markers. Of these, 10 had terminal deletion in the q arm, three had deletions in both p and q arms, two contained interstitial deletion in 10q and two carried deletions in 10p. In the 15 tumors with deletions in 10q, the minimal overlapping deletion region was in distal 10q between markers D10S587 and D10S216. Loci D10S587 and D10S216 are approximately mapped to a 5 cM region in 10q25.1.
This paper presents a 90-nm CMOS 10-Gb/s transceiver for chip-to-chip communications. To mitigate the effects of channel loss and other impairments, a 5-tap decision feedback equalizer (DFE) is ...included in the receiver and a 4-tap baud-spaced feed-forward equalizer (FFE) in the transmitter. This combination of DFE and FFE permits error-free NRZ signaling over channels with losses exceeding 30 dB. Low jitter clocks for the transmitter and receiver are supplied by a PLL with LC VCO. Operation at 10-Gb/s with good power efficiency is achieved by using half-rate architectures in both transmitter and receiver. With the transmitter producing an output signal of 1200mVppd, one transmitter/receiver pair and one PLL consume 300mW. Design enhancements of a half-rate DFE employing one tap of speculative feedback and four taps of dynamic feedback allow its loop timing requirements to be met. Serial link experiments with a variety of test channels demonstrate the effectiveness of the FFE/DFE equalization
Background. Several host- and procedure-related factors have been reported to increase the risk of permanent pacemaker (PPM) infection on the basis of descriptive analyses of case series. The purpose ...of this study is to assess the risk factors for PPM infection using case-control study methods. Methods. All patients who had a PPM implanted at our institution from January 1991 to December 2003 were retrospectively reviewed. Each patient who experienced a PPM infection was matched with 2 control subjects by age, sex, year of implantation, and duration of follow-up. Univariate and multivariable analyses were performed to identify significant risk factors for PPM infection. Results. Twenty-nine case patients and 58 control subjects met inclusion criteria. The majority (83%) of case patients presented with a pocket infection; a minority (10%) had PPM-related endocarditis. Staphylococcus species (69%) were the most common pathogens. On univariate analysis, previous PPM infection, malignancy, long-term corticosteroid use, multiple device revisions, a permanent central venous catheter, the presence of <2 pacing leads, and a lack of antibiotic prophylaxis at the time of PPM placement were associated with an increased risk of PPM infection. A multivariable logistic regression model identified long-term corticosteroid use (odds ratio OR, 13.90; 95% confidence interval CI, 1.27–151.7; P = .03) and the presence of <2 pacing leads versus 2 leads (OR, 5.41; 95% CI, 1.44–20.29; P = .01) as independent risk factors for PPM infection. In contrast, use of antibiotic prophylaxis prior to PPM implantation had a protective effect (OR, 0.087; 95% CI, 0.016–0.48; P = .005). Conclusions. These findings should assist clinicians in identifying patients who are at increased risk of PPM infection, as well as in developing strategies to minimize the modifiable risks.
TRAIL/Apo-2L has shown promise as an anti-glioma drug, based on investigations of TRAIL sensitivity in established glioma cell lines, but it is not known how accurately TRAIL signalling pathways of ...glioma cells in vivo are reproduced in these cell lines in vitro. To replicate as closely as possible the in vivo behaviour of malignant glioma cells, 17 early passage glioma cell lines and 5 freshly resected gliomas were exposed to TRAIL-based agents and/or chemotherapeutic drugs. Normal human hepatocytes and astrocytes and established glioma cell lines were also tested. Cross-linked TRAIL, but not soluble TRAIL, killed both normal cell types and cells from three tumours. Cells from only one glioma were killed by soluble TRAIL, although only inefficiently. High concentrations of cisplatin were lethal to glioma cells, hepatocytes and astrocytes. Isolated combinations of TRAIL and chemotherapy drugs were more toxic to particular gliomas than normal cells, but no combination was generally selective for glioma cells. This study highlights the widespread resistance of glioma cells to TRAIL-based agents, but suggests that a minority of high-grade glioma patients may benefit from particular combinations of TRAIL and chemotherapy drugs. In vitro sensitivity assays may help identify effective drug combinations for individual glioma patients.
Background: The National Cancer Institute (NCI)-sponsored clinical trials cooperative groups place more than 25 000 American patients in treatment trials every year. Equal access and proportional ...representation of all races/ethnicities is desired. Purpose: Our objectives were to evaluate the inclusion of African-Americans, Hispanics, and non-Hispanic whites in NCI-sponsored treatment trials and to determine if there is proportional racial/ethnic representation. Methods: During the period of January 1, 1991, through June 30, 1994, 99 495 cancer patients were enrolled in clinical trials and declared themselves as non-Hispanic black, non-Hispanic white, or Hispanic (of any race). In the analysis, participants in NCI treatment trials were subdivided into three age groups: birth to 19 years, 20–49 years, and 50 or more years. The racial/ethnic composition of each of these age groups was compared with the racial/ethnic makeup of the American population with cancer. Estimates of the number of incident cancer cases per year were made for each racial/ethnic group within each age group using data from the Surveillance, Epidemiology, and End Results (SEER) Program and the 1990 Census. The percentage of all cancer patients who were in each racial/ethnic group were compared with the population that entered clinical trials. Comparisons are also made separately for patients with leukemia and breast, colorectal, lung, and prostate cancers. Results: Among patients 0–19 years old, 20–49 years old, and 50 years old or older there is relatively proportional representation of non-Hispanic blacks, Hispanics, and non-Hispanic whites in trials. It is noted that more than 70% of cancer patients aged 0–19 years are estimated to enter cooperative group clinical trials compared with 4.0% of cancer patients aged 20–49 years and 1.5% of patients aged 50 years or older. Conclusions: Accrual of American cancer patients to NCI-sponsored treatment trials generally parallels the incident burden of disease among non-Hispanic African-Americans, Hispanics, and non-Hispanic whites. Implications: This study shows that the NCI clinical trials are, as a whole, racially/ethnically representative of the American population and suggests that there is equal access to NCI clinical trials.
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