HLA transgenic mice as models of human autoimmune diseases

MHC class II alleles have been linked to several human autoimmune diseases such as rheumatoid arthritis (RA), Type I diabetes, and multiple sclerosis (MS). Although the mechanisms by which expression of certain MHC class II molecules predispose an individual to a particular autoimmune disease are not known, it is clear that increased susceptibility is associated with the polymorphic regions unique to these predisposing HLA alleles. These polymorphic differences may influence susceptibility by selecting potential autoreactive T cells during thymic education. Alternatively, nonsusceptible alleles may either delete or fail to select these potential autoimmune T cells, thus reducing the possibility of developing disease. In the periphery, the unique specificity of the HLA molecule derived from a susceptible allele may then recognize and present an autoantigenic peptide or foreign peptide that may cross-react with an autoantigen, activating these autoreactive T cells and leading to disease. To dissect these possibilities and to determine the exact role of particular HLA-DR or DQ molecules in disease susceptibility, we have generated several lines of HLA-DR and DQ transgenic mice. In this review, we present data summarizing the functions of these HLA class II molecules using well-established mouse models for autoimmune diseases.     

Modulation transfer functions of tomographic systems

The modulation transfer function for an elliptical tomographic scan is derived. Its imaging characteristics are compared with those of linear and circular scans

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Zusammenfassung Die Modulationsaustauschfunktion einer elliptischen tomographischen Abastung wird abgeleitet. Ihre Abbildungsmerkmale werden mit denen von linearen und runden Abtastungen verglichen.

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Sommaire La fonction de transfert de modulation d'un balayage tomographique elliptique est dérivée dans cet article. Ses caratéristiques d'image sont comparées avec celles des balayages circulaires et linéaires.

     

Diagnosis of retinoblastoma by fine-needle aspiration and aqueous cytology

This article reports the cytodiagnosis of three cases of retinoblastoma in children aged 1.5, 2.5, and 5 yr. Two of them were diagnosed by fine-needle aspiration cytology of the primary tumor and one by aqueous cytology. The tumor cells were usually round to oval, small and uniform, with scanty cytoplasm; they generally occurred in closely packed clusters of variable sizes. We discuss the differential diagnosis of retinoblastoma with other round-cell tumors of childhood involving the orbit.     

Isolation and preliminary characterization of Escherichia coli mutants resistant to lethal action of the bacteriophage lambda P gene.

Both spontaneous and NTG-induced mutants of Escherichia coli 594 insensitive to the lethal action of lambda P gene were isolated and called rpl (resistant to P lethality). These mutants were of two types, showing different phenotypes. On type I rpl mutants, lambda cl- and lambda v1v3 did not plate, while lambda vir, lambda cl- c17, lambda imm434, and lambda imm21 did; plasmid pMR45 carrying the lambda P gene could not complement lambda imm21P- phage in type I mutants. On the other hand, the type II rpl mutants support the growth of all the above phages including lambda cl-. Neither type of rpl mutation affects growth of the bacteria.     

Novel missense mutations and a 288-bp exonic insertion in PAX9 in families with autosomal dominant hypodontia

We describe the molecular analysis of three families with hypodontia involving primarily molar teeth and report two novel mutational mechanisms. Linkage analysis of two large families revealed that the hypodontia was linked to the PAX9 locus. These two families revealed missense mutations consisting of a glutamic acid substitution for lysine and a proline substitution for leucine within the paired domain of PAX9. A pair of identical twins affected with hypodontia in a third family demonstrated a 288-bp insertion within exon 2 that resulted in a putative frameshift mutation and a premature stop codon. The insertion was associated with the loss of 7-bp from exon 2. A block of 256-bp of sequence within the insertion was completely identical to downstream sequence from the second intron of the PAX9 gene. These studies extend the spectrum of mutations in PAX9 associated with hypodontia to include heretofore undescribed categories, including missense mutations.     

Fine-needle aspiration (FNA) cytology diagnosis of small round cell tumors: value and limitations

Small round cell tumors (SRCTs) are a group of malignancies (non-Hodgkin lymphoma, neuroblastoma, retinoblastoma, hepatoblastoma, nephroblastoma, rhabdomyosarcoma, small cell anaplastic carcinoma, Ewing sarcomal peripheral neuroectodermal tumor, and desmoplastic small round cell tumor), characterized both cytologically and histologically by a predominantly small round to oval, and relatively undifferentiated cells. Together they form a formidable group and an overwhelming majority of childhood malignancies. The patients may present in later (inoperable) stage with huge intrathoracic and intraabdominal mass, when chemotherapy and/or radiation therapy may be the first or only line of treatment. As a less invasive procedure fine needle aspiration (FNA) cytology has definite advantage over surgical excision biopsy to arrive at a tissue diagnosis before initiation of therapy. Because of the morphologic similarities, the SRCTs may pose a differential diagnostic problem in the practice of clinical cytology, especially when they are poorly differentiated. Important cytomorphological features, which help in the identification of various SRCTs include completely dissociated cell population and lymphoglandular bodies (cytoplasmic fragments) in non-Hodgkin lymphoma (NHL), eosinophilicfibrillar material and Homer-Wright rosettes along with cellular processes in neuroblastoma, acinar formation in hepatoblastoma, blastema cells with tubular differentiation in nephroblastoma, tadpole shaped cells in embryonal rhabdomyosarcoma, extreme nuclear molding and perinuclear blue inclusion in small cell anaplastic carcinoma (SCAC), irregular, punched out and large cytoplasmic vacuolations due to glycogen in Ewing sarcoma, and sheets of undifferentiated small round cells surrounded by collageneous stroma in desmoplastic small round cell tumor (DSRCT). Some of these features such as nuclear molding, rosette, and acinar formation are noticed in more than one type of SRCTs. Moreover, the characteristic cytomorphological features may be present in 70-80% cases and for categorization of the remaining cases, contribution from ancillary studies is essential. It is suggested that cytomorphological features along with one or more of the parameters such as special stains (cytochemistry), immunocytochemistry (ICC), electron microscopy (EM), tissue culture, DNA ploidy, karyotype and molecular analysis can increase the diagnostic accuracy of SRCTs. However, these facilities may not be available in all the laboratories, especially in the developing countries, and even if available in a limited form, a tissue diagnosis has to be offered often by FNA cytology based on morphological features, as a life saving measure in seriously ill patients before the results of ancillary studies are finalized.     

Correlations between apoptotic and proliferative indices in cervical intraepithelial neoplasia and carcinoma

Aims of the present paper was to study cell death by apoptosis and cell proliferation in normal cervical biopsies, cervical intraepithelial neoplasms (CIN) and squamous cell carcinomas of cervix (CaCx). There were each seven cases of normal cervical biopsy, CIN1 and CIN2 along with 10 cases of CIN3 and 14 cases of CaCx. Percentage of apoptotic cells and bodies (i.e. apoptotic index, AI) and mitoses (i.e. mitotic index, MI) and turnover index (TI - AI + MI) were counted in formalin fixed, paraffin embedded, haematoxylin and eosin stained slides. AgNOR stain was done and mean AgNOR dots per cell was also estimated. AI, MI and TI were correlated with histology grade of CIN and invasive carcinoma cervix. Mean AI, MI, TI and AgNOR count increased from lower to higher grades of CIN. AI, MI & TI raised significantly from CIN3 to carcinomas; AI, TI & AgNOR count raised significantly from CIN1 to combined CIM2 & 3; TI & AgNOR count were high in CIN1 to CIN2; AI & TI were significantly raised in normal to CIN1. In conclusion, TI is probably more important for cell kinetic analysis of CIN and carcinoma of cervix because it reflects the frequency of two important events i.e. mitosis and cell death. Sudden increase of AI, MI, TI count from CIN3 to CaCx may indicate the possibility of genetic alteration of cells of CIN3 which induces a frank malignant transformation from CIN3 to CaCx.     

Genetic variation at three VNTR loci in three tribal populations of Orissa,India

BACKGROUND: The variable number of tandem repeats (VNTR) loci are robust, simple and rapid tools for genetic characterization of both individuals and populations. This paper presents data on the distribution of three VNTRs (APOB, YNZ22 and D1S80) in three tribal populations (Gadaba, Kuvi-Khond and Paroja) of the Koraput district of Orissa, India with a view to enlarge our understanding of molecular genetic diversity among these tribes and the usage of these VNTRs in anthropogenetic studies. SUBJECTS AND METHODS: Three tribal populations were genotyped for APOB, YNZ22 and D1S80 loci using the polymerase chain reaction (PCR) technique. Gadaba are an Austro-Asiatic tribe while Kuvi-Khond and Paroja are Dravidian tribes. All samples were collected, with consent, from unrelated individuals. RESULTS: The observed allelic variation in these tribes is comparable with many Indian populations, but they showed significant overall and inter-population variability within the region. Allele *24 was the most common allele at the D1S80 locus in all populations, with Gadabas having the highest frequency (50%) followed by Paroja (32%) and Kuvi-Khond (23%). Gadabas also showed a higher frequency of allele *19 (13%) and *31 (9%) compared to other Indian and European populations. In the Apo B system, allele *37 was the most common in all three populations, with Gadabas having the highest frequency (39%) followed by Paroja (24%) and Kuvi-Khond (21%). This allele is present in high frequencies in other Indian (except Gonds) and European populations. Alleles *33 (17%), *35 (20%) and *45 (12%) were also common in the Gadabas, but Kuvi-Khond showed higher frequencies of *31(10%), *35(13%) and the larger allele *49(16%). Paroja, on the other hand, had higher frequencies of *31 (14%), *33 (17%) and *45 (13%). Allele *49 was also present in Paroja (10%) but was absent in the Gadaba. For the YNZ22 system, allele *4 was the most common in Kuvi-Khond (25%) and Paroja (21.4%), and allele *2 was the predominant allele in the Gadaba (33%). However allele *4 still occurs at relatively high frequency in Gadaba (27%). Allele *2 also occurs at relatively high frequency in Kuvi-Khond (20%) and intermediate frequency in Paroja (11%). Average heterozygosity was relatively low for Gadaba (0.7597 +/- 0.0191) and high for Kuvi-Khond (0.8618 +/- 0.0149) and Paroja (0.8512 +/- 0.0190), perhaps a reflection of effective population size and limitations to mating. The level of gene differentiation is, however, low (3-4%) for the three systems studied in these tribal populations and in data compiled from previous studies from the region. CONCLUSIONS: The VNTRs are polymorphic in the tribal populations studied and there is extensive allelic variation. Gadabas are isolated but Kuvi-Khond and Paroja show clear affinities with the Gonds, a major tribal group of Central India. Overall, allele frequency distribution, heterozygosity and genetic diversity analysis show that genetic diversity observed is socially, linguistically and geographically structured in this region.     

DAT1 3'-UTR 9R allele: preferential transmission in Indian children with attention deficit hyperactivity disorder.

Genetic alterations in the dopaminergic system are frequently observed in association with attention deficit hyperactivity disorder (ADHD) and a 40 bp variable number of tandem repeats (VNTR) in the 3'-untranslated region (3'-UTR) of the dopamine transporter gene (DAT1) has been investigated in different populations. Both significant association and lack of association with the10 repeat allele (10R) of DAT1 VNTR have been reported. Objective of the present investigation was to examine association of this polymorphism with ADHD in Indian children. Genotypic data obtained from ADHD probands (n = 79), their parents (n = 148) and control individuals (n = 153) were analyzed for haplotype-based haplotype relative risk analysis (HHRR), transmission disequilibrium test (TDT), and family-based association test (FBAT). HHRR analysis revealed significant (P = 0.009) transmission of shorter alleles (< or =9R). TDT analysis of informative ADHD families (n = 32) also exhibited highly significant transmission of the shorter alleles (P = 0.002). Further analysis by FBAT showed preferential transmission (P = 0.019) of the 9R allele from parents to ADHD probands. It can be inferred from the data obtained that the DAT1 3'-UTR 9R allele may confer risk of ADHD in the Indian population.