An origin of excess vibrational entropies at grain boundaries in Al, Si and MgO: a first-principles analysis with lattice dynamics.

First-principles lattice dynamics is applied to symmetric tilt grain boundaries (GBs) in Al, Si and MgO, with the goal of revealing critical factors in determining excess vibrational entropies at the atomic level. Excess vibrational entropies at GBs are found to vary depending on the substances. Al GBs tend to show larger excess entropies and hence larger temperature dependence of the GB free energies than those in Si and MgO. Most of the Si GBs show small excess entropies. For Al and MgO, atom-projected vibrational entropies are well correlated with bond-length changes at GB cores, and have large positive values as bond lengths increase for GB atoms. This demonstrates that a similar mechanism likely dominates excess vibrational entropies of GBs for both substances, despite their dissimilar bonding nature. For Si GBs, atoms with threefold coordination do not simply follow such a correlation, implying the importance of other factors that are different from bond-length changes. These systematic comparisons will be a foothold for understanding a physical origin of excess entropies at GBs even in more complex substances.

Retrospective analysis of the survival benefit of chemotherapy for recurrent or advanced epithelial ovarian carcinoma in patients previously treated with paclitaxel plus platinum-based chemotherapy.

AIM: The outcomes of treatment for women with recurrent or advanced epithelial ovarian carcinoma previously treated with pacli- taxel plus platinum-based chemotherapy were analyzed. MATERIALS AND METHODS: Retrospective analysis was performed in a total of 65 series of treatments provided for 35 patients with a history of paclitaxel plus platinum-based chemotherapy. The chemotherapy regimens used were classified into the following four types for analysis: conventional paclitaxel plus carboplatin therapy (TC arm), pegylated liposomal doxorubicin-containing regimens (PLD arm), CPT-11-containing regimens (CPT-11 arm), and others. Disease-control rates (DCRs) were compared and subjected to univariate analysis. Progression-free survival (PFS) was determined from the date of the first cycle of each chemotherapy with the Kaplan-Meier method, and comparisons were performed using the log-rank test. RESULTS: DCR was 80%, 71%, and 26% for the TC, PLD, and CPT-l arms, respectively. The median PFS was 286, 372, and 76 days for the TC, PLD, and CPT-11 arms, respectively. There was no discernible difference in PFS between the TC and the PLD arm. In contrast, PFS of the CPT- 11 arm was significantly shorter than that of the TC and PLD arms. In addition, three of seven (42.9%) treatments in the PLD arm maintained a progression-free period for longer than one year, while only one of 25 (4%) treatments in the TC arm maintained a progression-free period for more than one year. CONCLUSIONS: The PFS of PLD is similar to that of TC. PLD-containing regimens might have a potential benefit with a higher PFS over one year than the TC regimen.

Unexpected ovarian malignancy following laparoscopic excision of adnexal masses.

STUDY QUESTION: What are the frequency of, and the prognosis for, ovarian malignancies among patients who have undergone laparoscopic surgery for an adnexal mass? SUMMARY ANSWER: The rate of unexpected ovarian malignancy resected by laparoscopy was 1.5%, and the presence of an early-stage unexpected ovarian malignancy did not alter patient prognosis. WHAT IS KNOWN ALREADY: Even when laparoscopic surgery is used for the resection of an adnexal mass that is most likely benign, some patients are found to have malignant tumors post-operatively. STUDY DESIGN, SIZE, DURATION: The pathologic reports of 884 women who underwent laparoscopic resection of an adnexal mass between May 2007 and September 2013 at the Department of Obstetrics and Gynecology of Aichi Medical University Hospital, Nagakute, Japan, were reviewed retrospectively. PARTICIPANTS/MATERIALS, SETTING, METHODS: We conducted a systematic review of the medical records of patients diagnosed post-operatively with ovarian malignancies and abstracted their demographic, clinical and pathologic data. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 1128 adnexal masses were resected, and 13 patients (1.5%) had ovarian malignancies: 6 ovarian cancer (1 mucinous, 1 endometrioid G1, 1 granulosa cell and 3 carcinoid) and 7 borderline tumors (BOTs; 5 mucinous and 2 serous). Of these, two patients with mucinous BOTs underwent fertility-sparing surgery and six patients underwent staging laparotomy. Due to cyst rupture during surgery, nine patients (69.2%) were upgraded to tumor stage IC. Secondary surgeries were performed in eight patients, with a mean interval of 88.9 days (range, 39-182 days) between the surgeries. All patients were alive and without evidence of disease at follow-up (mean follow-up, 38 months; range, 6-80 months). LIMITATIONS, REASONS FOR CAUTION: This was a retrospective study with a small case number and a short follow-up period. WIDER IMPLICATIONS OF THE FINDINGS: The presence of an early-stage unexpected ovarian malignancy did not alter the patient's prognosis, even if there was a significant delay in surgical staging after the finding of an unexpected malignancy during laparoscopy. STUDY FUNDING/COMPETING INTERESTS: No funding was obtained for this study and the authors report no conflicts of interest.

Nonrandom point defect configurations and driving force transitions for grain boundary segregation in trivalent cation doped ZrO2.

The energetically favorable spatial configuration of M(3+) ions and oxide-ion vacancies near a symmetrical grain boundary (GB) in cubic zirconia is determined for various trivalent species M(3+) (M = Al, Sc, Y, Gd, La), and the driving force for grain boundary segregation (GBS) quantitatively examined using atomistic Monte Carlo simulations in conjunction with static lattice calculations. For a high concentration of ∼10 mol %, it is found that point defects near a GB plane preferentially occupy specific sites to minimize total lattice energy, rather than being randomly distributed. Systematic analysis shows that energetically stable configurations of segregants vary depending on their ionic radii. Analysis of the driving force for GBS as a function of dopant concentration reveals that three important factors govern GBS. First, occupation of specific sites by point defects is necessary to minimize the total lattice energy; enrichment of point defects near the GB plane with random configuration does not decrease the total lattice energy significantly because of strong Coulombic interactions. Second, the factors governing GBS change with increasing dopant concentration. At dilute concentrations, relief of bond strain is the dominant factor, while at high concentrations Coulombic interactions, which depend strongly on the specific arrangement of defects, become another dominant factor. Third, the stabilization of matrix cations, Zr(4+) ions, is the dominant factor to lower the driving force for GBS at all concentrations. In contrast, the stabilization of M(3+) ions does not necessarily contribute to GBS of point defects at high concentrations. These findings suggest practical ways to control GBS to enhance materials' properties or minimize detrimental effects.

First-principles based theoretical calculations of atomic structures of hydroxyapatite surfaces and their charge states in contact with aqueous solutions.

Surface charge states of biomaterials are often important for the adsorption of cells, proteins, and foreign ions on their surfaces, which should be clarified at the atomic and electronic levels. First-principles calculations were performed to reveal thermodynamically stable surface atomic structures and their charge states in hydroxyapatite (HAp). Effects of aqueous environments on the surface stability were considered using an implicit solvation model. It was found that in an air atmosphere, stoichiometric {0001} and P-rich {101̄0} surfaces are energetically favorable, whereas in an aqueous solution, a Ca-rich {101̄0} surface is the most stable. This difference suggests that preferential surface structures strongly depend on chemical environments with and without aqueous solutions. Their surface potentials at zero charge were calculated to obtain the isoelectric points (pHPZC). pHPZC values for the {0001} surface and the Ca-rich {101̄0} surface were obtained to be 4.8 and 8.7, respectively. This indicates that in an aqueous solution at neutral pH, the {0001} and Ca-rich {101̄0} surfaces are negatively and positively charged, respectively. This trend agrees with experimental data from chromatography and zeta potential measurements. Our methodology based on first-principles calculations enables determining macroscopic charge states of HAp surfaces from atomic and electronic levels.

Half-integer quantized anomalous thermal Hall effect in the Kitaev material candidate α-RuCl3.

Half-integer thermal quantum Hall conductance has recently been reported for the two-dimensional honeycomb material α-RuCl3 We found that the half-integer thermal Hall plateau appears even for a magnetic field with no out-of-plane components. The measured field-angular variation of the quantized thermal Hall conductance has the same sign structure as the topological Chern number of the pure Kitaev spin liquid. This observation suggests that the non-Abelian topological order associated with fractionalization of the local magnetic moments persists even in the presence of non-Kitaev interactions in α-RuCl3.

Role of interleukin 6 for differential responsiveness of naive and memory CD4+ T cells in CD2-mediated activation.

The present study was undertaken to elucidate different requirements for CD2-mediated activation of naive (CD45RO-) and memory (CD45RO+) CD4+ T cells. A mitogenic combination of anti-CD2 (anti-T11(2) and anti-T11(3] mAbs could effectively induce the proliferation of memory CD4+ T cells even in the absence of monocytes. In marked contrast, naive CD4+ T cells did not disclose any proliferative responses to anti-CD2 mAbs, when monocytes were absent in culture. This differential responsiveness of naive and memory CD4+ T cells appeared to be related largely to a difference in IL-6-producing ability between both populations. IL-6 among monocyte-derived cytokines could correct unresponsiveness of naive CD4+ T cells to anti-CD2 stimulation. Unlike naive CD4+ T cells, memory CD4+ T cells produced IL-6 by themselves, with its mRNA being expressed on anti-CD2 stimulation. Anti-IL-6R mAb significantly inhibited proliferation of memory CD4+ T cells seen in the anti-CD2-stimulated cultures without monocytes, indicating the involvement of their own production of IL-6 in CD2-mediated activation. The results suggest an essential role of IL-6 for triggering of CD4+ T cells via the CD2 molecule.

Monosomy and trisomy of 15q24-qter with cleft lip and palate.

Chromosome 15 aberrations clinically present as facial dysmorphisms such as a prominent nose, low-set ears, micrognathia and a short neck; a cleft lip and palate have not been reported. This is the first reported case of de-novo terminal deletion at 15q24 with a cleft lip and palate and low-set ears. The baby boy had a complete cleft lip and palate on the left side and incomplete cleft lip and palate on the right. A chromosomal study revealed partial monosomy and trisomy of the long arm of chromosome 15, with a karyotype of 46,XY,add(15)(24q) de novo. Surgery for lip plasty was performed at 6 months old and for palate plasty at 1 year and 9 months. Both operations were uneventful, although preoperative and postoperative examinations showed high creatinine phosphokinase values. At 3 years old, mild mental retardation was observed, but his physical development was normal.

Identification of a regulatory region that mediates glucose-dependent induction of the Saccharomyces cerevisiae enolase gene ENO2.

There are two yeast enolase genes, designated ENO1 and ENO2, which are expressed differentially in vegetative cells grown on glucose and in cells grown on gluconeogenic carbon sources. ENO2 is induced more than 20-fold in cells grown on glucose, whereas ENO1 expression is similar in cells grown on glucose and in cells grown on gluconeogenic carbon sources. Sequences within the 5' flanking region of ENO2 which are required for glucose-dependent induction were identified by deletion mapping analysis. These studies were carried out by using a fused gene containing the ENO2 5' flanking sequences and the ENO1 coding sequences. This fused gene undergoes glucose-dependent induction and is expressed at the same level as the resident ENO2 gene in cells grown on glucose or gluconeogenic carbon sources. Expression of fused genes containing deletion mutations within the ENO2 5' flanking region was monitored after integration at the ENO1 locus of a strain carrying a deletion of the resident ENO1 coding sequences. This analysis showed that there are two upstream activation sites located immediately upstream and downstream from a position 461 base pairs upstream from the transcriptional initiation site. Either one of these upstream activation sites is sufficient for glucose-dependent induction and normal gene expression in the presence of gluconeogenic carbon sources. Deletion of both regulatory regions results in a complete loss of gene expression. The regulatory regions function normally in both orientations relative to the coding sequences. Mutant fused genes containing small deletions within the regulatory regions were constructed; these genes were expressed normally in gluconeogenic carbon sources but were not induced in the presence of glucose. Based on this analysis, ENO2 contains a cis-acting regulatory region which is required for gene expression and mediates glucose-dependent induction of gene expression.

The GCR1 gene encodes a positive transcriptional regulator of the enolase and glyceraldehyde-3-phosphate dehydrogenase gene families in Saccharomyces cerevisiae.

The intracellular concentrations of the polypeptides encoded by the two enolase (ENO1 and ENO2) and three glyceraldehyde-3-phosphate dehydrogenase (TDH1, TDH2, and TDH3) genes were coordinately reduced more than 20-fold in a Saccharomyces cerevisiae strain carrying the gcr1-1 mutation. The steady-state concentration of glyceraldehyde-3-phosphate dehydrogenase mRNA was shown to be approximately 50-fold reduced in the mutant strain. Overexpression of enolase and glyceraldehyde-3-phosphate dehydrogenase in strains carrying multiple copies of either ENO1 or TDH3 was reduced more than 50-fold in strains carrying the gcr1-1 mutation. These results demonstrated that the GCR1 gene encodes a trans-acting factor which is required for efficient and coordinate expression of these glycolytic gene families. The GCR1 gene and the gcr1-1 mutant allele were cloned and sequenced. GCR1 encodes a predicted 844-amino-acid polypeptide; the gcr1-1 allele contains a 1-base-pair insertion mutation at codon 304. A null mutant carrying a deletion of 90% of the GCR1 coding sequence and a URA3 gene insertion was constructed by gene replacement. The phenotype of a strain carrying this null mutation was identical to that of the gcr1-1 mutant strain.

Transcription of the constitutively expressed yeast enolase gene ENO1 is mediated by positive and negative cis-acting regulatory sequences.

There are two enolase genes, ENO1 and ENO2, per haploid yeast genome. Expression of the ENO1 gene is quantitatively similar in cells grown on glucose or gluconeogenic carbon sources. In contrast, ENO2 expression is induced more than 20-fold in cells grown on glucose as the carbon source. cis-Acting regulatory sequences were mapped within the 5'-flanking region of the constitutively expressed yeast enolase gene ENO1. A complex positive regulatory region was located 445 base pairs (bp) upstream from the transcriptional initiation site which was required for ENO1 expression in cells grown on glycolytic or gluconeogenic carbon sources. A negative regulatory region was located 160 bp upstream from the transcriptional initiation site. Sequences required for the function of this negative regulatory element were mapped to a 38-bp region. Deletion of all or a portion of these latter sequences permitted glucose-dependent induction of ENO1 expression that was quantitatively similar to that of the glucose-inducible ENO2 gene. The negative regulatory element therefore prevents glucose-dependent induction of the ENO1 gene. Hybrid 5'-flanking regions were constructed which contained the upstream regulatory sequences of one enolase gene fused at a site upstream from the TATAAA box in the other enolase gene. Analysis of the expression of enolase genes containing these hybrid 5'-flanking region showed that the positive regulatory regions of ENO1 and ENO2 were functionally similar, as were the regions extending from the TATAAA boxes to the initiation codons. Based on these studies, we conclude that the negative regulatory element plays the critical role in maintaining the constitutive expression of the ENO1 structural gene in cells grown on glucose or gluconeogenic carbon sources.

Fetus-specific CYP3A7 and adult-specific CYP3A4 expressed in Chinese hamster CHL cells have similar capacity to activate carcinogenic mycotoxins.

To assess whether CYP3A4 and CYP3A7 have a similar capacity to activate carcinogenic mycotoxins, we established cell lines stably expressing human CYP3A4 and CYP3A7, which are adult- and fetal-specific forms of cytochrome P450 in human livers, respectively. Each cDNA was introduced into CR-119 cells which had been established by introducing guinea pig NADPH-cytochrome P450 reductase cDNA into Chinese hamster lung cells. The cell lines (4-line and 7-line) stably expressed the mRNA and the protein corresponding to CYP3A4 and CYP3A7, respectively. The concentration-response for aflatoxin B1 (AFB1) cytotoxicity in 4-line and 7-line, respectively, was compared. 4-10 and 7-40 cells were approximately 17- and 20 times more sensitive to AFB1 than the parental CR-119 cells, respectively. In addition, the sensitivities to AFB1 of both 4-10 and 7-40 cells were enhanced approximately seven times by the addition of 10 microM alpha-naphthoflavone, a known activator of CYP3A enzyme, while the sensitivities were suppressed approximately four times by the addition of 100 microM troleandomycin, which forms a metabolite intermediate complex with CYP3A enzyme. Moreover, both cell lines showed approximately 10 and 2 times higher sensitivity to sterigmatocystin and aflatoxin G1 than CR-119 cells, respectively. These results indicate that CYP3A4 and CYP3A7 have essentially similar capacities to activate AFB1, sterigmatocystin, and aflatoxin G1 to produce toxic metabolites.

In vivo activation of aflatoxin B1 in C57BL/6N mice carrying a human fetus-specific CYP3A7 gene.

The in vivo activation of aflatoxin B1 (AFB1) was assessed by using two transgenic mouse lines, M2 and M10, in which the human fetus-specific CYP3A7 was expressed in the kidney (M2) and the liver (M10), respectively. Male mice of 8 weeks old from these two lines were treated with a single i.p. injection of AFB1 (4 mg/kg body weight). AFB1-N7-guanine adduct was quantified by high-performance liquid chromatography. DNA damage was measured using the alkaline elution technique 2 and 6 h after AFB1 treatment. Administration of AFB1 resulted in a significantly higher level of AFB1-N7-guanine in the livers of M10 transgenic mice compared with their nontransgenic littermates (16.5 +/- 4.2 versus 10.4 +/- 1.2 ng/mg DNA, P < 0.01). The level of this biomarker was also significantly higher in the kidney of the M2 mice compared with control mice (73.0 +/- 6.3 versus 50.2 +/- 9.5 ng/mg DNA, P < 0.01). Similar results were also observed with DNA damage expressed as normalized area above curve (NAAC) in the two transgenic lineages, e.g., NAAC values were significantly higher in the livers of M10 and the kidneys of M2 mice. A dose-response relationship of NAAC values was observed in the livers of M10 mice when treated with AFB1 at different doses ranging from 1 to 16 mg/kg body weight, whereas in nontransgenic mice, only slight but not statistically significant increases of NAAC values were observed. Both the mouse CYP3A11 and GST-Yc subunit were expressed at identical levels in these transgenic lines. The results of this study present further evidence that human fetuses are also under the carcinogenic attack of AFB1 as adults if exposed to this potent carcinogen.

Involvement of beta-glucuronidase in intestinal microflora in the intestinal toxicity of the antitumor camptothecin derivative irinotecan hydrochloride (CPT-11) in rats.

Irinotecan hydrochloride (CPT-11), an antitumor camptothecin derivative, causes severe forms of diarrhea clinically. We characterized CPT-11-induced diarrhea histologically and enzymologically and assessed the relationships between intestinal toxicity and the activity of the enzymes that play a key role in the major metabolic pathway of CPT-11 in rats. CPT-11 (60 mg/kg i.v. for 4 days) induced intestinal toxicity characterized by severe chronic diarrhea, loss of body weight, and anorexia. Histological damage was most severe in the cecum. The segmental difference in the degree of the damage showed good correlation with the beta-glucuronidase activity in the contents of the lumen in each case, but not with the intestinal tissue carboxylesterase activity, which converts CPT-11 to its active form (7-ethyl-10-hydroxycamptothecin). Inhibition of the beta-glucuronidase activity in the intestinal microflora by antibiotics (1 mg penicillin and 2 mg streptomycin per ml of drinking water) markedly ameliorated the diarrhea and reduced cecal damage. Analysis of CPT-11 and its metabolites in the feces indicated that antibiotics completely inhibited the deconjugation of the glucuronic conjugate of 7-ethyl-10-hydroxycamptothecin by beta-glucuronidase. It is suggested that CPT-11-induced diarrhea would be attributable to the damage to the cecum, and that the inhibition of the beta-glucuronidase activity in the intestinal microflora is a major protective effect of antibiotics.

Ultrastructural characterization of the retrovirus particles (Sm-MTV) liberated from the mammary tumor cell line (Sm-MT) of a house musk shrew, Suncus murinus (Insectivora).

Detailed ultrastructure of a new type of retrovirus (Sm-MTV) released by cultured cells (Sm-MT) of a spontaneous mammary tumor from a house musk shrew Suncus murinus, Insectivora, is described. The virus particles were revealed as three forms: intracellular; budding; and extracellular. The intracellular type A particles were similar in profile to those associated with mouse mammary tumor cells and tended to form a small cluster of several particles in the cytoplasm. In addition, horseshoe-shaped particles as well as smaller particles in clusters, with doughnut-shaped morphology similar in structure to type A particles, were identified near the clusters of type A particles, although in smaller numbers. The budding particles contained a doughnut-shaped nucleoid, although the nucleoids decreased in size as compared with intracytoplasmic type A particles. The extracellular virions consisted of an envelope and a centrally located nucleoid. In routinely fixed specimens, the former was covered with irregularly distributed fuzzy materials in its surface, and the latter was further composed of a small electron dense core surrounded by an intermediate layer. Tannic acid treatment of cells resulted in the visualization of surface projections on the envelope of virions. Similar projections were also detected exclusively on the plasma membrane where virus budding took place, and not on the normal plasma membrane. The presence of surface projections on the viral envelope was further confirmed by the whole-cell-mounting technique. Together with our previous results of biochemical and immunological investigations, we concluded that Sm-MTV seemed to have closer phylogenetic relatedness with type D viruses of primates than with murine mammary tumor virus.

Molecular cloning and sequence analysis of hamster CYP2E1.

Two cDNA clones, pHSj31 and pHSj3, coding for CYP2E1 were isolated from a hamster liver cDNA library. The sequence analyses revealed that they encoded the same polypeptide of 493 amino acid residues (M(r) = 56,616) and differed from the length of their 3'-untranslated region. The deduced amino acid sequence of hamster CYP2E1 showed approx. 90% identities with those of the rats and mice, and approx. 80% identities with those of the rabbits, monkeys and humans. The NH2-terminal 35 deduced amino acid sequences of hamster CYP2E1 were completely identical with purified protein, ha P-450j. The Northern blot analysis showed that CYP2E1 was expressed in livers and to lesser extents in kidneys and lungs.

Identification of protein disulfide isomerase and calreticulin as autoimmune antigens in LEC strain of rats.

Long Evans Cinnamon (LEC) rats, showing spontaneous hereditary hepatitis and hepatic carcinoma, were found to possess autoimmune antibodies to liver microsomal proteins, particularly to proteins with the molecular weight of 56kD and 55kD. The antibodies occurred in association with acute lethal hepatitis in the LEC rats in our previous study. Two-dimensional immunoblot analysis of the antigenic proteins revealed that the 56kDa and 55kDa proteins showed 4.2 and 4.0 pI values and were estimated to be protein disulfide isomerase (PDI) and calreticulin, respectively, from NH2-terminal amino acid sequence analysis. These proteins were further identified by immunoblot analyses using purified proteins and specific antibodies. PDI was a major autoimmune antigenic protein.

Rat liver flavin-containing monooxygenase (FMO): cDNA cloning and expression in yeast.

A rat liver cDNA clone, RFMO1, coding for a flavin-containing monooxygenase (FMO) was isolated. This cDNA clone encoded a protein of 532 amino acids. The deduced amino acid sequence was 84, 82 and 82% identical to those of the pig, human (Form 1) and rabbit (Form 1) liver FMOs, while it was only 52, 50, 54, 56 and 54% identical to the human (Form II), human (Form 2) and rabbit liver FMOs (Form 2) and rabbit and guinea pig lung FMOs. RNA blot analysis showed that rat liver FMO was also expressed in lung and kidney and to a lesser extent in the heart and brain. An expression plasmid, pAMFMO, was constructed and the FMO protein expressed in yeast (AH22). This FMO protein catalyzed thiobenzamide S-oxidation, and NADPH oxidation associated with the S- or N-oxidation of thiourea, N,N-dimethylaniline, trimethylamine, imipramine, chlorpromazine, N,N-dimethylhydrazine, thioacetamide as substrates. The S-oxidation activities of thiobenzamide and thiourea were enhanced by n-octylamine, a known enhancer of FMO, and inhibited by alpha-naphthylthiourea, a known inhibitor of FMO. This is the first report in which FMO with catalytic activities was stably expressed.

Molecular markers for the agouti coat color locus of the mouse.

The agouti (a) coat color locus of the mouse acts within the microenvironment of the hair follicle to control the relative amount and distribution of yellow and black pigment in the coat hairs. Over 18 different mutations with complex dominance relationships have been described at this locus. The lethal yellow (Ay) mutation is the top dominant of this series and is uniquely associated with an endogenous provirus, Emv-15, in three highly inbred strains. However, we report here that it is unlikely that the provirus itself causes the Ay-associated alteration in coat color, since one strain of mice (YBR-Ay/a) lacks the provirus but still retains a yellow coat color. Using single-copy mouse DNA sequences from the regions flanking Emv-15 we have detected three patterns of restriction fragment length polymorphisms (RFLPs) within this region that can be used as molecular markers for different agouti locus alleles: a wild-type agouti (A) pattern, a pattern which generally cosegregates with the nonagouti (a) mutation, and a pattern which is specific to Emv-15. We have used these RFLPs and a panel of 28 recombinant inbred mouse strains to determine the genetic linkage of these sequences with the agouti locus and have found complete concordance between the two (95% confidence limit of 0.00 to 3.79 centimorgans). We have also physically mapped these sequences by in situ hybridization to band H1 of chromosome 2, thus directly confirming previous assignments of the location of the agouti locus.

Brachial-ankle pulse wave velocity: an index of central arterial stiffness?

Brachial-ankle pulse wave velocity (baPWV) is a promising technique to assess arterial stiffness conveniently. However, it is not known whether baPWV is associated with well-established indices of central arterial stiffness. We determined the relation of baPWV with aortic (carotid-femoral) PWV, leg (femoral-ankle) PWV, and carotid augmentation index (AI) by using both cross-sectional and interventional approaches. First, we studied 409 healthy adults aged 18-76 years. baPWV correlated significantly with aortic PWV (r = 0.76), leg PWV (r = 0.76), and carotid AI (r = 0.52). A stepwise regression analysis revealed that aortic PWV was the primary independent correlate of baPWV, explaining 58% of the total variance in baPWV. Additional 23% of the variance was explained by leg PWV. Second, 13 sedentary healthy men were studied before and after a 16-week moderate aerobic exercise intervention (brisk walking to jogging; 30-45 min/day; 4-5 days/week). Reductions in aortic PWV observed with the exercise intervention were significantly and positively associated with the corresponding changes in baPWV (r = 0.74). A stepwise regression analysis revealed that changes in aortic PWV were the only independent correlate of changes in baPWV (beta = 0.74), explaining 55% of the total variance. These results suggest that baPWV may provide qualitatively similar information to those derived from central arterial stiffness although some portions of baPWV may be determined by peripheral arterial stiffness.