Transgenic mice with a rhodopsin mutation (Pro23His): a mouse model of autosomal dominant retinitis pigmentosa.

We inserted into the germline of mice either a mutant or wild-type allele from a patient with retinitis pigmentosa and a missense mutation (P23H) in the rhodopsin gene. All three lines of transgenic mice with the mutant allele developed photoreceptor degeneration; the one with the least severe retinal photoreceptor degeneration had the lowest transgene expression, which was one-sixth the level of endogenous murine rod opsin. Of two lines of mice with the wild-type allele, one expressed approximately equal amounts of transgenic and murine opsin and maintained normal retinal function and structure. The other expressed approximately 5 times more transgenic than murine opsin and developed a retinal degeneration similar to that found in mice carrying a mutant allele, presumably due to the overexpression of this protein. Our findings help to establish the pathogenicity of mutant human P23H rod opsin and suggest that overexpression of wild-type human rod opsin leads to a remarkably similar photoreceptor degeneration.

Sox18 expression in blood vessels and feather buds during chicken embryogenesis.

Sox18 encodes a transcription factor known to be important for the development of blood vessels and hair follicles in mice. In order to study the functional conservation of this gene through evolution, we have isolated and characterized Sox18 in chickens. cSox18 shows a high degree of sequence homology to both the mouse and human orthologues, particularly in the high mobility group DNA-binding domain and to a lesser extent in the transcriptional activation domain. A region of unusually high sequence conservation at the C-terminus may represent a further, previously unrecognized functional domain. Both the chicken and human proteins appear to be truncated at the N-terminus relative to mouse SOX18. In situ hybridization analyses showed expression in the developing vasculature and feather follicles, consistent with reported expression in the mouse embryo. In addition, cSox18 mRNA was observed in the retina and claw beds.

Immunoglobulin abnormalities and measles antibody response in chronic myelopathy.

Patients with chronic myelopathy of unknown origin were separated into two groups on the basis of presence or absence of oligoclonal immunoglobulin G (lgG) in cerebrospinal fluid (CSF). Thirty-nine of 48 patients (81%) with oligoclonal lgG in CSF had measles virus antibodies in the CSF and 31 (65%) showed reduced serum/CSF measles virus antibody ratios, in comparison with the corresponding ratios of adenovirus, group-specific, penton hemagglutination-enhancement and poliovirus neutralization-enhancement antibodies. Of 25 patients with myelopathy, but without oligoclonal lgG in their CSF, three had detectable titers of measles CSF antibodies and one of these had a greatly reduced serum/CSF ratio. The conditions of patients with chronic myelopathy of unknown origin and oligoclonal lgG in CSF may be diagnosed as probable multiple sclerosis (MS), in contrast to patients with this disease who lack oligoclonal lgG IN CSF. However, the clinical features of the disease in these two groups do not differ substantially.

HLA haplotypes in families with high frequency of multiple sclerosis.

Eight families from southern Sweden having two or more members with multiple sclerosis (MS) were typed for various alleles of the HLA system. The MS patients within each family shared one major histocompatibility system (MHS) haplotype, which was identical to the hitherto-described MS-associated haplotype A3B7Dw2 only in two of the families. Healthy relatives of MS patients were often found to carry the same haplotype as the affected members, which makes an estimate of the degree of penetrance of disease in individuals carrying the MS-predisposing MHS-linked gene possible.

Antineural antibodies in Guillain-Barré syndrome and lymphocytic meningoradiculitis (Bannwarth's syndrome).

Antineural antibodies occur in Guillain-Barré syndrome (GBS), but have not been studied in lymphocytic meningoradiculitis (Bannwarth's syndrome), which has clinical features in common with GBS. Employing a sensitive complement-fixation assay with homogenates of nerve root and brain as antigens, we recorded positive serum reactions to either tissue in 14 of 18 samples from patients with GBS during the first three weeks of the disease. Five of nine samples were positive during the fourth to eighth weeks, whereas all seven patients sampled thereafter had negative reactions. Four GBS serum samples reacted only with nerve root, seven reacted only with brain, and eight reacted with both antigen preparations. One of 12 patients with meningoradiculitis and one of 50 supposedly healthy blood donors had serum antibodies to brain. Our results support the concept of an autoimmune mechanism in GBS, while in Bannwarth's syndrome an infectious cause related to that of Lyme disease may be suspected.

Gamma globulins of CSF and serum in multiple sclerosis: isoelectric focusing on polyacrylamide gel and agar gel electrophoresis.

Cerebrospinal fluid (CSF) and serum from 139 patients with MS were analyzed with electrophoresis on agar gel (AGE) and isoelectric focusing (IEF) on polyacrylamide gel. In both methods, 82 percent of the patients had abnormal patterns of oligoclonal IgG bands in the gamma globulin and alkaline regions. With IEF, 10 percent of the serum samples contained faint bands corresponding to the bands in CSF. Most of the bands were found in the cathodal part of the alkaline IEF region, but there was no correlation with clinical characteristics. Each patient seems to have a special band pattern which does not change throughout the disease. The gamma-trace protein was seen in 77 percent of the patients on IEF and in 29 percent on AGE. On IEF it appeared at two positions, at pH 8.0 and 9.3, but about 10 other bands were seen in the "normal" alkaline CSF region, making the band pattern of IEF more difficult to interpret than that of AGE. This limits the routine clinical value of IEF, even if the high resolution capacity of this method is useful in research.

Gene of type II autosomal dominant retinitis pigmentosa maps on the long arm of chromosome 3.

Linkage analysis has been performed on a large Australian family segregating for the autosomal dominant form of retinitis pigmentosa (ADRP). The majority of patients had no subjective symptoms of night blindness until their second decade and good visual acuity until late in life. The disease in this family has been classified as Type II ADRP according to the subdivisions provided by both Massof and Finkelstein and Fishman and colleagues. Linkage (Omax:0.08 at Zmax:4.78) is here demonstrated between the disease locus and D3S47 (a marker locus on the long arm of chromosome 3), which showed in an earlier study very close linkage without recombination to the disease locus in an Irish pedigree with a clinically more severe and early onset (Type I) ADRP.

Age-standardized incidence and prevalence of Parkinson's disease in a Swedish community.

Parkinson's disease (PD) shows a geographical variation. All prescriptions for anti-parkinsonian drugs were recorded for a half-year in a region with low L-dopa consumption. Hospital and outpatient records were studied and physicians were asked to supply details of PD patients in the region, with 147,777 inhabitants. The crude prevalence was 115 PD per 100,000 inhabitants, based on 170 cases. In contrast to other studies we report an age-standardized prevalence, which was 76 per 100,000, using the European Standard Population as reference. The corresponding approximate incidences were 11.0 (crude) and 7.9 (age-standardized) per 100,000 person-years. Male preponderance appeared in all age groups. Mean age at onset was 65.6 years, the highest figure reported. Variation between studies for age at onset, differences in prevalence, and male preponderance suggest environmental risk factors to be of importance for PD.

The cerebrospinal fluid and plasma concentrations of gamma-trace and beta2-microglobulin at various ages and in neurological disorders.

The concentrations of gamma-trace and beta2-microglobulin in cerebrospinal fluid (CSF) and plasma were determined in 64 individuals of various ages without signs of organic disorder in the central nervous system (CNS). A strong connection was found between the CSF level of gamma-trace and the age of the individual, with the CSF level of newborns being 3--4 times that of adults. A similar, but less marked, connection was found for the CSF level of beta2-microglobulin and the age of the individual. The plasma levels of the two proteins also varied with the age of the individual, but the variations were not as great as those of the CSF levels. The results strongly emphasize the necessity of using age-matched reference values when CSF and plasma levels of the proteins are to be evaluated in different groups of patients. Thirteen children and 98 adults with various neurological disorders were also examined. Significantly increased CSF levels of gamma-trace and beta2-microglobulin as well as increased plasma concentration of gamma-trace and CSF/plasma gradient of beta2-microglobulin were found in infectious disorders. Increased gamma-trace concentration in plasma and beta2-microglobulin concentration in CSF were seen in cerebrovascular disorders. The mechanisms which regulate the turnover of proteins in CSF are discussed.

The diagnostic value of spectrophotometric analysis of the cerebrospinal fluid in cerebral hematomas.

On a clinical basis it is sometimes impossible to distinguish between small intracerebral hematomas and reversible ischemic strokes (RIND). Analysis of the cerebrospinal fluid (CSF) has been used in ths context for several years and is still of importance even since the introduction of computerized tomography (CT) of the brain. CSF has been examined in 23 patients with intracerebral hematomas. Typical cell changes with an increase of poly- and mononuclear white cells are seen within the first days after the stroke, whereas clearly pathological spectrophotometric changes are not seen until about one week after the stroke. None of the investigated patients had a significant increase of the absorbance values at the wavelenths 406 and 415 nm (met- and oxyhemoglobin) until 5 days after the stroke.

Immunoglobulin abnormalities in multiple sclerosis. Relation to clinical parameters: disability, duration and age of onset.

Cerebrospinal fluid (CSF) and serum from 35 pairs of multiple sclerosis (MS) patients were analysed as regards mononuclear pleocytosis, concentrations of total protein, immunoglobulin G and A and beta-trace protein, and kappa:lambda ratios, as well as the serum/CSF ratios of IgG and albumin. The disability of the patients differed, whereas the age and the duration of the disease were similar in each pair. Similar analyses were also performed on CSF and serum from 72 patients, who were subdivided according to age at onset and severity of the disease. The highest mean values of the CSF-IgG and the lowest mean values of the serum/CSF IgG ratios were found in the more disabled patients. CSF immunoglobulin abnormalities were encountered more often and were more pronounced in the patients with the most malignant course of the disease, i.e., in those with severe disability after a short duration of the disease (less than 10 yr) and in severely disabled patients with an early age at onset of the disease(less than 25 yr). Contrarily, normal mean values of CSF-IgG concentrations and serum/CFS/IgG ratios were found in the groups of patients without disability after a duration of the disease of 10 years or more, and patients without disability and an early age at onset of the disease (less than 25 yr). The observations indicate that the immune response is most vigorous in disabled patients with a short duration or with an early age at onset of the disease. MS patients with a late age at onset (greater than 35 yr) showed a less pronouced immune response within the CNS, irrespective of the occurrence of disability. The most disabled patients also showed the most severe blood-brain barrier damage as manifested by high mean values of total protein in CSF and low serum/CSF albumin ratios. The patients with severe disability and a long duration of the disease (greater than 10 yr) had the highest content of beta-trace protein in the CSF, probably as a sign of destruction of brain matter.

Dopa-responsive dystonia with depigmentation of the substantia nigra and formation of Lewy bodies.

The patient, who died at 23 years of age, was first diagnosed when she was 12 year old as having a dopa-responsive dystonia with decreased concentrations of monoamine metabolites in the cerebrospinal fluid. Also the concentrations of other neurotransmitters including somatostatin, substance P and metenkefalin were lowered indicating a more widespread damage of the cerebral neurotransmitter systems. At autopsy the brain was essentially intact except for pronounced gliosis and extreme loss of melanotic nerve cells in the substantia nigra. Several remaining nerve cells showed the presence of Lewy bodies.

Neurotologic findings in basilar migraine.

Treatment of a patient with otologic symptoms and associated migraine-like headache presents the otolaryngologist with formidable problems. Although clinical practice and scientific publications recognize their frequent association, relationships have yet to be well defined. This study seeks to add order to disarray by delineating symptoms and signs of a clearly identified group of migraine patients. Fifty patients with well-defined basilar migraine underwent a thorough neurotologic examination, as well as comprehensive auditory and vestibular testing. Patients were selected from 5880 patients seen over a 2-year period and were prospectively entered into the study after detailed questionnaires and testing were completed for each patient. The most common symptoms found were dysequilibrium, phonophobia, and head pressure. The most common signs were positional nystagmus, low-frequency hearing loss, abnormal loudness discomfort level, and an abnormality on caloric examination. Advanced vestibular testing showed abnormal amplitude scaling, abnormal toes-down pertubation, and an abnormal sway (condition 6) on dynamic posturography. There was frequently an asymmetry on computerized rotation. The author concludes that the majority of patients have subtle findings on testing, but a few have severe peripheral injury due to the basilar migraine. Findings are consistent with the theory that basilar migraine is a central nervous system maladaptation syndrome which creates otoneurologic symptoms and, in a small percentage of cases, may injure the peripheral end-organ.

Explosion-related deaths in Sweden--a forensic-pathologic and criminalistic study.

All cases of death caused by explosions of explosive solids, fluids and gases in Sweden during the 6-year period 1979-1984 were analyzed. Among the total of 61 fatalities 33 (54%) were due to accidents (2/3 of them occupational and 1/3 miscellaneous accidents), 25 (41%) were suicides, and only 3 (5%) were associated with terrorist activity. About one half of the occupational accidents were caused by deficient safety devices or defective equipment, while the other half was due to transgression of regulations. All suicides were males, relatively elderly, the majority of them burdened with somatic and mental diseases, alcoholism, social or economical problems, most of them being familiar with explosives. The anatomical localization of suicidal explosive injuries was regular and symmetric, while the accidental and terrorist injuries showed great variations. The terrorist-associated deaths had common features different from all other death cases, strongly suggesting the same type of bomb and the same terrorist group. Explosives caused only superficial burns or singes. Symmetric hemorrhages of the vocal folds and fracture of the laryngeal skeleton were found, as well as ruptures of trachea and lungs. When not ruptured, the lungs showed to different types of injury: hyperinflation, probably due to the blast-induced barotrauma to the respiratory passages, or lung contusions. In cases of suspected terrorist explosions close collaboration between the forensic pathologists and police investigators is mandatory since the bodies of victims protect parts of the bomb from fire or from being spread over a larger area and thus constitute a part of the crime scene.

Work-related, noise-induced hearing loss: evaluation including evoked potential audiometry.

This article reviews the evaluation of 246 workers (492 ears) who underwent otologic and audiologic testing as part of a worker's compensation claim for work-related, noise-induced hearing loss. Tinnitus was present in 58% of the patients, but was rarely a major symptom. Other otologic symptoms or a history of ear disease were virtually nonexistent. Standard audiometry showed a downsloping, high-frequency sensorineural hearing loss in 85% of the ears tested, with only 37% having a characteristic "noise notch" at 4000 or 6000 hertz. Asymmetric hearing loss was not uncommon, with 48 patients (20%) undergoing magnetic resonance scanning, all of whom showed no central lesion responsible for the loss. Proven malingering was surprisingly uncommon (9%). In this study, evoked response audiometry was a valuable adjunct to confirm behavioral thresholds in the evaluation of possible work-related, noise-induced hearing loss. The middle latency response was more effective than the auditory brainstem response as a result of the high-frequency steepness of the audiometric curve.

Human beta-trace in normal and pathological CNS tissues, genital organs and body fluids.

The function of BTP is still unknown. In CNS, the high amount of BTP in the white CNS matter and the glial cells as well as in genital organs of the stroma of epididymis suggest that BTP has a supportive function. Slight evidence of a synthesis in patients with MS and slightly increased CSF values in stroke patients may suggest that BTP is involved in repair mechanism of damaged brain tissue, or may be related from destroyed brain tissue. In samples of CSF, determination of BTP could be of value as differentiating glial cell tumors from tumors of other kinds, as well as the recently suggested diagnostic value of the Creutzfeldt-Jakob disease (20). However, also other functions of BTP has been suggested. (21, 22).

Vestibular disorders.

This article reviews and updates the pathology associated with the labyrinth and peripheral central nervous system. It serves as an overview to aid in the diagnosis and treatment of vertigo.

The evaluation of facial paralysis.

The clinician faces a major challenge in the evaluation of acute facial nerve paralysis. Not only must he or she differentiate the large proportion of patients with idiopathic palsy who will resolve spontaneously from that critical small group that will not, but must also diagnose correctly the other rather unusual to rare conditions that cause facial paralysis. This article reviews the differential diagnosis, initial clinical evaluation, natural history, and long-term follow up of patients with acute facial dysfunction.

[Binswanger disease. A blood pressure-related dementia]. / Binswangers sjukdom. En blodtrycks-relaterad demens.

Interest in Binswanger's disease has increased during the past decade, owing to the possibility of detecting white matter changes with computerised and magnetic resonance tomography. This paper consists in a summary of clinical symptoms and signs and possible diagnostic criteria, discussion of differential diagnosis, and the presentation of two own cases. Both patients manifested mild dementia and gait disturbance, and one had frequent drop attacks. Severe supra- and infra-tentorial white matter changes were present in both cases. It is important to consider a possible diagnosis of Binswanger's disease, as treatment of the appropriate risk factors may prevent or delay the development of dementia.