Heritability and clinical features of multigenerational families with obsessive-compulsive disorder and hoarding.

To date, only one complete genome screen for obsessive-compulsive disorder (OCD) has been published. That study identified a region of suggestive linkage (maximum lod score of 2.25) with a relatively small sample size (N = 56; 27 with OCD). Additional complete genome screens are needed to confirm this finding and identify other regions of linkage. We present the clinical characteristics and power to detect linkage of 11 multigenerational families with OCD and hoarding (N = 92; 44 with OCD), as well as heritability estimates for several quantitative traits. Families with at least two individuals with OCD were identified through probands with childhood-onset OCD. Expected lod scores were calculated for simulated genetic marker data under an additive and two dominant models assuming a dense SNP marker map. All affected individuals had an early age of onset (18 or younger). Hoarding was present in 46% of subjects. Obsessive-compulsive symptoms and hoarding were highly heritable. The maximum mean expected lod score was 3.31 for OCD and 1.39 for hoarding. We found reasonable power to detect regions of interest (lod = 2) for OCD in these families, but will need to expand our family collection to have adequate power to detect regions of interest for hoarding.     

Dpc4 is expressed in virtually all primary and metastatic pancreatic endocrine carcinomas

DPC4/Smad4 is inactivated in about 50% of pancreatic ductal cancers. It has been recently reported that this gene is also inactivated in neoplasms arising from pancreatic islet cells, a phenomenon suggested to be related to similar progressions of malignancy found in common ductal cancers. To evaluate this possibility, we analysed 20 metastases of pancreatic endocrine carcinomas and their corresponding primary lesion for inactivation of DPC4 using immunohistochemical staining. In fact, immunohistochemical labelling has been shown to correlate with DPC4 gene status with high sensitivity and specificity. The cancers included 18 nonfunctioning tumours, one gastrinoma and one ViPoma all with liver, nodal and/or adrenal metastases. Seventeen were well-differentiated and three poorly differentiated endocrine carcinomas. Dpc4 expression was absent in only one primary well-differentiated endocrine cancer and its liver metastasis, while all the remaining 19 primary tumours and their metastases stained positive for the protein. All positively staining cases showed diffuse cytoplasmic and nuclear staining in virtually all neoplastic cells. Our data suggest that DPC4 is only rarely involved in pancreatic endocrine tumourigenesis and give further weight to the hypothesis that tumours arising from pancreatic exocrine and endocrine epithelia are genetically distinct.     

Detection of clonal immunoglobulin gene rearrangements in the peripheral blood progenitor cells of patients with multiple myeloma: the potential role of purging with CD34 positive selection

Aims—To determine the extent of clonal cell contamination of peripheral blood progenitor cell (PBPC) collections in patients with multiple myeloma (MM) and to assess the purging efficacy of CD34 positive selection.     

Herpesvirus saimiri has a gene specifying a homologue of the cellular membrane glycoprotein CD59.

Herpesvirus saimiri (HSV) is a T-lymphotropic tumor virus that causes fulminant lymphomas and leukemias in various New World primates other than its natural host, the squirrel monkey (Saimiri sciureus). In the course of completing the nucleotide sequence of its genome, we identified an open reading frame of 363 nucleotides, designated HVS-15, that has no detectable homology to any other viral sequences to date. HVS-15 encodes a 121-amino-acid protein which shows significant similarities to human CD59, a phosphatidyl-inositol-glycan-anchored glycoprotein involved in T-cell activation and restriction of complement-mediated lysis. The predicted HVS-15 gene product is more similar to human CD59 than to the related murine Ly-6 antigens. A nucleotide sequence identity of 64% was found between HVS-15 and the CD59 reading frame, and a 48% identity exists between the corresponding protein sequences. The comparison of the amino acid sequences revealed a number of conserved structural features such as a similar pattern of hydrophobic termini and an identical cysteine skeleton.     

Pyrimidinone (bropirimine) mediated alteration of T lymphocyte subsets during murine cytomegalovirus infection.

Murine cytomegalovirus (MCMV) infection of mice resulted in suppression of mitogen induced proliferation and interleukin 2 (IL-2) responses of splenic cells. This suppression was also evident as a reduction in the number of cells expressing Thy-1 or L3T4 and a reduction in the ratio of T helper/T suppressor cells. The pyrimidinone compound, bropirimine, when administered to MCMV infected mice was able to restore mitogen-induced proliferative and IL-2 responses of splenic cells, to increase the number of cells expressing Thy-1 or L3T4, to restore the ratio of T helper/T suppressor cells and to increase the number of cells inducible for expression of IL-2 receptors.     

Early precursors of B lymphocytes I. Rabbit/mouse species differences in the physical properties and surface phenotype of pre-B cells,and in the maturation sequence of early B cells

Cells that possess low levels of internal IgM (or μ chain), with none detectable on the surface, can be identified by immunofluorescence. These “pre-B cells” in rabbits have been characterized and been compared with those of mice, in terms of their ontogeny, physical properties and surface phenotype — partly to reveal features that could be exploited in their purification. The timing of their appearance and their tissue distribution are, in principle, very similar, though they first appear 5-7 days later in the rabbit than in the mouse. Thus, pre-B cells could not be detected in rabbit fetal liver until days 17-20 of gestation; however, their progenitors appeared to be present before that, since, in preliminary experiments, pre-B cells (and subsequently B cells) were generated de novo in closed organ cultures initiated at earlier times. In other respects, pre-B cells are strikingly different in the two species. Rabbit pre-B cells bear detectable surface Fc receptors, not found on these cells in the mouse, and they are almost uniformly large and low in density, whereas mouse pre-B cells are much more heterogeneous and less readily purified. The evidence summarized here that the large pre-B cells identified by immunofluorescence are equivalent to those detected by others in functional assays, amounts to a strong case for their precursor status. In the mouse, their immediate progeny seem to be small pre-B cells which apparently already behave, in functional assays, like the newly developed B cells into which they can rapidly convert. This heterogeneity seen in pre-B cells in mice is apparent instead in the B cells of rabbit lymphopoietic tissues. These vary considerably, not only in size and density, but also in their membrane Ig staining intensity, whereas the B cells in mouse bone marrow are almost exclusively small lymphocytes. In view of their relatively high frequencies in fetal tissues, it is proposed that the conspicuous large, low-density rabbit B cells are intermediates in the development of pre-B cells into small B lymphocytes, and it is therefore concluded that surface Ig and Fc receptors both appear at relatively earlier stages in the rabbit than in the mouse. This conclusion could be tested by culturing these immature B cells after purifying them by exploiting their distinctive properties.