Myositis with sarcoplasmic inclusions in Nakajo-Nishimura syndrome: a genetic inflammatory myopathy.

AIMS: Nakajo-Nishimura syndrome (NNS) is an autosomal recessive disease caused by biallelic mutations in the PSMB8 gene that encodes the immunoproteasome subunit ß5i. There have been only a limited number of reports on the clinicopathological features of the disease in genetically confirmed cases. METHODS: We studied clinical and pathological features of three NNS patients who all carry the homozygous p.G201V mutations in PSMB8. Patients' muscle specimens were analysed with histology and immunohistochemistry. RESULTS: All patients had episodes of typical periodic fever and skin rash, and later developed progressive muscle weakness and atrophy, similar to previous reports. Oral corticosteroid was used for treatment but showed no obvious efficacy. On muscle pathology, lymphocytes were present in the endomysium surrounding non-necrotic fibres, as well as in the perimysium perivascular area. Nearly all fibres strongly expressed MHC-I in the sarcolemma. In the eldest patient, there were abnormal protein aggregates in the sarcoplasm, immunoreactive to p62, TDP-43 and ubiquitin antibodies. CONCLUSIONS: These results suggest that inflammation, inclusion pathology and aggregation of abnormal proteins underlie the progressive clinical course of the NNS pathomechanism.

Sequence and localization of an ultraviolet (sws1) opsin in the retina of the Japanese sardine Sardinops melanostictus (Teleostei: Clupeiformes).

A full-length complementary (c)DNA encoding ultraviolet (UV)-sensitive opsin (sws1) was isolated from the retina of the Japanese sardine Sardinops melanostictus. The sws1 phylogenetic tree showed a sister group relationship with the Cypriniformes, following the ray-finned fish phylogeny. By expressing reconstituted opsin in vitro, it was determined that the maximum absorbance spectrum (λmax ) of sws1 is around 382 nm, being intermediate in position between two subtypes of sws1 pigment that are UV sensitive (λmax = 355-380 nm) and violet sensitive (λmax = 388-455 nm), which have been reported to date. The ocular media transmitted >20% transmittance of light in the range of 360-600 nm. In situ hybridization analyses revealed that sws1 messenger (m)RNA is localized in a central single cone surrounded by four double cones in a square mosaic. The square mosaic occupies the ventro-temporal quadrant of the retina and the in situ hybridization signals were dominant in this area suggesting that the fish may use UV vision when looking upward. Based on these results, considerable significances of potential UV sensitivity, in relation to characteristic habits of S. melanostictus, are discussed.

Divergent selection for opsin gene variation in guppy (Poecilia reticulata) populations of Trinidad and Tobago.

The guppy is known to exhibit remarkable interindividual variations in spectral sensitivity of middle to long wavelength-sensitive (M/LWS) cone photoreceptor cells. The guppy has four M/LWS-type opsin genes (LWS-1, LWS-2, LWS-3 and LWS-4) that are considered to be responsible for this sensory variation. However, the allelic variation of the opsin genes, particularly in terms of their absorption spectrum, has not been explored in wild populations. Thus, we examined nucleotide variations in the four M/LWS opsin genes as well as blue-sensitive SWS2-B and ultraviolet-sensitive SWS1 opsin genes for comparison and seven non-opsin nuclear loci as reference genes in 10 guppy populations from various light environments in Trinidad and Tobago. For the first time, we discovered a potential spectral variation (180 Ser/Ala) in LWS-1 that differed at an amino acid site known to affect the absorption spectra of opsins. Based on a coalescent simulation of the nucleotide variation of the reference genes, we showed that the interpopulation genetic differentiation of two opsin genes was significantly larger than the neutral expectation. Furthermore, this genetic differentiation was significantly related to differences in dissolved oxygen (DO) level, and it was not explained by the spatial distance between populations. The DO levels are correlated with eutrophication that possibly affects the color of aquatic environments. These results suggest that the population diversity of opsin genes is significantly driven by natural selection and that the guppy could adapt to various light environments through color vision changes.

Clinical characteristics classified by the serum KL-6 level in patients with organizing pneumonia.

BACKGROUND: The serum Krebs von der Lungen-6 (KL-6) level is a useful marker correlated with the severity of various interstitial lung diseases. There have been few reports about the clinical characteristics of organizing pneumonia (OP) associated with the serum KL-6 levels. OBJECTIVE: This study was performed to determine whether the serum KL-6 levels can help determine the optimal treatment for OP. DESIGNS: Patients diagnosed with OP by clinical, radiological and histopathological findings were retrospectively reviewed. The OP patients were classified into two groups based on their serum KL-6 levels: normal KL-6 and high KL-6 groups. The two groups were compared with regard to their clinical and radiological data and therapeutic response one month after the start of treatment. RESULTS: The clinical records of twenty-two patients diagnosed with OP were reviewed. The serum KL-6 level was elevated in 11 of the 22 patients. There were no obvious differences in the clinical data between the two groups, although patients in the normal KL-6 group tended to have a fever. There were no significant differences in the chest X-ray (CXR) score or computed tomography (CT) score between the two groups. The CXR scores were correlated with the serum KL-6 levels. At 1 month after the diagnosis, 11 patients who needed treatment with prednisolone were included in the high KL-6 group. CONCLUSIONS: Patients with normal KL-6 levels showed lower CXR and CT scores. The serum KL-6 level on admission is a useful marker to judge the need for corticosteroid treatment in OP patients.

Effects of nicotine on cultured cells suggest that it can influence the formation and resorption of bone.

The acute effects of nicotine [1-methyl-2-(3-pyridyl)pyrrolidine] on the formation and resorption of bone were examined in cultures of clonal rat calvarial osteogenic cells (ROB-C26) and clonal mouse calvarial preosteoblastic cells (MC3T3-E1), as well as in osteoclast-like cells formed during coculture of mouse bone marrow cells and clonal stromal cells from mouse bone marrow, ST2 cells, at concentrations that occur in the saliva of smokeless tobacco users. Nicotine stimulated the rate of deposition of Ca(2+) by ROB-C26 cells, as well as the alkaline phosphatase activity of these cells, in a dose-dependent manner. However, both activities decreased in MC3T3-E1 cells that had been exposed to nicotine. These results indicate that nicotine affected osteoblastic differentiation in osteoblast-like cells. By contrast, nicotine reduced, in a dose-dependent manner, the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (MNCs) and the formation of pits on slices of dentine, both of which are typical characteristics of osteoclasts. Our results suggest that nicotine might have critical effects on bone metabolism.

Low serum cholic acid concentration of Duchenne muscular dystrophy.

Serum bile acids of 15 patients with Duchenne muscular dystrophy (DMD) were analyzed by gas-liquid chromatography. The serum cholic acid values were unusually low (0.16 +/- 0.13 microM), even less than 0.01 microgram/ml in 4, compared with controls (1.47 +/- 0.17 microM). HDL-cholesterol was within normal limits. The low concentration of serum cholic acid may be causative of abnormal calcium mobilization in DMD. The intracellular calcium mobilization seems to be affected by serum cholic acid as indicated by the enhanced rate of loss of intracellular calcium from the muscle exposed to cholic acid, which acts as a calcium-ionophore and reversibly forms soluble complexes with calcium ions.

Multimodality evoked potentials in progression of metachromatic leukodystrophy.

A 2-yr-3-mo-old girl with metachromatic leukodystrophy (MLD) was examined using serial multiple electrophysiological procedures. Sensory nerve conduction velocity was delayed earlier and more severely than motor nerve conduction velocity. Visual evoked potentials (VEPs) showed prolonged latency of wave IV. Auditory brainstem responses (ABRs) showed prolonged latency of waves I and V, and the I-V interval. As to the interpeak latency of somatosensory evoked potentials (SEPs), the P9-P14 and the P14-N20 intervals were prolonged on admission. Two months later, both intervals were more prolonged, but the prolongation of the P9-P14 interval was the most prominent. The demyelination in our case may have started in the cerebral white matter, progressed to the peripheral nerves, and at last via the spinal root reached the brainstem. An electrophysiological follow-up study may be valuable in the understanding of the progressive pathological changes and in the evaluation of therapeutic measures.

Developmental change of short latency somatosensory evoked potential waves between P3 and N1 components in children.

We attempted to isolate and identify the negative waves between the conventional P3 and N1 components of short latency somatosensory evoked potentials (S-SEPs) in children. Twenty normal children ranging in age from 3 months to 12 years, and 11 adolescents and adults were studied. The median nerve was stimulated and recordings from F (F3 or F4) and C' (1-2 cm posterior to C3 or C4) contralateral to the stimulation site were simultaneously obtained in order to identify each negative wave in the C' recording. The wave of C' coincident with that of F was regarded as the far-field potential, and the wave of C' that diverged from F as the near-field potential at the scalp. There were one negative wave (N1) in the far-field potential and 2 negative waves (N2 and N1(3)) in the near-field potential, after the P3 component. "N1(3)" was conventional N1 and "N2" was the negative wave just before N1(3). In infants and younger children, the interpeak latencies of P3-N1(3) and P3-N2 were markedly elongated in comparison with that in older children. These interpeak latencies may be useful as an index of cerebral maturation.

[Clinical significance of serum cardiac myosin light chain I in patients with muscular dystrophy].

We examined serum cardiac myosin light chain I (LCI), serum creatine kinase (CK) levels and left ventricular function in patients with muscular dystrophy and secondary cardiac involvement. LCI levels were determined by a two-site immunoradiometric assay method in 25 patients with muscular dystrophy and 10 normal subjects. This study included 15 patients with Duchenne muscular dystrophy (DMD), 8 patients with Fukuyama type congenital muscular dystrophy (FCMD) and 2 sisters with non-Fukuyama type congenital muscular dystrophy (nFCMD). We measured the value of left ventricular fractional shortening (FS) using echocardiography. All patients with DMD and FCMD showed moderate or severe skeletal muscle weakness. The mean values of LCI were significantly higher in patients with DMD (11.0 +/- 8.3 ng/ml, p less than 0.01) and in patients with FCMD (1.6 +/- 1.4 ng/ml, p less than 0.05) than in normal subjects (0.3 +/- 0.2 ng/ml). In patients with DMD, LCI level correlated closely with CK level (r = 0.81, p less than 0.01) but not with FS (r = 0.35, n.s.). In patients with FCMD, LCI level correlated significantly with CK level (r = 0.75, p less than 0.05) but not with FS (r = 0.44, n.s.). Close correlation between LCI and CK levels was thought to result from the cross reaction between cardiac LCI and myosin light chains of skeletal muscle in the assay method we used. Two siblings with nFCMD showed mild skeletal muscle weakness. A 22-year-old sister with mild left ventricular dysfunction (FS = 0.41) showed high level of CK (4794/U/L) and mild elevation of LCI (7.3 ngml).(ABSTRACT TRUNCATED AT 250 WORDS)

[Evaluation of cardiac complications in patients with Duchenne muscular dystrophy using echocardiography--a comparison between patients with and without mechanical ventilation].

Two-dimensional echocardiography and Doppler echocardiography were performed in 19 patients with Duchenne muscular dystrophy for evaluating right ventricular overload and left ventricular function. Five of 19 patients were treated with mechanical ventilation. We defined right ventricular overload as right ventricular enlargement and the presence of paradoxical ventricular septal motion. The right ventricular dimensions in patients with mechanical ventilation were significantly larger than in patients without mechanical ventilation (p less than 0.01). All the patients with and without mechanical ventilation showed no significant right ventricular enlargement and none of them showed paradoxical ventricular septal motion. As for left ventricular function, there were no significant differences in the incidence of regional or diffuse wall motion abnormalities between two groups. However, the left ventricular fractional shortening was significantly lower in patients with mechanical ventilation than in patients without it (p less than 0.05), and the incidence of mitral regurgitation was significantly higher in the former than in the latter (p less than 0.01). Our findings suggest that right ventricular function is preserved even in patients with respiratory failure by appropriate respiratory treatment. Therefore, we should give attention to the progression of left ventricular dysfunction in long term prognosis.

[The clinical effect of mechanical ventilatory assistance with tracheotomy in terminal phase muscular dystrophy].

The clinical effect of mechanical ventilatory assistance with tracheotomy in respiratory failure of terminal phase muscular dystrophy was studied. The subjects were 6 Duchenne muscular dystrophy cases and 1 Ullrich type congenital muscular dystrophy case. Duration of the longest survival case was 4 years and 5 months. General physical conditions, complications, ADL and muscular atrophy were examined. By ventilatory assistance respiratory failure improved, and the physical condition stabilized and took good progress. Arterial hemorrhage which is lethal complication was observed in 2 cases. Mechanical ventilatory assistance with tracheotomy is an effective symptomatic therapy for the improvement of respiratory failure that can be applied when life prolongation is wished for by the patients or their families.

[Nutritional assessment of severely retarded children and adults].

The nutritional status was assessed with physical and biochemical parameters on 39 severely retarded children and adults, 17 males and 22 females, ranging from 6 to 40 years of age. In the anthropometric measurements, a majority of the cases showed short stature, light body weight, decreased triceps skinfold thickness and decreased mid-upper arm muscle circumference. The analysis of serum amino acids showed decreases of the sum of essential amino acids, the sum of branched chain amino acids, the ratio of the sum of essential amino acids to the sum of nonessential amino acid, and the ratio of the [methionine + tryptophan] to [valine + lysine + threonine]. The levels of prealbumin and transferrin in the serum were within normal limits. Other biochemical parameters were lower limits, including total protein, albumin, total cholesterol, triglyceride, phospholipid and total lipids in the serum. In addition, the level of fasting blood glucose tended to be low, and levels of serum free fatty acid were markedly different between before and after breakfast. These results suggest the presence of nutritional disturbances in most of severely retarded children and adults.

The transcript for a novel protein with a zinc finger motif is expressed at specific stages of mouse spermatogenesis.

The cDNA for an RNA that is expressed predominantly in mouse spermatogenic cells was cloned and characterized. It was found to encode novel zinc finger protein. We first generated a cDNA fragment from mouse osteoblastic cells by the differential display method. To our surprise, Northern blot analysis revealed that the corresponding transcript was expressed at high levels in the testis rather than in osteoblastic cells. Therefore, using this fragment as a probe, we isolated the full-length cDNA (3340 bp) from a mouse testis cDNA library. Analysis of the open reading frame of the cDNA indicated that the encoded protein was a polypeptide of 942 amino acids residues that included three distinct domains, namely, a zinc finger domain of the Cys(2)-His(2) type, four basic amino acid-rich domains, and a myosin II-homology domain. In situ hybridization indicated that the transcript was present in seminiferous tubules of adult mice. Elevated expression of the transcript during testicular development in mice was restricted to spermatocytes at the pachytene stage of meiotic prophase and to round and elongated spermatids, as indicated by Northern blot analysis and RT-PCR. Our results suggest that this novel zinc finger protein might act as a transcriptional regulator during spermatogenesis and, in particular, during meiotic division.

Long survival in Fukuyama congenital muscular dystrophy: occurrence of neurofibrillary tangles in the nucleus basalis of Meynert and locus ceruleus.

Three patients with Fukuyama congenital muscular dystrophy (FCMD), who died aged 23, 29 and 34 years, are reported. There was extensive brain malformation, but the most severe pattern of cortical dysplasia was absent in one case and in the other two localized bilaterally to small areas near the occipital poles. In two cases, numerous neurofibrillary tangles were observed in the locus ceruleus and nucleus basalis of Meynert. Electron microscopy revealed paired helical filaments, with a maximal width of about 25 nm and regular constrictions at approximately 80 nm intervals. The occurrence of neurofibrillary tangles, which is unknown in younger patients, suggests the presence of degenerative processes in the brains of the older patients with FCMD.

Decreased incidence of Duchenne muscular dystrophy in western Japan 1956-1980.

In 50 patients from 41 families of Duchenne muscular dystrophy (DMD) born between 1956 and 1980 in the San-in area of Japan, the changes in DMD incidence rate were analyzed through five periods of time: 1956-1960, 1961-1965, 1966-1970, 1971-1975 and 1976-1980. The overall incidence decreased from 22.31 X 10(-5) live male births in the first period to 14.51 X 10(-5) in the last. This decrease was mainly related to the group of mothers who were definite carriers (p less than 0.005), and was probably due to genetic counselling of definite carrier families. For a further decrease in the incidence of DMD, the newborn male screening system for creatine phosphokinase (CPK) and appropriate genetic counselling might be effective. From an analysis of 28 families without previous family history, the expected proportion of maternal carriers was 0.57.