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A gene for lymphedema-distichiasis, a dominantly inherited syndrome with onset of lymphedema at of just after puberty, which has been mapped to 16q24.3 is discussed. Three families with LD have been studied, and possible candidate genes include that for the cell matrix-adhesion regulator, CMAR, that for the metalloprotease PRSM1, and that for N-proteinase for type 3 collagen. Distichiasis is the appearance of fine hairs arising inappropriately from meibomian gland openings on the inner eyelid.

Peripheral lymph was collected from the skin and liver of sheep, and from the intestine of rats. The dendritic macrophages contained in it were isolated by centrifuging the lymph over a layer of ‘Nycodenz’. Similar cells were produced by culturing mononuclear cells from venous blood, but the yields were very small. The numbers of dendritic cells in the lymph from the legs of sheep increased five-fold after xylene had been applied to the skin. Dendritic macrophages displayed abundant class II histocompatibility antigens on their surfaces, as well as immunoglobulins. Although the latter were probably acquired passively, they remained present for several days on cells cultured in vitro. When in vitro, dendritic cells could be shown to phagocytose marker particles, such as latex beads, but their performance was unimpressive compared to macropbages from the peritoneal cavities of rats. In contrast, their ability to phagocytose rapidly T4 phage or influenza viruses was unequivocal and striking. [ABSTRACT FROM AUTHOR]

The binding to rat splenic and peritoneal macrophages of affinity-purified monoclonal rat IgGs. representing all IgG subclasses, was measured by the direct binding of 125I-labelled proteins using an assay that did not require the removal of unbound Ig by washing. Only rat monomeric IgGs of the subclass IgG2b bound specifically and in large amounts to rat macrophages. The binding was temperature dependent and more IgG2b bound to the cells at 4° than at 37°. Spleen macrophages bound approximately 10 times more IgG2b than the same number of peritoneal macrophages, although the association constants (Kas) for the binding were similar for both types of macrophage. The calculated values for the Kas, which varied slightly with each experiment and increased with decrease in temperature, fell within the range 1·3–5·3 × 108 M-1; the number of binding sites was estimated as about 105/splenic macrophage and 104/peritoneal macrophage. The binding of 125I- IgG2b to splenic macrophages was inhibited only by unlabelled proteins of the IgG2b isotype and not by IgG1, IgG2a and IgG2c proteins. Soluble IgG2b-antigen complexes also bound to the FcR for monomer but a soluble IgG2a-antigen complex did not inhibit the binding of monomeric IgG2b. [ABSTRACT FROM AUTHOR]

Rat monoclonal IgG2b immunoglobulins labeled with 125I or biotin were localized in the red pulp areas but were not found in the marginal zones of the white pulp of the spleen 8 hr after their i.v. injection. In cell suspensions made from the spleen, 90% of red pulp macrophages (mΦ) bound 125I-IgG2b monomeric proteins in vitro, whereas similar estimates for marginal zone MΦ were 12–30%. Red pulp and marginal zone MΦ were distinguished primarily by monoclonal antibodies (mAb) ED2 and ED3, but also by their ability to take up FITC-labelled Ficoll in vivo. [ABSTRACT FROM AUTHOR]

The structural properties of hair are largely determined by the state of the surface. Advanced imaging modes of atomic force microscopy, where the surface mechanics can be correlated with surface topography, have been used to spatially map variations in hair surfaces following chemical and mechanical treatments. Through analysis of multilayered data obtained in this way, we show that the processes of bleaching and combing of hair not only alter the surface roughness, but also alter the mechanical stiffness, adhesion properties, and surface potential of hair, in terms of the mean values and their distributions. These treatments are shown to have a significant effect on the nanoscale surface properties, consistent with what has previously been observed at the macroscopic fiber-level scale.

Surveys for evidence of exposure to pseudorabies virus (PRV), Brucella suis, swine influenza virus (SIV; human-like H1N1, reassortant type H1N1, H1N2-like H1N1 and H3N2), porcine circovirus 2 (PCV 2), and porcine respiratory and reproductive syndrome virus (PRRSV) in feral swine (Sus scrofa) were conducted in areas where feral swine were geographically associated with high densities of transitional swine premises in South Carolina and high densities of commercial swine production in North Carolina. In South Carolina, 10/50 (20.0%), 7/50 (14.0%), and 29/49 (59.2%) feral swine tested antibody positive for PRV, B. suis, and PCV-2, respectively. Antibodies to PRRSV (0/49) and SIV (0/49) were not detected. In North Carolina, antibodies to PRV and B. suis were not detected in serum samples from 120 feral swine; however, antibodies to PRRSV (1/120 [0.8%]), PCV-2 (86/120 [71.7%]; these included 80 positives plus six suspects), and SIV (108/119 [90.7%]) were present. The presence of PRV and B. suis in South Carolina may have been due to the introduction of infected feral swine into the area or to a previous association of feral swine with infected transitional swine. Their absence in the North Carolina populations may have been due to the absence of these disease agents in the feral swine originally introduced into the area and the lack of a potential for contact with infected commercial swine. Feral swine associated with commercial swine in North Carolina may have been exposed to SIV subtypes circulating in commercial swine via airborne spread of SIV from commercial swine facilities. Feral swine seropositive for PCV-2 were prevalent in both states, which may indicate efficient transmission from commercial swine and transitional swine, or that PCV-2 is widespread in feral swine. The low prevalence of animals with antibodies against PRRSV may indicate a less-than-efficient means of transmission from commercial to feral swine. Additional epidemiologic studies are needed to understand the risks and mechanisms of transmission of disease agents among commercial, transitional, and feral swine, and the role of feral swine as reservoirs of these disease agents.

PALB2 interacts with BRCA2, and biallelic mutations in PALB2 (also known as FANCN), similar to biallelic BRCA2 mutations, cause Fanconi anemia. We identified monoallelic truncating PALB2 mutations in 10/923 individuals with familial breast cancer compared with 0/1,084 controls (P = 0.0004) and show that such mutations confer a 2.3-fold higher risk of breast cancer (95% confidence interval (c.i.) = 1.4-3.9, P = 0.0025). The results show that PALB2 is a breast cancer susceptibility gene and further demonstrate the close relationship of the Fanconi anemia-DNA repair pathway and breast cancer predisposition.

The CHEK2 1100delC protein-truncating mutation has a carrier frequency of approximately 0.7% in Northern and Western European populations and confers an approximately 2-fold increased risk of breast cancer. It has also been suggested to increase risks of colorectal and prostate cancer, but its involvement with these or other types of cancer has not been confirmed. The incidence of cancer other than breast cancer in 11,116 individuals from 734 non-BRCA1/2 breast cancer families from the United Kingdom, Germany, Netherlands, and the United States was compared with that predicted by population rates. Relative risks (RR) to carriers and noncarriers were estimated by maximum likelihood, via the expectation-maximization algorithm to allow for unknown genotypes. Sixty-seven families contained at least one tested CHEK2 1100delC mutation carrier. There was evidence of underreporting of cancers in male relatives (422 cancers observed, 860 expected) but not in females (322 observed, 335 expected); hence, we focused on cancer risks in female carriers. The risk of cancers other than breast cancer in female carriers was not significantly elevated, although a modest increase in risk could not be excluded (RR, 1.18; 95% confidence interval, 0.64-2.17). The carrier risk was not significantly raised for any individual cancer site, including colorectal cancer (RR, 1.60; 95% confidence interval, 0.54-4.71). However, between ages 20 to 50 years, the risks of colorectal and lung cancer were both higher in female carriers than noncarriers (P = 0.041 and 0.0001, respectively). There was no evidence of a higher prostate cancer risk in carriers than noncarriers (P = 0.26), although underreporting of male cancers limited our power to detect such a difference. Our results suggest that the risk of cancer associated with CHEK2 1100delC mutations is restricted to breast cancer, although we cannot rule out a small increase in overall cancer risk.

We identified constitutional truncating mutations of the BRCA1-interacting helicase BRIP1 in 9/1,212 individuals with breast cancer from BRCA1/BRCA2 mutation-negative families but in only 2/2,081 controls (P = 0.0030), and we estimate that BRIP1 mutations confer a relative risk of breast cancer of 2.0 (95% confidence interval = 1.2-3.2, P = 0.012). Biallelic BRIP1 mutations were recently shown to cause Fanconi anemia complementation group J. Thus, inactivating truncating mutations of BRIP1, similar to those in BRCA2, cause Fanconi anemia in biallelic carriers and confer susceptibility to breast cancer in monoallelic carriers.

We screened individuals from 443 familial breast cancer pedigrees and 521 controls for ATM sequence variants and identified 12 mutations in affected individuals and two in controls (P = 0.0047). The results demonstrate that ATM mutations that cause ataxia-telangiectasia in biallelic carriers are breast cancer susceptibility alleles in monoallelic carriers, with an estimated relative risk of 2.37 (95% confidence interval (c.i.) = 1.51-3.78, P = 0.0003). There was no evidence that other classes of ATM variant confer a risk of breast cancer.

Mutations in known breast cancer susceptibility genes account for a minority of the familial aggregation of the disease. To search for further breast cancer susceptibility genes, we performed a combined analysis of four genome-wide linkage screens, which included a total of 149 multiple case breast cancer families. All families included at least three cases of breast cancer diagnosed below age 60 years, at least one of whom had been tested and found not to carry a BRCA1 or BRCA2 mutation. Evidence for linkage was assessed using parametric linkage analysis, assuming both a dominant and a recessive mode of inheritance, and using nonparametric methods. The highest LOD score obtained in any analysis of the combined data was 1.80 under the dominant model, in a region on chromosome 4 close to marker D4S392. Three further LOD scores over 1 were identified in the parametric analyses and two in the nonparametric analyses. A maximum LOD score of 2.40 was found on chromosome arm 2p in families with four or more cases of breast cancer diagnosed below age 50 years. The number of linkage peaks did not differ from the number expected by chance. These results suggest regions that may harbor novel breast cancer susceptibility genes. They also indicate that no single gene is likely to account for a large fraction of the familial aggregation of breast cancer that is not due to mutations in BRCA1 or BRCA2., ((c) 2006 Wiley-Liss, Inc.)

The genes predisposing to familial breast cancer are largely unknown, but 5 of the 6 known genes are involved in DNA damage repair. RAD50 is part of a highly conserved complex important in recognising, signalling and repairing DNA double-strand breaks. Recently, a truncating mutation in the RAD50 gene, 687delT, was identified in 2 Finnish breast cancer families. To evaluate the contribution of RAD50 to familial breast cancer, we screened the whole coding region for mutations in 435 UK and 46 Finnish familial breast cancer cases. We identified one truncating mutation, Q350X, in one UK family. We screened a further 544 Finnish familial breast cancer cases and 560 controls for the 687delT mutation, which was present in 3 cases (0.5%) and 1 control (0.2%). Neither Q350X nor 687delT segregated with cancer in the families in which they were identified. Functional analyses suggested that RAD50 687delT is a null allele as there was no detectable expression of the mutant protein. However, the wild-type allele was retained and expressed in breast tumors from mutation carriers. The abundance of the full-length RAD50 protein was reduced in carrier lymphoblastoid cells, suggesting a possible haploinsufficiency mechanism. These data indicate that RAD50 mutations are rare in familial breast cancer and either carry no, or a very small, increased risk of cancer. Altogether, these results suggest RAD50 can only be making a very minor contribution to familial breast cancer predisposition in UK and Finland.

Fanconi Anemia (FA) is an autosomal recessive syndrome characterized by congenital abnormalities, progressive bone marrow failure, and susceptibility to cancer. FA has eight known complementation groups and is caused by mutations in at least seven genes. Biallelic BRCA2 mutations were shown recently to cause FA-D1. Monoallelic (heterozygous) BRCA2 mutations confer a high risk of breast cancer and are a major cause of familial breast cancer. To investigate whether heterozygous variants in other FA genes are high penetrance breast cancer susceptibility alleles, we screened germ-line DNA from 88 BRCA1/2-negative families, each with at least three cases of breast cancer, for mutations in FANCA, FANCC, FANCD2, FANCE, FANCF, and FANCG. Sixty-nine sequence variants were identified of which 25 were exonic. None of the exonic variants resulted in translational frameshifts or nonsense codons and 14 were polymorphisms documented previously. Of the remaining 11 exonic variants, 2 resulted in synonymous changes, and 7 were present in controls. Only 2 conservative missense variants, 1 in FANCA and 1 in FANCE, were each found in a single family and were not present in 300 controls. The results indicate that FA gene mutations, other than in BRCA2, are unlikely to be a frequent cause of highly penetrant breast cancer predisposition.