Medical diagnostic decision support systems--past, present, and future: a threaded bibliography and brief commentary.

Considerable evidence suggests that the development of systemic lupus erythematosus (SLE) has a strong genetic basis. Recent studies have emphasized that this disease, like other autoimmune diseases, is a complex genetic trait with contributions from major histocompatibility complex (MHC) genes and multiple non-MHC genes. Etiologic genes in these disorders determine susceptibility, and no particular gene is necessary or sufficient for disease expression. Studies of murine models of lupus have provided important insight into the immunopathogenesis of IgG autoantibody production and lupus nephritis, and genetic analyses of these mice overcome certain obstacles encountered when studying patients. Genome-wide linkage studies of different crosses have mapped the position of at least 12 non-MHC disease-susceptibility loci in the New Zealand hybrid model of lupus. Although the identity of the actual genes is currently unknown, recent studies have begun to characterize how these genetic contributions may function in the autoimmune process, especially in terms of their role in autoantibody production. Studies of MHC gene contributions in New Zealand mice have shown that heterozygosity for particular haplotypes greatly increases pathogenic autoantibody production and the incidence of severe nephritis. The mechanism for this effect appears to be genetically complex. Studies in human SLE have mostly focused on the association of disease with alleles of immunologically relevant genes, especially in the MHC. Associations with various complement component deficiencies and an allele of a particular Fc gamma receptor gene (FCGR2A) also have been described. In a diversion from previous association studies, a recent directed linkage analysis of sibpairs with SLE was based on mapping studies in murine lupus and may be an important step toward identifying a new disease-susceptibility gene in patients. Since the genes that predispose to autoimmunity are probably related to key events in pathogenesis, their identification in patients and murine models will almost certainly provide important insight into the breakdown of immunological self-tolerance and the cause of autoimmune disease.

Genetic susceptibility to systemic lupus erythematosus

Retinal projections and visual thalamo-cortical connections were studied in the subterranean mole rat, belonging to the superspecies Spalax ehrenbergi, by anterograde and retrograde tracing techniques. Quantitative image analysis was used to estimate the relative density and distribution of retinal input to different primary visual nuclei. The visual system of Spalax presents a mosaic of both regressive and progressive morphological features. Following intraocular injections of horseradish peroxidase conjugates, the retina was found to project bilaterally to all visual structures described as receiving retinal afferents in non-fossorial rodents. Structures involved in form analysis and visually guided behaviors are reduced in size by more than 90%, receive a sparse retinal innervation, and are cytoarchitecturally poorly differentiated. The dorsal lateral geniculate nucleus, as defined by cyto- and myelo-architecture, cytochrome oxidase, and acetylcholinesterase distribution as well as by afferent and efferent connections, consists of a narrow sheet 3-5 neurons thick, in the dorsal thalamus. Connections with visual cortex are topographically organized but multiple cortical injections result in widespread and overlapping distributions of geniculate neurons, thus indicating that the cortical map of visual space is imprecise. The superficial layers of the superior colliculus are collapsed to a single layer, and the diffuse ipsilateral distribution of retinal afferents also suggests a lack of precise retinotopic relations. In the pretectum, both the olivary pretectal nucleus and the nucleus of the optic tract could be identified as receiving ipsilateral and contralateral retinal projections. The ventral lateral geniculate nucleus is also bilaterally innervated, but distinct subdivisions of this nucleus or the intergeniculate leaflet could not be distinguished. The retina sends a sparse projection to the dorsal and lateral terminal nuclei of the accessory optic system. The medial terminal nucleus is not present. In contrast to the above, structures of the "non-image forming" visual pathway involved in photoperiodic perception are well developed in Spalax. The suprachiasmatic nucleus receives a bilateral projection from the retina and the absolute size, cytoarchitecture, density, and distribution of retinal afferents in Spalax are comparable with those of other rodents. A relatively hypertrophied retinal projection is observed in the bed nucleus of the stria terminalis. Other regions which receive sparse visual input include the lateral and anterior hypothalamic areas, the retrochiasmatic region, the sub-paraventricular zone, the paraventricular hypothalamic nucleus, the anteroventral and anterodorsal nuclei, the lateral habenula, the mediodorsal nucleus, and the basal telencephalon.(ABSTRACT TRUNCATED AT 400 WORDS)

Visual system of a naturally microphthalmic mammal: The blind mole rat, Spalax ehrenbergi

Congenital colobomata of the eye are important causes of childhood visual impairment and blindness. Ocular coloboma can be seen in isolation and in an impressive number of multisystem syndromes, where the eye phenotype is often seen in association with severe neurological or craniofacial anomalies or other systemic developmental defects. Several studies have shown that, in addition to inheritance, environmental influences may be causative factors. Through work to identify genes underlying inherited coloboma, significant inroads are being made into understanding the molecular events controlling closure of the optic fissure. In general, severity of disease can be linked to the temporal expression of the gene, but this is modified by factors such as tissue specificity of gene expression and genetic redundancy.

https://jmg.bmj.com/content/jmedgenet/41/12/881.full.pdf

Ocular coloboma: a reassessment in the age of molecular neuroscience

It is estimated that at least 200,000 children in India have severe visual impairment or blindness and approximately 15,000 are in schools for the blind. Although this represents a small percentage of the estimated 5 million blind in India, it is significant in terms of 'blind-years'. Strategies to combat childhood blindness require accurate data on the causes to allocate resources to appropriate preventive and curative services. Since socio-economic factors vary in different areas of this industrializing country data should be representative of the country as a whole. This is the first multi-state study to be undertaken in India using the Record for Children with Blindness and Low Vision from the World Health Organization/PBL Programme. A total of 1411 children in 22 schools from nine states in different geographical zones were examined by an ophthalmologist and optometrist. Of these, 1318 children were severely visually impaired or blind (SVI/BL). The major causes of SVI/BL in this study were: (1) corneal staphyloma, scar and phthisis bulbi (mainly attributable to vitamin A deficiency) in 26.4%; (2) microphthalmos, anophthalmos and coloboma in 20.7%; (3) retinal dystrophies and albinism in 19.3%; and (4) cataract, uncorrected aphakia and amblyopia in 12.3%. This mixed pattern of causes lies in an intermediate position between the patterns seen in developing countries and those seen in industrialised countries. The causes identified indicate the importance both of preventive public health strategies and of specialist paediatric ophthalmic and optical services in the management of childhood blindness in India.

/pdf/childhood-blindness-in-india-causes-in-1318-blind-school-4zn27gc7qr.pdf

Childhood blindness in India : causes in 1318 blind school students in nine states

To determine the association of HLA antigens with SLE and the clinical findings of the disease, HLA antigens were tested in 58 Japanese patients with SLE, who fulfilled the ARA diagnostic criteria, along with 97 normal controls. HLA class I and II antigens were typed serologically using the antisera provided by the 11th HLA Workshop. Among the HLA class II antigens, further DRB, DQ and DP alleles were defined by DNA typing using the PCR/SSOP method. There were significantly more SLE patients with HLA-B39, DRB1*1501, DRB5*0101 and DQB1*0602 than normal controls. This result suggested that the haplotype of HLA-DRB1*1501-DRB5*0101-DQA1*0102-DQB1*0602 consists of the SLE-associated MHC markers in Japan. There were some positive and negative associations between the HLA antigens and clinical or serological findings in SLE. There is a possibility that some HLA alleles might be related to the clinical and/or serological subsets of SLE.

HLA Antigens in Japanese Patients with Systemic Lupus Erythematosus

Data of 1313 microphthalmos probands and 5325 sibs in 1290 families based on a nation-wide genetic survey of the visually handicapped in 1959 and 1964 in Japan, were analyzed. The probability of ascertainment and prevalence of microphthalmos in the Japanese population was estimated at 0.34 and 3.9×10−5, respectively. The consanguinity among the normal parents of probands was higher in families with more affected sibs (inbreeding coefficient (F)=0.0192, first cousin marriages=27%) than in isolated cases where only the proband was affected (F=0.0057, first cousin marriages=8%).The rate of recessive inheritance was estimated at 12% by an inbreeding analysis The incidence of the affected sibs of probands was empirically determined: 2.2% (two normal parents), 13.6% (one parent affected) and 18.8% (both parents affected).By means of segregation analysis the proportion of monogenic modes of simple recessive, dominant inheritance and unknown etiology was 14.7, 21.7 and 63.6%, respectively. It was shown that cases...

Genetic analysis of microphthalmos

The outcome of long-term treatment of lupus nephritis under different immunotherapies, together with the factors affecting the outcome of lupus nephritis, was studied. A total of 212 lupus nephritis patients were classified into 5 groups according to their different modes of treatment: (1) initial dose of prednisolone (PSL) below 39 mg/day, (2) initial dose of PSL above 40 mg/day, (3) pulse therapy and steroids, (4) steroids and immunosuppressants, and (5) combination therapy of plasmapheresis with other therapies. The outcome of lupus nephritis was evaluated into 5 grades. As a result, the complete remission rate of lupus nephritis was 9.4%. The 5-year survival rates increased with all modes of treatment. However, it was impossible to identify which mode of therapy could bring about the highest rate of remission. Decreases in extrarenal involvement and low complement levels were observed together with increases in IgM anti-DNA antibodies among the lupus nephritis patients with remission.

Studies on the outcome of lupus nephritis according to long-term treatment employing different modes of immunotherapy.

Follow up study on the changes in the clinical features and prognosis of Japanese patients with systemic lupus erythematosus during the past 3 to 4 decades

A medical interview is a very important part of medical treatment since it is conducted when a patient is first admitted to a hospital and treatment is decided afterwards. However, these interviews are not always carried out in sufficient detail because physicians have very heavy work-loads. The development of automated medical questioning equipment which tabulates the answers to questions into a form easily understood by physicians, which enumerates data on doubtful diseases and which indicates pertinent medical examinations may come to the aid of patients and physicians. This paper presents a new diagnostic theory for the design of automated medical questioning equipment. Diagnostic theories can be classified into batch and sequential theories; the authors have investigated the sequential one, because decisions are made using minimal data. The techniques supporting this theory are multi-class recognition systems based on independently designed dual-class recognition systems and Wald's Sequential Probability Ratio Test. To discuss the properties inherent in the present theory, classification of three pattern classes was made. These were normal, hypertension and myocardial infarction classes of patients. The mean error probability of classification was found to be 3.08%.

Kazuyuki Kabasawa

Papers

HLA Antigens in Japanese Patients with Systemic Lupus Erythematosus

Genetic analysis of microphthalmos

Studies on the outcome of lupus nephritis according to long-term treatment employing different modes of immunotherapy.

Follow up study on the changes in the clinical features and prognosis of Japanese patients with systemic lupus erythematosus during the past 3 to 4 decades

A sequential diagnostic model for medical questioning.