Localization of a gene for otosclerosis to chromosome 15q25-q26

Among white adults otosclerosis is the single most common cause of hearing impairment. Although the genetics of this disease are controversial, the majority of studies indicate autosomal dominant inheritance with reduced penetrance. We studied a large multi- generational family in which otosclerosis has been inherited in an autosomal dominant pattern. Five of16 affected persons have surgically confirmed otosclerosis; the remaining nine have a conductive hearing loss but have not undergone corrective surgery. To locate the disease- causing gene we completed genetic linkage analysis using short tandem repeat polymorphisms (STRPs) distributed over the entire genome. Multipoint linkage analysis showed that only one genomic region, on chromosome 15q, generated a lod score >2.0. Additional STRPs were typed in this area, resulting in a lod score of 3.4. STRPs FES (centromeric) and D15S657 (telomeric) flank the 14. 5 cM region that contains an otosclerosis gene.      

Visualizing cytokine-secreting cells in situ in the rhesus macaque model of chronic gut inflammation

Cytokine-producing cells in gut-associated lymphoid tissues of rhesus macaques with chronic enterocolitis were studied. The confocal microscopy technique that we developed enables simultaneous in situ visualization of multiple extra- and/or intracellular antigens at a resolution higher than that allowed by light or epifluorescence microscopy. The presence of interleukin-6 (IL-6)-, tumor necrosis factor alpha (TNF-alpha)-, and IL-1-alpha-producing cells was focally intense in the colon lamina propria of the affected animals. The IL-1-alpha-producing cells were T lymphocytes (CD3+), while the TNF-alpha-producing cells were both macrophages (CD68+/HAM56+/LN5+) and T lymphocytes (CD3+). The IL-6-producing cells within the colon consisted of T lymphocytes and macrophages. The amount of IL-6-producing cells seen in macaques with enterocolitis was significantly higher (P<0.001) than that seen in the healthy control animal, while TNF-alpha- and IL-1-alpha-producing cells were seen only in macaques with enterocolitis. Most of the T lymphocytes that produced cytokines were detected in the lamina propria, while the macrophages were most prominent in highly inflamed regions of the lamina propria. Taken together, our findings indicate that there might be immunological similarity between chronic enterocolitis of rhesus macaques and humans, suggesting the potential use of the nonhuman primate model for the validation of novel therapies.     

Human mtDNA hypervariable regions, HVR I and II, hint at deep common maternal founder and subsequent maternal gene flow in Indian population groups

We have analysed the hypervariable regions (HVR I and II) of human mitochondrial DNA (mtDNA) in individuals from Uttar Pradesh (UP), Bihar (BI) and Punjab (PUNJ), belonging to the Indo-European linguistic group, and from South India (SI), that have their linguistic roots in Dravidian language. Our analysis revealed the presence of known and novel mutations in both hypervariable regions in the studied population groups. Median joining network analyses based on mtDNA showed extensive overlap in mtDNA lineages despite the extensive cultural and linguistic diversity. MDS plot analysis based on Fst distances suggested increased maternal genetic proximity for the studied population groups compared with other world populations. Mismatch distribution curves, respective neighbour joining trees and other statistical analyses showed that there were significant expansions. The study revealed an ancient common ancestry for the studied population groups, most probably through common founder female lineage(s), and also indicated that human migrations occurred (maybe across and within the Indian subcontinent) even after the initial phase of female migration to India.     

Glycolipids of Mycobacterium tuberculosis Strain H37Rv Are Potential Serological Markers for Diagnosis of Active Tuberculosis

A simple and cost-effective diagnostic tool (TB Screen Test) for the screening of patients with pulmonary and extrapulmonary tuberculosis and for differentiation of those individuals from individuals without tuberculosis, other common infections, and healthy controls has been developed. The serological responses of purified mycobacterial glycolipid antigens were examined by a liposome agglutination assay. The assay was able to detect very low antiglycolipid antibody concentrations in the infected individuals. The sera from the tuberculosis patient group had significantly higher concentrations of antiglycolipid antibody than the sera from uninfected control subjects, with 94% sensitivity and 98.3% specificity. Glycolipids of Mycobacterium tuberculosis H37Rv antigens were isolated, purified, and characterized. After interchelation with liposome particles, these purified antigens specifically bound to the antiglycolipid antibodies present in the sera of patients with tuberculosis, resulting in the formation of a blue agglutination. This protocol clearly differentiates healthy controls and M. bovis BCG-vaccinated subjects from those with active tuberculosis. The resultant diagnostic tool, the TB Screen Test, is more economical and rapid (4 min) than other currently available products and can be used for the mass screening of a heavily afflicted population.     

Personal relationships with an intelligent interactive telephone health behavior advisor system: a multimethod study using surveys and ethnographic interviews

The burgeoning of consumer health informatics and virtual health care can help people improve their health. However, little is known about individuals' reactions to such systems. We conducted an evaluation of the telephone-linked care (TLC) system, a computer-based telecommunications system, that functions as an at home monitor, educator, and counselor for patients with chronic health conditions. Our multimethod assessment of individuals' reactions to using TLC included both quantitative and qualitative methods. Ethnographic in-depth open-ended interviews indicated more subtle and surprising reactions to TLC than the overall positive responses from surveys: individuals formed personal relationships with this technology. This relationship formation suggests that TLC designers may have been successful in their attempts to emulate a conversation with a human being. Our study adds to evidence that technology can serve as a projective device for peoples' values and psychological issues. Both designers and users project values and goals onto computer-based technologies and take on different identities through it. Different groups of users, therefore, may see the same technology differently. People also form relationships with technologies, as they did with TLC. These findings, as well as implications for system design and health outcomes, need to be explored in additional studies.     

The murine NF2 homologue encodes a highly conserved merlin protein with alternative forms

The recently isolated gene for neuroflbromatosls type 2 (NF2)encodes a 595 amlno acid protein, named merlin, which Is relatedto the cytoskeleton-assoclated proteins moesln, ezrin and radlxin.To Identify evolutionarily conserved regions and to providesequence Information necessary for the establishment of a mousemodel for NF2, we have determined the cDNA sequence of the mouseNF2 tumor suppressor gene, and mapped It In the mouse genome.Mouse merlin is a 596 amino acid protein, 98% identical to humanmerlin, but one amlno acid longer due to the Insertion of aproline residue near the C-terminus. Of the nine amlno aciddifferences between mouse and humans, seven occur in the C-termlnal20% of the protein, far from the protein 4. 1 domain that definesthis family. Two of the NF2 cDNA clones reveal evidence of alternativesplicing events that alter the predicted merlin product, oneremoving a 45 amlno acid segment from the middle section ofthe protein and the other changing the C-terminus. The existenceof several different forms of merlin potentially with differentprimary roles will complicate the Identification of the precisefunction that must be disrupted to cause the NF2-assoclatedtumors. The mouse NF2 homologue maps to Chr 11, in a regionhomologous to human Chr 22, but devoid of any mouse mutationswhich could be models of the human disorder.     

A human recessive neurosensory nonsyndromic hearing impairment locus is a potential homologue of the murine deafness (dn) locus

A locus for recessive neurosensory nonsyndromic hearing impairmentmaps to chromosome 9q13–q21 in two regionally separateconsanguineous families from India. Each family demonstratesa LOD score greater than 4.5 to this region. D9S15, tightlylinked to the Friedreich's ataxia locus, a region that has beendefined with over 1 Mb of YAC contig information and severalexpressed sequences, is one of the flanking markers. In mice,the deafness (dn) locus maps to mouse chromosome 19 and flankingloci are syntenic to human chromosome 9q11–q21. The dnmouse is a potential model for the hearing impairment foundin both these families.