NDUFAF3 variants that disrupt mitochondrial complex I assembly may associate with cavitating leukoencephalopathy.

Genetic abnormalities in mitochondrial complex assembling factors are associated with leukoencephalopathy. We present a 1-year-old girl with consciousness disturbance after a respiratory infection. Brain MRI revealed leukoencephalopathy with bilaterally symmetrical hyperintensity in the substantia nigra, medial thalamic nuclei, and basal nuclei, as well as cavities in the cerebral white matter and corpus callosum. Lactate levels in the spinal fluid were high, while magnetic resonance spectroscopy of the cerebral white matter and basal nuclei showed high peak lactate levels, suggesting mitochondrial dysfunction. The respiratory enzyme activity of complex I was reduced to 17% to 21% in skeletal muscle. Whole exome sequencing identified compound heterozygous variations in NDUFAF3, involved in the assembly of mitochondrial complex I (c.342_343insGTG:p.117Valdup, c.505C > A:p.Pro169Thr). Two-dimensional, blue-native polyacrylamide gel electrophoresis (PAGE) and sodium dodecyl sulfate-PAGE revealed reductions in Q-module (NDUFS2, NDUFS3, and NDUFA9) and P-module (NDUFB10 and NDUFB11) subunits, indicating disruption of mitochondrial complex I assembly. Our report expands the spectrum of clinical phenotypes associated with pathogenic variants of NDUFAF3.

Basic research and clinical application of beta-tricalcium phosphate (ß-TCP).

The mechanism of bone substitute resorption involves two processes: solution-mediated and cell-mediated disintegration. In our previous animal studies, the main resorption process of beta-tricalcium phosphate (ß-TCP) was considered to be cell-mediated disintegration by TRAP-positive cells. Thus, osteoclast-mediated resorption of ß-TCP is important for enabling bone formation. We also report the results of treatment with ß-TCP graft in patients since 1989. Two to three weeks after implantation, resorption of ß-TCP occurred from the periphery, and then continued toward the center over time. Complete or nearly complete bone healing was achieved in most cases within a few years and was dependent upon the amount of implanted material, the patient's age, and the type of bone (cortical or cancellous). We have previously reported that an injectable complex of ß-TCP granules and collagen supplemented with rhFGF-2 enabled cortical bone regeneration of rabbit tibiae. Based on the experimental results, we applied this technique to the patients with femoral and humeral fractures in elderly patients, and obtained bone union.

Does Gadolinium Deposition Lead to Metabolite Alteration in the Dentate Nucleus? An MRS Study in Patients with MS.

BACKGROUND AND PURPOSE: Repeat contrast-enhanced MR imaging exposes patients with relapsing-remitting MS to frequent administration of gadolinium-based contrast agents. We aimed to investigate the potential metabolite and neurochemical alterations of visible gadolinium deposition on unenhanced T1WI in the dentate nucleus using MRS. MATERIALS AND METHODS: This prospective study was conducted in a referral university hospital from January 2020 to July 2021. The inclusion criteria for case and control groups were as follows: 1) case: patients with relapsing-remitting MS, visible gadolinium deposition in the dentate nucleus (ribbon sign), >5 contrast-enhanced MR images obtained; 2) control 1: patients with relapsing-remitting MS without visible gadolinium deposition in the dentate nucleus, >5 contrast-enhanced MR images obtained; 3) control 2: patients with relapsing-remitting MS without visible gadolinium deposition in the dentate nucleus, <5 contrast-enhanced-MR images obtained; and 4) control 3: adult healthy individuals, with no contrast-enhanced MR imaging. Dentate nucleus and pontine single-voxel 12 × 12 × 12 MRS were analyzed using short TEs. RESULTS: Forty participants (10 per group; 27 [67.5%] female; mean age, 35.6 [SD, 9.6] years) were enrolled. We did not detect any significant alteration in the levels of NAA and choline between the studied groups. The mean concentrations of mIns were 2.7 (SD, 0.73) (case), 1.5 (SD, 0.8) (control 1), 2.4 (SD, 1.2) (control 2), and 1.7 (SD, 1.2) (control 3) (P = .04). The mean concentration of Cr and mIns (P = .04) and the relative metabolic concentration (dentate nucleus/pons) of lipid 1.3/Cr (P = .04) were significantly higher in the case-group than in healthy individuals (controls 1-3). Further analyses compared the case group with cumulative control 1 and 2 groups and showed a significant increase in lactate (P = .02), lactate/Cr (P = .04), and Cr (dentate nucleus/pons) (P = .03) in the case group. CONCLUSIONS: Although elevated concentrations of Cr, lactate, mIns, and lipid in the dentate nucleus of the case group indicate a metabolic disturbance, NAA and choline levels were normal, implying no definite neuronal damage.

New MRI Findings in Fukuyama Congenital Muscular Dystrophy: Brain Stem and Venous System Anomalies.

BACKGROUND AND PURPOSE: Leptomeningeal glioneuronal heterotopia of the brain stem and cerebral migration abnormality were pathologically reported in Fukuyama congenital muscular dystrophy, but the radiologic assessments of the brain stem and cerebral venous system (which may be involved in the development of the anomaly) were insufficient. Here, we evaluated the brain stem and cerebral veins on MR imaging in patients with Fukuyama congenital muscular dystrophy. MATERIALS AND METHODS: We retrospectively reviewed the MR imaging findings of 27 patients with Fukuyama congenital muscular dystrophy. We visually assessed the hypoplasia, superficial structures, and signal intensity of the brain stem on T2WI, FLAIR, and double inversion recovery images and the cerebral, superficial, and deep veins with and without hemorrhage on T2WI and SWI. RESULTS: Brain stem fluffy structures were seen in 96.3% of the cases on T2WI. Superficial high signal intensity on T2WI and FLAIR images was seen in 96.3% and 92.6%, respectively. Abnormally located superficial vessels beneath the cortex were seen in 11.1% on T2WI. Hypoplasia of the superficial cerebral veins was noted in all patients who underwent SWI. Dilated and tortuous subependymal veins were seen in 40.0% on SWI. Hemorrhages were seen in 11.1% on T2WI and in 60.0% on SWI. CONCLUSIONS: Superficial brain stem structural and signal abnormalities would be useful MR imaging findings to diagnose Fukuyama congenital muscular dystrophy as well as venous system abnormalities. Clinicians must keep in mind that this disease has a high risk of hemorrhage.

Surgical treatment of early-infantile epileptic encephalopathy with suppression-bursts associated with focal cortical dysplasia.

A surgically treated case of early-infantile epileptic encephalopathy (EIEE) with suppression-bursts associated with focal cortical dysplasia is reported. Tonic-clonic seizures followed by a series of spasms occurred at age of a few days. Interictal electroencephalogram (EEG) revealed a suppression-burst pattern and magnetic resonance imaging suggested focal cortical dysplasia in the left prefrontal area. Combination therapies of antiepileptic treatments showed only partial efficacy. The patient underwent lesionectomy at 4 months of age and the spasms decreased to zero to two series daily. At age 2 years, his seizures increased in number and EEG showed that residual left hemisphere was the main epileptogenic focus. Modified functional hemispherectomy of the left hemisphere was applied at age 3 years. The patient, now 5 years old, is free from seizure and gaining psychomotor development gradually. In cases of EIEE with focal cortical dysplasia, surgical treatment may have beneficial effects on both psychomotor development and seizure control.

Tremor and seizures associated with chronic manganese intoxication.

Tremor and seizures developed in a 2-year-old girl receiving total parenteral nutrition. T1-weighted images on MRI revealed areas of hyperintensity in the basal ganglia, brainstem and cerebellum. Blood manganese was elevated. The symptoms and MRI abnormalities disappeared after withdrawal of manganese administration. The recommendation of daily parenteral manganese intake was discussed.

Connatal Pelizaeus-Merzbacher disease associated with the jimpy(msd) mice mutation.

In a patient with connatal Pelizaeus-Merzbacher disease with the same mutation in the proteolipid protein gene as in jimpy(msd) mice the immunohistochemical study of the brain demonstrated deficiencies of myelin and proteolipid protein despite good expression of myelin basic protein. The mechanism of myelination is partly disturbed by the mutation; therefore jimpy(msd) mice can be used as a suitable model for further studies in connatal Pelizaeus-Merzbacher disease.

Brasilicardin A, a new terpenoid antibiotic from pathogenic Nocardia brasiliensis: fermentation, isolation and biological activity.

A novel tricyclic diterpenoid antibiotic, brasilicardin A, was isolated from the culture broth of Nocardia brasiliensis IFM 0406. The antibiotic exhibited immunosuppressive activity in a mouse mixed lymphocyte reaction (MLR) assay system and its IC50 value was 0.057 microg/ml. Although the inhibitory activity of cyclosporin A (CyA) against IL-2 production was confirmed in the MLR assay system, brasilicardin A did not have the activity. The results of in vitro toxicity testing of brasilicardin A against various human cell lines were compared with those of CyA.

Brasiliquinones A, B and C, new benz[alpha]anthraquinone antibiotics from Nocardia brasiliensis. I. Producing strain, isolation and biological activities of the antibiotics.

New benz[alpha]anthraquinone antibiotics (brasiliquinones A, B and C) with an ethyl group at C-3 were isolated. The producer was identified as Nocardia brasiliensis. The antibiotics were active against Gram-positive bacteria including Mycobacterium sp., but not active against Gram-negative bacteria or fungi. They were also active against multiple drug-resistant P388/ADR tumor cells.

Brasilinolide A, a new macrolide antibiotic produced by Nocardia brasiliensis: producing strain, isolation and biological activity.

A new 32-membered macrolide antibiotic, brasilinolide A was isolated from the fermentation broth of Nocardia sp. IFM 0406. The producer was identified as Nocardia brasiliensis. The antibiotic was only active against Aspergillus niger, but not active against other fungi including yeasts as well as other filamentous like fungi and bacteria. Brasilinolide A exerted an immunosuppressive activity in the assay system of a mixed lymphocyte reaction (MLR).

[Evaluation of the E-test: comparison of E-test and microbroth dilution method in azole antifungal susceptibility test].

The susceptibilities of clinical isolates of Candida spp. to fluconazole (FLCZ), itraconazole (ITCZ) and ketoconazole (KCZ) were determined by a new method, E-test (AB BIODISK, Sweden) and compared with those obtained by the microbroth dilution method. The MIC values of the 3 azoles obtained by the two methods were, in general, in good agreement. While MICs of FLCZ and KCZ demonstrated higher essential agreement rates and better correlation by both methods, MIC values of ITCZ by the E-test had a tendency to be higher than those of the microbroth dilution method in azole resistant strains. Potential usability of E-test as a broth dilution method for susceptibility tests for clinically isolated Candida spp. including azole resistant strains was discussed.

[Assessment of the brainstem and the cerebellar lesions and myelination using magnetic resonance images in children with Down syndrome].

Magnetic resonance images were carried out in the children with Down syndrome aged 2-4 years old compared with the values of the age-matched controls. The pons and cerebellar vermis were significantly smaller and the cerebral peduncles were narrower in Down syndrome. None of the patients showed delay of myelination. These findings suggest hypoplasia of the pons and cerebellum in Down syndrome.

[Improvement of obstructive sleep apnea by uvulopalatopharyngoplasty and tonsillectomy in a case of Duchenne muscular dystrophy].

A 10-year-old boy with Duchenne muscular dystrophy (DMD) underwent uvulopalatopharyngoplasty and tonsillectomy for obstructive sleep apnea (OSA). He has snored loudly during nocturnal sleep since infancy, and OSA developed one and a half years after he was wheel chair-bound at 8 years. Magnetic resonance imaging (MRI), conventional spirometry and overnight polysomnography were performed before and after the surgery. MRI before surgery revealed moderate tonsillar hypertrophy and a long uvula which narrowed the upper airway. After the surgery, his vital capacity (VC) was not changed (% VC; from 77 to 78%), but forced expiratory volume (FEV) was improved (FEV 1.0%; from 75 to 86%). A preoperative apnea index of 32.8/hour decreased to 0.8/hour postoperatively. REM-related falls in HbSaO2 improved remarkably. The present case suggests that subjects with DMD with tonsillar hypertrophy and a redundant uvula tend to develop noctrurnal OSA earlier than DMD cases with a normal tonsil and uvula. Assessment of respiratory function, particularly FEV 1.0%, is important for determining surgical indication of OSA in patients with DMD.

[Successful treatment with tegafur and PSK in a patient with gallbladder cancer].

A 56-year-old man was admitted to Miyazaki Prefectural Hospital with a complaint of pain in the right upper quadrant. The liver was moderately enlarged on palpation with tenderness in the upper abdomen. Ultrasonography and abdominal CT showed gallbladder tumor with multiple space-occupying lesions in the liver. In addition, serum levels of CEA and CA19-9 were markedly elevated. These findings suggested gallbladder cancer with liver metastasis, and he was soon started on tegafur rectally (1,000 mg/day) and PSK orally (3.0 g/day). Two months later, the lesions in the liver almost disappeared, although little change in size of the gallbladder tumor was noted. This condition lasted for 6 months indicating partial response. Subsequently, he died of liver failure 14 months after the start of treatment. Since few antineoplastic agents have been reported to be effective against gallbladder cancer, tegafur and PSK might be a good combination for this disease.

An Injectable Complex of ß-tricalcium Phosphate Granules, Hyaluronate, and rhFGF-2 on Repair of Long-bone Fractures with Large Fragments.

We evaluated the effects of an injectable complex of ß-tricalcium phosphate (ß-TCP) granules, hyaluronate, and recombinant human fibroblast growth factor-2 (rhFGF-2) on repair of unstable intertrochanteric fractures in elderly patients. Twenty-five patients (range, 76-91 years) having 31.A2 fractures (AO classification) were treated with injection of the complex followed by intramedullary nails. Bone regeneration and ß-TCP resorption, unions of intertrochanteric fractures and displaced lesser trochanters to the shaft, and varus deformity of the femoral neck were assessed by X-ray and CT scans. Fracture union occurred in all cases and union of the displaced lesser trochanter to the shaft was obtained in 24 cases by 12 weeks. It is of interest that ß-TCP granules were completely resorbed and marked new bone formation around the lesser trochanter was observed in all cases compared to cases not treated with the complex. Based on the results of intertrochanteric fractures, we applied this technique to two patients with subtrochanteric or humeral fractures in elderly patients, and obtained bone union. This complex is a paste-like material that is easy to handle, and it may be of considerable use in treatment of both unstable intertrochanteric fractures and other cortical bone defects with minimal surgical invasion.