BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer

BACKGROUND: To define the incidence of BRCA1 mutations among patients seen in clinics that evaluate the risk of breast cancer, we analyzed DNA samples from women seen in this setting and constructed probability tables to provide estimates of the likelihood of finding a BRCA1 mutation in individual families. METHODS: Clinical information, family histories, and blood for DNA analysis were obtained from 263 women with breast cancer. Conformation-sensitive gel electrophoresis and DNA sequencing were used to identify BRCA1 mutations. RESULTS: BRCA1 mutations were identified in 16 percent of women with a family history of breast cancer. Only 7 percent of women from families with a history of breast cancer but not ovarian cancer had BRCA1 mutations. The rates were higher among women from families with a history of both breast and ovarian cancer. Among family members, an average age of less than 55 years at the diagnosis of breast cancer, the presence of ovarian cancer, the presence of breast and ovarian cancer in the same woman, and Ashkenazi Jewish ancestry were all associated with an increased risk of detecting a BRCA1 mutation. No association was found between the presence of bilateral breast cancer or the number of breast cancers in a family and the detection of a BRCA1 mutation, or between the position of the mutation in the BRCA1 gene and the presence of ovarian cancer in a family. CONCLUSIONS: Among women with breast cancer and a family history of the disease, the percentage with BRCA1 coding-region mutations is less than the 45 percent predicted by genetic-linkage analysis. These results suggest that even in a referral clinic specializing in screening women from high-risk families, the majority of tests for BRCA1 mutations will be negative and therefore uninformative.     

Analysis of course errors on CVOR antennas (including effects ofmutual coupling between elements)

A VHF omnidirectional radio range (VOR) is a navigation aid radio beacon facility, which provides aircraft with azimuth information relative to the VOR station in question as the origin. In Japan, two types of VOR-the conventional type (referred to as a CVOR) and the Doppler type (referred to as a DVOR)-are currently in use. An element known as the Alford loop antenna (ALA), which changes the loading reactance, is used for the VOR because the horizontally polarized wave and nondirectivity in the horizontal plane are preferred. A VOR antenna consists of a carrier antenna and a sideband antenna-an aircraft receives separate signals from these two antennas and compares them to obtain azimuth information. The mutual coupling between the elements forming the carrier and the sideband antenna affects the directivity of the single elements, resulting in errors in azimuth information. With the mutual coupling between the antenna elements being taken into consideration, a quantitative calculation was made by using the moment method-the results of the calculation made it clear that a loading reactance value of -320 Ω is better to make not mutually coupled elements nondirectional while a loading reactance value of -600 Ω is optimum to minimize the azimuth error of a CVOR     

Modulation characteristic of waveguide-type optical frequency combgenerator

We report the modulation characteristics of a waveguide-type optical frequency comb generator (WG-OFCG) with the advantages of compactness, high modulation index and low driving power. The characteristics of the optical frequency comb (OFC) generated when the modulation index exceeds 2π are discussed. The power of the modulation sidebands was measured by the optical heterodyne method with an external-cavity laser as a local oscillator. The dependence of the modulation index of the WG-OFCG on the modulation frequency up to 40 GHz was measured. The generation span of the OFC at the modulation frequency detuned from an integer multiple of the free spectral range (FSR) is discussed     

Compatibility of alkaline earth metal (Mg, Ca, Sr)-doped lanthanum chromites as separators in planar-type high-temperature solid oxide fuel cells

The mechanical, electrical and thermal properties of alkaline earth metal (Mg, Ca and Sr)-doped LaCrO₃ have been examined as separators in planar-type high-temperature solid oxide fuel cells. The maximum three-point bending strength at 1000°C in air was measured and found to be 186 MPa for LaCr_0.9Mg_0.1O₃, 36 MPa for La_0.9Ca_0.1CrO₃ and 77 MPa for La_0.9Sr_0.1CrO₃. The La_0.8Sr_0.2CrO₃ separator placed in both an oxidizing and a reducing environment at 1000°C showed almost the same electrical conductivities of the H₂ atmosphere, and the conductivity was independent of sample thickness in the range 0.5–3.0 mm. For all the doped LaCrO₃ perovskites, a difference between the thermal expansion behaviours of air and the H₂ atmosphere was observed. In particular, the thermal expansion slope for the first heating cycle under the H₂ atmosphere showed a marked change. The volume changes were due to the formation of oxygen defects in the perovskite structure. This revised version was published online in November 2006 with corrections to the Cover Date.     

Central motor conduction evaluation in glycogenosis type III

We report a 20-year-old man affected by glycogenosis type III with distal muscle weakness, more severe in distal leg muscles. The electromyogram showed myopathic features. Nerve conduction studies and central motor conduction after magnetic stimulation of the brain were normal. Our results suggest that there is no involvement of central motor pathways in this disease.     

Age-related changes in innervation in hypertrophic pyloric stenosis

BACKGROUND/PURPOSE: Recent reports have identified abnormal innervation of the circular muscle layer involving the fine intramuscular nerve fibers in hypertrophic pyloric stenous (HPS). HPS presenting after 3 months of age is rare. The aim of this study was to determine the distribution pattern of nerve fibers in the smooth muscle layers in HPS and correlate this with age at presentation. METHODS: Full-thickness pyloric muscle biopsy specimens were obtained from eight patients with HPS (five age 3 to 5 weeks, two age 3 months, and one age 7 months) and five controls with normal pylorus (age 5 days to 3 years). All specimens were stained with monoclonal antibody to the neural cell adhesion molecule (NCAM) using immunohistochemistry. RESULTS: There were many NCAM-positive nerve fibers in the circular and longitudinal muscle layers in the controls. No NCAM positive nerve fibers were seen in the circular or longitudinal muscle layers in the five cases of HPS in which the patients were less than 5 weeks old. In the two cases in which the patients were 3 months old, occasional NCAM-positive nerve fibers were seen in the circular layer, and moderate numbers of NCAM positive fibers were seen in the longitudinal muscle layers. Moderate numbers of NCAM-positive nerve fibers in the circular muscle layer and many NCAM positive nerve fibers in the longitudinal muscle layers were identified in the 7-month-old HPS patient. CONCLUSIONS: The data suggest that the pyloric muscle lacks innervation in the young HPS infant. Whereas, at 3 months of age the hypertrophied pyloric muscle is partially innervated, and at 7 months of age the pyloric muscle has practically normal innervation.     

Symbol rate and modulation level-controlled adaptivemodulation/TDMA/TDD system for high-bit-rate wireless data transmission

This paper proposes a time-division multiple-access/time-division duplex (TDMA/TDD)-based symbol rate and modulation level-controlled adaptive modulation system for high-bit-rate data transmission. The proposed system controls both the symbol rate and modulation level for the next transmission time slot according to the estimated carrier power to noise spectral density ratio (C/N₀) and delay spread for the time slot to achieve higher bit rate and higher transmission quality as well as higher delay-spread immunity. It is demonstrated by computer simulation and laboratory experiments that the proposed system can achieve a higher average bit rate with higher transmission quality in comparison with the fixed-rate quaternary phase-shift keying (QPSK) system and modulation level-controlled adaptive modulation system in both flat Rayleigh and frequency-selective fading environments. The simulated and experimental results also show that the proposed adaptive modulation techniques can be applied to 1-2-Mb/s indoor and outdoor microcellular systems with its delay spread of up to 250 ns and its terminal mobility of up to pedestrian speed without employing any special antifrequency-selective fading techniques, such as the adaptive equalizer and space diversity     

Phase I study of mitoxantrone plus etoposide with multidrug blockade by SDZ PSC-833 in relapsed or refractory acute myelogenous leukemia

PURPOSE: Expression of the multidrug resistance gene (MDR1) p170 protein is frequent in leukemic blasts from patients with relapsed acute myelogenous leukemia (AML). A phase I study using the nonimmunosuppressive MDR1 blocker SDZ PSC-833 (PSC) in combination with mitoxantrone (MITO) and etoposide (VP) was performed. PATIENTS AND METHODS: Starting doses (LVL0) of MITO (3.25 mg/m2/d on days 1 and 3 to 6) and VP (210 mg/m2/d on days 1 and 3 to 5) were 40% of the maximal-tolerated dose (MTD) from a prior study. A 1.5-mg/kg loading dose of PSC was followed by a 120-hour continuous infusion of 10 mg/kg/d on days 2 to 6. Blood samples for PSC, MITO, and VP pharmacokinetics (PK) were taken on days 1 and 3, and samples for MDR1 expression were taken on day 0. RESULTS: Severe mucositis developed in all patients at LVL0; therefore, MITO and VP doses were reduced to 2.5 and 170 mg/m2 (LVL-1) for the next seven patients, and this dose proved to be MTD. All LVL0 and three LVL-1 patients had transient elevations in the serum bilirubin level to > or = 4 mg/dL. Serum creatinine level increased to greater than 2 mg/dL in one case. There were no other grade 3 or 4 nonhematologic toxicities observed. The peripheral blood was cleared of leukemia in three LVL0 and four LVL-1 patients. The marrow was cleared of leukemic cells in one LVL0 and five LVL-1 patients, and a significant reduction in marrow leukemic infiltrate was observed in eight of 10. No patient achieved complete remission (CR), and all died of progressive disease (n = 8) or infection (n = 2). MDR1 expression was detected by fluorescent-activated cell sorter (FACS) analysis in five of seven cases. An elevated MDR1 mRNA level was detected by quantitative polymerase chain reaction (Q-PCR) in six of eight cases studied. Clearing of leukemia cells from the marrow occurred in four of six MDR1-positive and one of three MDR1-negative patients. Despite the fact that LVL0 doses had to be reduced due to toxicity, coadministration of PSC did not produce a consistent effect on MITO PK; however, it did repeatedly lead to increased levels of VP in the serum. CONCLUSION: We conclude that PSC-MITO-VP is a tolerable regimen with antileukemic activity. Addition of PSC necessitated a 66% reduction in MITO and VP doses from a prior study without PSC.     

Protective effects of CD-832 on organ damage in stroke-prone spontaneously hypertensive rats

Effects of a newly developed Ca2+ channel antagonist, (4R)-(-)-2-(nicotinoylamino)ethyl 3 nitrooxypropyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl) 3,5-pyridine-dicarboxylate (CD-832), on hypertensive complications in stroke-prone spontaneously hypertensive rats (SHRSPs) were compared with effects of diltiazem. We examined changes in histological and hematological parameters in SHRSPs given the following treatments at 8 to 20 weeks of age: (a) CD-832; (b) diltiazem; (c) no treatment. CD-832 and diltiazem were added to the diet, in doses of 0.05 and 0.15% (approximately 30 and 100 mg/kg per day), respectively, throughout the experimental period. In untreated control SHRSPs, systolic blood pressure increased and severe renal lesions such as fibrinoid necrosis, smooth muscle proliferation, glomerular and tubular lesions and some cardiac fibrosis were observed at age 20 weeks. 12-week repeated-administration of CD-832 and diltiazem led to a comparable hypotension and decreased heart rate. CD-832 and diltiazem decreased the ratios of weights of kidney and heart to body weight and the concentration of blood urea nitrogen and creatinine in serum, compared to values in controls. In SHRSPs treated with CD-832 and diltiazem, the incidence of renal lesions and myocardial fibrosis was significantly reduced when compared with control SHRSPs. These results suggest that 12-week repeated-administration of CD-832 prevents the development of hypertension and the incidence of organ damage in SHRSPs. CD-832 and diltiazem were equally efficacious in preventing organ damage but this organ-protective effect was obtained at a lower dose for CD-832 (30 mg/kg per day) than that of diltiazem (100 mg/kg per day).     

The molecular interaction of Fas and FAP-1. A tripeptide blocker of human Fas interaction with FAP-1 promotes Fas-induced apoptosis

Fas (APO-1/CD95), which is a member of the tumor necrosis factor receptor superfamily, is a cell surface receptor that induces apoptosis. A protein tyrosine phosphatase, Fas-associated phosphatase-1 (FAP-1), that was previously identified as a Fas binding protein interacts with the C-terminal 15 amino acids of the regulatory domain of the Fas receptor. To identify the minimal region of the Fas C-terminal necessary for binding to FAP-1, we employed an in vitro inhibition assay of Fas/FAP-1 binding using a series of synthetic peptides as well as a screen of random peptide libraries by the yeast two-hybrid system. The results showed that the C-terminal three amino acids (SLV) of human Fas were necessary and sufficient for its interaction with the third PDZ (GLGF) domain of FAP-1. Furthermore, the direct cytoplasmic microinjection of this tripeptide (Ac-SLV) resulted in the induction of Fas-mediated apoptosis in a colon cancer cell line that expresses both Fas and FAP-1. Since t(S/T)X(V/L/I) motifs in the C termini of several other receptors have been shown to interact with PDZ domain in signal transducing molecules, this may represent a general motif for protein-protein interactions with important biological functions.