Pharmacokinetics, safety, and efficacy of 20% subcutaneous immunoglobulin (Ig20Gly) administered weekly or every 2 weeks in Japanese patients with primary immunodeficiency diseases: a phase 3, open-label study.

This phase 3, open-label, multidose study (NCT04346108) evaluated the pharmacokinetics, safety, tolerability, and efficacy of immunoglobulin subcutaneous (human) 20% solution (Ig20Gly) administered weekly and every 2 weeks in Japanese patients with primary immunodeficiency diseases (PIDs). The study was conducted at eight study sites in Japan and enrolled patients aged ≥2 years with PIDs treated using a stable intravenous immunoglobulin dose for ≥3 months prior to the study. Patients received intravenous immunoglobulin every 3 or 4 weeks at pre-study dose (200-600 mg/kg) for 13 weeks (Epoch 1), subcutaneous Ig20Gly (50-200 mg/kg) once weekly for 24 weeks (Epoch 2), and Ig20Gly (100-400 mg/kg) every 2 weeks for 12 weeks (Epoch 3). The primary endpoint was serum total immunoglobulin G (IgG) trough levels during Epochs 2 and 3. Overall, 17 patients were enrolled (median [range] age: 24 [5-69] years; 59% male) and participated in Epochs 1 and 2; seven patients entered Epoch 3. Serum total IgG trough levels were maintained at >8 g/l: geometric means (95% confidence intervals) at the end of Epochs 2 and 3 were 8.56 (8.03-9.12) g/l and 8.39 (7.89-8.91) g/l, respectively. Related treatment-emergent adverse events were all mild in severity; the most common treatment-emergent adverse events (excluding infections) in Epochs 2 and 3 were injection site swelling (24%) and injection site erythema (18%). This is the first trial to demonstrate the efficacy and favourable safety profile of 20% subcutaneous immunoglobulin administered every 2 weeks in adult and paediatric Japanese patients with PIDs.

Real-world treatment patterns and patient-reported outcomes in episodic and chronic migraine in Japan: analysis of data from the Adelphi migraine disease specific programme.

BACKGROUND: In Japan, detailed information on the characteristics, disease burden, and treatment patterns of people living with migraine is limited. The aim of this study was to compare clinical characteristics, disease burden, and treatment patterns in people with episodic migraine (EM) or chronic migraine (CM) using real-world data from clinical practice in Japan. METHODS: This was an analysis of data collected in 2014 by the Adelphi Migraine Disease Specific Programme, a cross-sectional survey of physicians and their consulting adult patients in Japan, using physician and patient questionnaires. We report patient demographics, prescribed treatment, work productivity, and quality-of-life data for people with CM (≥15 headache days/month) or EM (not fulfilling CM criteria). In descriptive analyses, continuous and categorical measures were assessed using t-tests and Chi-squared tests, respectively. RESULTS: Physicians provided data for 977 patients (mean age 44.5 years; 77.2% female; 94.5% with EM, 5.5% with CM). A total of 634/977 (64.9%) invited patients (600 with EM; 34 with CM) also provided data. Acute therapy was currently being prescribed in 93.7% and 100% of patients with EM and CM, respectively (p = 0.069); corresponding percentages for current preventive therapy prescriptions were 40.5% and 68.5% (p < 0.001). According to physicians who provided data, preventive therapy was used at least once by significantly fewer patients with EM than with CM (42.3% vs. 68.5%, respectively; p < 0.001). Among patients who provided physicians with information on issues with their current therapy (acute therapy: n = 668 with EM, n = 38 with CM; preventive therapy: n = 295 with EM, n = 21 with CM), lack of efficacy was the most frequently identified problem (acute therapy: EM 35.3%, CM 39.5% [p = 0.833]; preventive therapy: EM 35.3%, CM 52.4% [p = 0.131]). Moderate-to-severe headache-related disability (Migraine Disability Assessment total score ≥ 11) was reported by significantly fewer patients with EM than with CM (21.0% vs. 60.0%, respectively; p < 0.001) among patients who provided data. CONCLUSIONS: Preventive treatment patterns in people with EM versus CM differ in Japan, with both types of migraine posing notable disease burdens. Our findings demonstrate that more effective migraine therapies are required to reduce the burden of the disease.

Analysis of HAM-D scores and working ability in an observational study of Japanese patients with major depressive disorder and painful physical symptoms treated with duloxetine or SSRI monotherapy.

OBJECTIVE: To investigate the relationship between Hamilton Depression Rating Scale (HAM-D) score and psychiatrists' judgment of working ability in patients with major depressive disorder (MDD) and painful physical symptoms. METHODS: This was a prospective, observational, 12-week study in patients who received duloxetine or a selective serotonin reuptake inhibitor. Patients were ≥20 years old, resided in Japan, and had at least moderate depression (Quick Inventory of Depressive Symptomatology ≥16) and at least moderate painful physical symptoms (Brief Pain Inventory-Short Form average pain ≥3). The main outcome in this post-hoc analysis was the HAM-D17 cutoff best corresponding with patients' working ability according to the investigator's judgment. Area under the receiver-operator curve was used to determine the time point with the strongest relationship between HAM-D17 and working ability. The optimal HAM-D17 cutoff was determined based on the maximum of sensitivity (true positive rate) minus ([1 minus specificity] [true negative rate]). For the evaluation of binary data, a mixed effects model with repeated measures analysis was used. RESULTS: For the estimation of the HAM-D17 cutoff, the area under the receiver-operator curve was maximal at 12 weeks, when a HAM-D17 score of 6 resulted in the best correspondence with working ability in the combined study population. At 12 weeks, a HAM-D17 score of 6 also resulted in the maximum predictive ability in each of the two treatment groups separately. For predicted working ability at 12 weeks, 52.7% of duloxetine-treated patients achieved the HAM-D17 cutoff of ≤6, whereas 48.5% of SSRIs-treated patients achieved HAM-D17 ≤6 (P=0.477). CONCLUSION: In this study of patients with major depressive disorder and painful physical symptoms, a HAM-D17 score ≤6 corresponded best with patients' working ability. This finding is consistent with previous studies showing that a HAM-D17 cutoff of ≤7 may overestimate functional recovery from MDD.

Associations among depression severity, painful physical symptoms, and social and occupational functioning impairment in patients with major depressive disorder: a 3-month, prospective, observational study.

PURPOSE: To investigate associations among depression severity, painful physical symptoms (PPS), and social and occupational functioning impairment in patients with major depressive disorder (MDD) who had achieved complete remission (CR) or partial remission (PR) after acute treatment. PATIENTS AND METHODS: This was a 12-week, multicenter, prospective, observational study. Patients with MDD treated with an antidepressant medication for the previous 12 weeks (±3 weeks) who had achieved CR (defined as a 17-item Hamilton Rating Scale for Depression [HAM-D17] score ≤7) or PR (HAM-D17 score ≥8 and ≤18) were enrolled. Depression severity, PPS, and impairment in social and occupational functioning were assessed using the HAM-D17, the Brief Pain Inventory (Short Form) (BPI-SF), and the Social and Occupational Functioning Assessment Scale (SOFAS), respectively, at enrollment (Week 12) and after 12 weeks (Week 24). RESULTS: Overall, 323 Japanese patients with MDD were enrolled (CR n=158, PR n=165) and 288 patients completed the study (CR n=139, PR n=149). HAM-D17 and SOFAS scores were strongly and negatively correlated at enrollment (Week 12; P<0.0001) and Week 24 (P<0.0001). A weak negative correlation between the BPI-SF and SOFAS was observed at Week 24 (P=0.0011), but not at enrollment (P=0.164). Remission status at enrollment (CR or PR) was associated with achieving normal social and occupational functioning (SOFAS score ≥80) at Week 24 in patients who had not achieved normal social and occupational functioning (SOFAS score <80) at enrollment (CR vs PR, OR=0.05 [95% CIs 0.01-0.18], P<0.0001). A greater proportion of patients with CR and no PPS at enrollment achieved SOFAS scores ≥80 at Week 24 than those with CR and PPS. CONCLUSION: Our results suggest that treating both depressive symptoms and PPS is important for achieving a normal level of functioning on a long-term basis in patients with MDD.

Predicting treatment outcomes of major depressive disorder by early improvement in painful physical symptoms: a pooled analysis of double-blind, placebo-controlled trials of duloxetine.

OBJECTIVE: We determined if early improvement in painful physical symptoms (PPS) can be a predictor of remission in the treatment of major depressive disorder (MDD). METHODS: We included randomized, double-blind, parallel-group clinical trials of duloxetine (40-60 mg/day) versus placebo for the acute treatment of MDD with associated PPS. Only those studies using the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Brief Pain Inventory - Short Form (BPI-SF) were included. Three studies met all criteria and included male or female outpatients aged ≥18 years who met the diagnostic criteria for MDD, had a MADRS total score ≥20, and had at least moderate pain (BPI-SF average pain score ≥3). Positive predictive values (PPVs) and negative predictive values (NPVs) of early improvement in PPS for remission were analyzed. PPVs were the proportion of patients with remission (MADRS total score ≤10) at week 8 out of patients who experienced early improvement in BPI-SF average pain score (≥30% decrease from baseline at week 1, 2, or 4). NPVs were the proportion of patients without remission (MADRS total score >10) at week 8 out of patients who did not experience early improvement in PPS. RESULTS: Data from 1,320 patients were analyzed (duloxetine N=641 and placebo N=679). The overall remission (MADRS total score ≤10 at week 8) rate for the duloxetine group was significantly higher than the placebo group (38.5% vs 21.8%; P<0.0001). For both treatment groups, PPVs of early improvement in BPI-SF (30% improvement from baseline) were higher than the overall remission rate for all weeks examined (weeks 1, 2, and 4); in general, NPVs of early improvement in BPI-SF for nonremission were higher than the overall nonremission rate. CONCLUSION: Early improvement in PPS can be a useful clinical indicator of subsequent treatment outcome for MDD patients with associated PPS.

An observational study of duloxetine versus SSRI monotherapy in Japanese patients with major depressive disorder: subgroup analyses of treatment effectiveness for pain, depressive symptoms, and quality of life.

OBJECTIVE: To examine how clinical and demographic patient baseline characteristics influence effectiveness of duloxetine versus selective serotonin reuptake inhibitor (SSRI) treatment, in real-world Japanese clinical settings of patients with major depressive disorder (MDD) and associated painful physical symptoms (PPS). METHODS: This was a multicenter, 12-week, prospective, observational study in patients with MDD (Quick Inventory of Depressive Symptomatology ≥16) and at least moderate PPS (Brief Pain Inventory-Short Form [BPI-SF] average pain ≥3). Patients received duloxetine or SSRIs (escitalopram, sertraline, paroxetine, or fluvoxamine). Assessments were made by using BPI-SF average pain, 17-item Hamilton Rating Scale for Depression (HAM-D17), EuroQol 5-dimension questionnaire, Social Adaptation Self-Evaluation Scale, Global Assessment of Functioning, and ability to work. Predefined subgroups included the number of previous episodes of depression (0 vs ≥1), baseline BPI-SF average pain score (≤6 vs >6), baseline HAM-D17 total score (≤18 vs >18), baseline HAM-D17 retardation (≤7 vs >7) and anxiety somatic subscale scores (≤6 vs >6), and age (<65 vs ≥65 years). RESULTS: Treatment effectiveness was evaluated in 523 patients (duloxetine N=273, SSRIs N=250). Treatment with duloxetine was superior to SSRIs on most outcome measures in patients experiencing their first depressive episode, those with higher baseline PPS levels, and in patients with more severe baseline depression. This was also the case for older patients. In patients with less severe depression, SSRI treatment tended to show more improvements in depression and quality of life measures versus duloxetine treatment. CONCLUSION: These preplanned subgroup analyses of data from a prospective observational study suggest that, for Japanese MDD patients with PPS, duloxetine is more effective than SSRIs in patients with a first episode of MDD, with more severe depression, or more severe PPS.

An observational study of duloxetine versus SSRI monotherapy for the treatment of painful physical symptoms in Japanese patients with major depressive disorder: primary analysis.

OBJECTIVE: The objective of this study was to assess the effectiveness of duloxetine monotherapy, in comparison with selective serotonin reuptake inhibitor (SSRI) monotherapy, in the treatment of painful physical symptoms (PPS) in Japanese patients with major depressive disorder (MDD) in real-world clinical settings. METHODS: This was a multicenter, 12-week prospective, observational study. This study enrolled MDD patients with at least moderate PPS, defined as a Brief Pain Inventory-Short Form (BPI-SF) average pain score (item 5) ≥3. Patients were treated with duloxetine or SSRIs (escitalopram, sertraline, paroxetine, or fluvoxamine) for 12 weeks, and PPS were assessed by BPI-SF average pain score. The primary outcome was early improvement in the BPI-SF average pain score at 4 weeks post-baseline. RESULTS: A total of 523 patients were evaluated for treatment effectiveness (duloxetine N=273, SSRIs N=250). The difference in BPI-SF average pain score between the two groups was not statistically significant at 4 weeks post-baseline, the primary endpoint (least-squares mean change from baseline [95% confidence interval]: duloxetine, -2.8 [-3.1, -2.6]; SSRIs, -2.5 [-2.8, -2.3]; P=0.166). There was a numerical advantage for duloxetine in improvement from 4 to 12 weeks post-baseline, and the difference was statistically significant at 8 weeks post-baseline (least-squares mean change from baseline [95% confidence interval]: duloxetine, -3.6 [-3.9, -3.3]; SSRIs, -3.1 [-3.4, -2.8]; P=0.023). The 30% and 50% responder rates were significantly higher in patients treated with duloxetine at 4 and 8 weeks post-baseline. There were no serious adverse events experienced by duloxetine-treated patients. The rate of discontinuations due to adverse events was similar for duloxetine and the SSRIs (1.0% and 0.8% of patients, respectively). CONCLUSION: In this observational study, BPI-SF improvement was not significantly different at 4 weeks, the primary endpoint; however, patients treated with duloxetine tended to show better improvement in PPS compared to those treated with SSRIs.

Identification of a Post-translational Modification with Ribitol-Phosphate and Its Defect in Muscular Dystrophy.

Glycosylation is an essential post-translational modification that underlies many biological processes and diseases. α-dystroglycan (α-DG) is a receptor for matrix and synaptic proteins that causes muscular dystrophy and lissencephaly upon its abnormal glycosylation (α-dystroglycanopathies). Here we identify the glycan unit ribitol 5-phosphate (Rbo5P), a phosphoric ester of pentose alcohol, in α-DG. Rbo5P forms a tandem repeat and functions as a scaffold for the formation of the ligand-binding moiety. We show that enzyme activities of three major α-dystroglycanopathy-causing proteins are involved in the synthesis of tandem Rbo5P. Isoprenoid synthase domain-containing (ISPD) is cytidine diphosphate ribitol (CDP-Rbo) synthase. Fukutin and fukutin-related protein are sequentially acting Rbo5P transferases that use CDP-Rbo. Consequently, Rbo5P glycosylation is defective in α-dystroglycanopathy models. Supplementation of CDP-Rbo to ISPD-deficient cells restored α-DG glycosylation. These findings establish the molecular basis of mammalian Rbo5P glycosylation and provide insight into pathogenesis and therapeutic strategies in α-DG-associated diseases.

Trajectories of depression symptom improvement and associated predictor analysis: An analysis of duloxetine in double-blind placebo-controlled trials.

BACKGROUND: In the treatment of major depressive disorder (MDD), it is not fully understood how individual symptoms improve over time (trajectory) in remitters. This study compared symptom improvement trajectories, as measured with the 17-item Hamilton Depression Rating Scale (HAM-D17), in remitters and nonremitters. METHODS: This analysis is based on 10 placebo-controlled, randomized, double-blind trials of duloxetine (40-60mg/day) for treatment of MDD from baseline up to week 8. Remission was defined as a HAM-D17 total score ≤7 at week 8 (last observation carried forward). Trajectories of HAM-D17 items were assessed by mixed model repeated measures analysis for treatment and remitter-nonremitter comparisons. Grouping of the trajectories was performed by factor analysis. Predictor analysis using HAM-D17 items was conducted by logistic regression. RESULTS: There were 1555 patients in the duloxetine group (489 [31.4%] remitters) and 1206 patients in the placebo group (290 [24.0%] remitters; P<.0001). For most items, the difference in trajectories between remitters and nonremitters appeared at early time points and increased over time. Treatment response trajectories were very similar for duloxetine and placebo remitters, while duloxetine nonremitters improved more than placebo nonremitters. For duloxetine remitters, we found 3 trajectory groups of HAM-D17 items. The predictor analysis showed that improvement in 6 individual items at week 1 or 2 was significantly associated with remission at week 8. LIMITATIONS: Generalizability of these results may be limited by the relatively short observation period used to define remission. CONCLUSIONS: Early monitoring of some symptoms of depression may prove useful in guiding treatment decisions.

Impaired viability of muscle precursor cells in muscular dystrophy with glycosylation defects and amelioration of its severe phenotype by limited gene expression.

A group of muscular dystrophies, dystroglycanopathy is caused by abnormalities in post-translational modifications of dystroglycan (DG). To understand better the pathophysiological roles of DG modification and to establish effective clinical treatment for dystroglycanopathy, we here generated two distinct conditional knock-out (cKO) mice for fukutin, the first dystroglycanopathy gene identified for Fukuyama congenital muscular dystrophy. The first dystroglycanopathy model-myofiber-selective fukutin-cKO [muscle creatine kinase (MCK)-fukutin-cKO] mice-showed mild muscular dystrophy. Forced exercise experiments in presymptomatic MCK-fukutin-cKO mice revealed that myofiber membrane fragility triggered disease manifestation. The second dystroglycanopathy model-muscle precursor cell (MPC)-selective cKO (Myf5-fukutin-cKO) mice-exhibited more severe phenotypes of muscular dystrophy. Using an isolated MPC culture system, we demonstrated, for the first time, that defects in the fukutin-dependent modification of DG lead to impairment of MPC proliferation, differentiation and muscle regeneration. These results suggest that impaired MPC viability contributes to the pathology of dystroglycanopathy. Since our data suggested that frequent cycles of myofiber degeneration/regeneration accelerate substantial and/or functional loss of MPC, we expected that protection from disease-triggering myofiber degeneration provides therapeutic effects even in mouse models with MPC defects; therefore, we restored fukutin expression in myofibers. Adeno-associated virus (AAV)-mediated rescue of fukutin expression that was limited in myofibers successfully ameliorated the severe pathology even after disease progression. In addition, compared with other gene therapy studies, considerably low AAV titers were associated with therapeutic effects. Together, our findings indicated that fukutin-deficient dystroglycanopathy is a regeneration-defective disorder, and gene therapy is a feasible treatment for the wide range of dystroglycanopathy even after disease progression.

Absence of post-phosphoryl modification in dystroglycanopathy mouse models and wild-type tissues expressing non-laminin binding form of α-dystroglycan.

α-Dystroglycan (α-DG) is a membrane-associated glycoprotein that interacts with several extracellular matrix proteins, including laminin and agrin. Aberrant glycosylation of α-DG disrupts its interaction with ligands and causes a certain type of muscular dystrophy commonly referred to as dystroglycanopathy. It has been reported that a unique O-mannosyl tetrasaccharide (Neu5Ac-α2,3-Gal-ß1,4-GlcNAc-ß1,2-Man) and a phosphodiester-linked modification on O-mannose play important roles in the laminin binding activity of α-DG. In this study, we use several dystroglycanopathy mouse models to demonstrate that, in addition to fukutin and LARGE, FKRP (fukutin-related protein) is also involved in the post-phosphoryl modification of O-mannose on α-DG. Furthermore, we have found that the glycosylation status of α-DG in lung and testis is minimally affected by defects in fukutin, LARGE, or FKRP. α-DG prepared from wild-type lung- or testis-derived cells lacks the post-phosphoryl moiety and shows little laminin-binding activity. These results show that FKRP is involved in post-phosphoryl modification rather than in O-mannosyl tetrasaccharide synthesis. Our data also demonstrate that post-phosphoryl modification not only plays critical roles in the pathogenesis of dystroglycanopathy but also is a key determinant of α-DG functional expression as a laminin receptor in normal tissues and cells.

[Recent Advances in α-dystroglycanopathy].

Fukuyama-type congenital muscular dystrophy (FCMD), muscle-eye-brain disease (MEB), and Walker-Warburg syndrome (WWS) are autosomal recessive disorders characterized by congenital muscular dystrophy with structural brain and eye abnormalities. Aberrant glycosylation of α-dystroglycan (α-DG) is a common pathomechanism of these disorders. In addition, genetic and glycobiological evidence has shown that abnormal glycosylation of α-DG is also seen in several forms of congenital and limb-girdle-type muscular dystrophies. These disorders are collectively called "α-dystroglycanopathy" and nowadays, this term is widely accepted because it is useful for illustrating a complicated genotype-phenotype correlation of these disorders. α-DG is a membrane-associated protein that interacts with extracellular matrix proteins such as laminin, and abnormal glycosylation of α-DG results in loss of its laminin-binding activity. A number of serine/threonine residues are present in the mucin-like domain of α-DG and are majorly composed of sugar chains. Among these glycans, an O-mannosyl tetrasaccharide (Neu5Ac-α2,3-Gal-ß1,4-GlcNAc-ß1,2-Man) is important for laminin-binding activity of α-DG. POMT1/2 and POMGnT1, protein products of causative genes of WWS and MEB, respectively, are enzymes that directly catalyze the biosynthesis of this glycan. Recent studies have suggested that a phosphodiester-linked structure on O-mannose is also important for the laminin-binding activity and that mutations in other causative genes of α-dystroglycanopathy, such as fukutin (originally identified as the gene responsible for FCMD) and LARGE, disrupt the post-phosphoryl structure. Here, we review the history of basic and clinical research on α-dystroglycanopathy and refine its clinical spectrum, which should be broadly extended. In addition, we reveal some progress in research on α-dystroglycanopathy including a novel disease mechanism and anti-sense oligonucleotide therapy for FCMD.

Pathogenic exon-trapping by SVA retrotransposon and rescue in Fukuyama muscular dystrophy.

Fukuyama muscular dystrophy (FCMD; MIM253800), one of the most common autosomal recessive disorders in Japan, was the first human disease found to result from ancestral insertion of a SINE-VNTR-Alu (SVA) retrotransposon into a causative gene. In FCMD, the SVA insertion occurs in the 3' untranslated region (UTR) of the fukutin gene. The pathogenic mechanism for FCMD is unknown, and no effective clinical treatments exist. Here we show that aberrant messenger RNA (mRNA) splicing, induced by SVA exon-trapping, underlies the molecular pathogenesis of FCMD. Quantitative mRNA analysis pinpointed a region that was missing from transcripts in patients with FCMD. This region spans part of the 3' end of the fukutin coding region, a proximal part of the 3' UTR and the SVA insertion. Correspondingly, fukutin mRNA transcripts in patients with FCMD and SVA knock-in model mice were shorter than the expected length. Sequence analysis revealed an abnormal splicing event, provoked by a strong acceptor site in SVA and a rare alternative donor site in fukutin exon 10. The resulting product truncates the fukutin carboxy (C) terminus and adds 129 amino acids encoded by the SVA. Introduction of antisense oligonucleotides (AONs) targeting the splice acceptor, the predicted exonic splicing enhancer and the intronic splicing enhancer prevented pathogenic exon-trapping by SVA in cells of patients with FCMD and model mice, rescuing normal fukutin mRNA expression and protein production. AON treatment also restored fukutin functions, including O-glycosylation of α-dystroglycan (α-DG) and laminin binding by α-DG. Moreover, we observe exon-trapping in other SVA insertions associated with disease (hypercholesterolemia, neutral lipid storage disease) and human-specific SVA insertion in a novel gene. Thus, although splicing into SVA is known, we have discovered in human disease a role for SVA-mediated exon-trapping and demonstrated the promise of splicing modulation therapy as the first radical clinical treatment for FCMD and other SVA-mediated diseases.

Endoplasmic reticulum stress response in P104L mutant caveolin-3 transgenic mice.

Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy 1C (LGMD1C). However, the precise molecular pathogenesis of caveolin-3-related muscular dystrophy remains uncertain. Here, we demonstrate the effect of gene dosage on the severity of the myopathic phenotype in P104L mutant caveolin-3 (mCav3(P104L)) transgenic mice, a model of LGMD1C. We analyzed the endoplasmic reticulum (ER) stress response in the transgenic mice and found upregulated transcription of the molecular chaperone, glucose-regulated protein (GRP78). Moreover, signaling downstream of GRP78 in the myofibers was activated toward apoptosis. However, terminal transferase dUTP nick end labeling assays detected a few apoptotic nuclei in transgenic mouse skeletal muscle, probably due to the transcriptional activation of Dad1, an anti-apoptotic factor in the ER. These findings suggest that the ER stress response caused by mCav3(P104L) plays a role in the pathogenesis of LGMD1C as a toxic gain of function effect.

Characteristics of depression in Parkinson's disease: evaluating with Zung's Self-Rating Depression Scale.

The purpose of the study was to elucidate characteristics of depression in Parkinson's disease (PD). Fifty-eight PD patients were evaluated with Zung's Self-Rating Depression Scale (SDS) and the Unified Parkinson's Disease Rating Scale (UPDRS). Scores for "suicidal ideation" on the SDS correlated with posture and gait disturbances on the UPDRS. Twenty-six patients with spinocerebellar degeneration (SCD) were also evaluated with the SDS. SDS scores for "indecisiveness" and "constipation" were significantly higher in PD patients than SCD patients. Our results suggest that depression is common in disabled persons but PD patients might have a characteristic clinical presentation.

[A case of orbital apex syndrome caused by localized invasive aspergillosis successfully treated with voriconazole].

A 71-year-old man with left periorbital pain and diplopia was hospitalized for evaluation and treatment. He had a past history of untreated diabetes mellitus. Shortly after admission, the patient experienced rapid onset of visual loss in the left eye. MRI and CT showed a lesion expanding from the left orbital apex to the left pterygopalatine fossa. Invasive aspergillosis was diagnosed by open biopsy of intrasinus mucosa via the left maxillary sinus. The patient was treated with voriconazole, an antifungal agent, and marked improvements in left periorbital pain and eye movement were subsequently obtained, although visual acuity was not recovered. This is the first report documenting the clinical utility of voriconazole for sino-orbital invasive aspergillosis.

[Posterior spinal cord infarction presenting Brown-Séquard syndrome].

We report a 56 year-old-woman with spinal cord infarction. She experienced left-sided girdle pain without precipitating symptoms and she developed monoparesis of her left leg and urinary retention. She also presented the segmental loss of total sensations in the Th10-11 area of the left trunk, the disturbance of position and vibration senses in the left leg and the disturbance of pain and temperature senses in the right leg. T2-weighted MR imagings showed high signal intensity lesion in the left half of the spinal posterior column at Th9-10 vertebral levels. Somatosensory evoked potentials confirmed that the loss of position and vibration senses was unilateral. Though she became able to walk with canes two months later, her sensory disturbance showed no improvement. This is a rare case of unilateral posterior spinal cord infarction presenting Brown-Séquard syndrome.

[Allergic skin rashes by methylprednisolone in a case with multiple sclerosis].

We reported a 34-year-old woman with multiple sclerosis showing an allergic reaction to methylprednisolone sodium succinate. She was admitted to our hospital with a complaint of hypesthesia in the right side of the face and body. MRI showed several high signal intensity lesions in her brain with Gd-DTPA enhancement effect. She was diagnosed as having an acute relapse of MS from previous episodes and clinical findings. We started a methylprednisolone pulse therapy. After the injection on the first day, skin rashes appeared on her trunk and thigh. On the second day, the skin rashes spread over her whole body. Patch test for methylprednisolone sodium succinate (MP) was positive. The steroid administration was substituted by intravenous injections of betamethasone 100mg/day for three days. Her neurological and radiological findings were successfully disappeared without any side effects. This case indicates the efficacy of substitution therapy of betamethasone for MP.