Comparing the safety and efficacy of nintedanib starting dose in patients with connective tissue disease-associated interstitial lung diseases.

OBJECTIVE: This study aimed to analyse whether initiating nintedanib treatment at a reduced dose could improve the treatment continuation rate while maintaining efficacy in patients with connective tissue disease (CTD)-associated interstitial lung disease. METHOD: In total, 51 patients (age 61.6 ± 13.2 years; 38 women, 13 men) were retrospectively analysed. The primary endpoint was the cumulative discontinuation rate due to adverse events. Secondary endpoints included changes in drug dosage, efficacy evaluated based on annual changes in forced vital capacity (FVC), and safety assessed based on the frequency of adverse events. RESULTS: Eighteen patients who started treatment at the standard dose of 300 mg (standard dosage group) were compared with 33 patients who started treatment at a reduced dose (reduced dosage group). Systemic sclerosis was the most common CTD (n = 32), followed by idiopathic inflammatory myopathies and, rarely, rheumatoid arthritis. Both groups exhibited comparable cumulative discontinuation rates due to adverse events and similar frequencies of adverse events. No significant differences were observed in maintenance doses between the two groups; however, patients in the reduced dosage group had a lower cumulative dose for up to 52 weeks than those in the standard dosage group. No significant differences were observed in changes in FVC between the two groups. CONCLUSION: There was no evidence for a difference between the two groups in terms of discontinuation rates, efficacy, and safety. To provide further evidence, future studies using more precise dose-escalation protocols are warranted.

FUT2 non-secretor status is associated with Type 1 diabetes susceptibility in Japanese children.

AIM: To examine the contribution of the FUT2 gene and ABO blood type to the development of Type 1 diabetes in Japanese children. METHODS: We analysed FUT2 variants and ABO genotypes in a total of 531 Japanese children diagnosed with Type 1 diabetes and 448 control subjects. The possible association of FUT2 variants and ABO genotypes with the onset of Type 1 diabetes was statistically examined. RESULTS: The se2 genotype (c.385A>T) of the FUT2 gene was found to confer susceptibility to Type 1A diabetes in a recessive effects model [odds ratio for se2/se2, 1.68 (95% CI 1.20-2.35); corrected P value = 0.0075]. CONCLUSIONS: The FUT2 gene contributed to the development of Type 1 diabetes in the present cohort of Japanese children.

Variants associated with autoimmune Type 1 diabetes in Japanese children: implications for age-specific effects of cis-regulatory haplotypes at 17q12-q21.

AIMS: The aim of this study was to clarify the significance of previously reported susceptibility variants in the development of autoimmune Type 1 diabetes in non-white children. Tested variants included rs2290400, which has been linked to Type 1 diabetes only in one study on white people. Haplotypes at 17q12-q21 encompassing rs2290400 are known to determine the susceptibility of early-onset asthma by affecting the expression of flanking genes. METHODS: We genotyped 63 variants in 428 Japanese people with childhood-onset autoimmune Type 1 diabetes and 457 individuals without diabetes. Possible association between variants and age at diabetes onset was examined using age-specific quantitative trait locus analysis and ordered-subset regression analysis. RESULTS: Ten variants, including rs2290400 in GSDMB, were more frequent among the people with Type 1 diabetes than those without diabetes. Of these, rs689 in INS and rs231775 in CTLA4 yielded particularly high odds ratios of 5.58 (corrected P value 0.001; 95% CI 2.15-14.47) and 1.64 (corrected P value 5.3 × 10-5 ; 95% CI 1.34-2.01), respectively. Age-specific effects on diabetes susceptibility were suggested for rs2290400; heterozygosity of the risk alleles was associated with relatively early onset of diabetes, and the allele was linked to the phenotype exclusively in the subgroup of age at onset ≤ 5.0 years. CONCLUSIONS: The results indicate that rs2290400 in GSDMB and polymorphisms in INS and CTLA4 are associated with the risk of Type 1 diabetes in Japanese children. Importantly, cis-regulatory haplotypes at 17q12-q21 encompassing rs2290400 probably determine the risk of autoimmune Type 1 diabetes predominantly in early childhood.

Experiment of fractioning animal cell culturing solution in high concentration under microgravity.

Culturing cells and electrophoretic separations of the multiplied cell culturing solution were carried out in Space. Simultaneously the ground control test concerning cell culture was also executed. The cell secretes an antibody "IgG", which is expected as a medicine for cancer treatment and diagnosis. Production process of the IgG consists of the cell culturing process, and the IgG separation process. Though the former had been enabled by the technological development to handle a larger volume, the latter remained behind the former, and became the bottleneck of the process. In order to solve the problem, space electrophoretic separation is expected and partly verified to increase the handling volume remarkably with much higher resolution due to absence of thermal convection. In the experiments on orbit, the cells were cultured for five days from the launch, subsequently stored in a freezer for five days, and injected into the free flow electrophoresis unit (FFEU) . The followings could be partly verified despite the bubble presence in the FFEU: (1) IgG in Space doubled that on Earth in the concentration. (2) Space electrophoresis was much stabler than that on earth. As a result, the space experiment indicated at least that space pharmaceutical production could be based on the microgravity conditions, despite the bubble problem left behind.

Analysis of the steroidogenic acute regulatory protein (StAR) gene in Japanese patients with congenital lipoid adrenal hyperplasia.

Genomic DNA from 19 Japanese patients with congenital lipoid adrenal hyperplasia (lipoid CAH) representing 16 different families was examined to identify the genetic alterations of steroidogenic acute regulatory protein (StAR). Ten of 19 patients had a 46,XX karyotype and nine had a 46,XY karyotype. Six of the 46,XX patients have experienced spontaneous pubertal changes including breast development and irregular menstruation whereas none of the 46,XY subjects displayed pubertal changes. Eight different mutations were identified. Sixteen patients were either homozygotes or compound heterozygotes for the Q258X mutation. The seven other mutations identified were 189delG, 246insG, 564del13bp, 838delA, Q212X, A218V and M225T. The 189delG, 246insG, 546del13bp and Q212X mutants encode truncated proteins. COS-1 cells transfected with expression vectors encoding cDNAs for the mutant StAR proteins which affect the C-terminus, 838delA, A218V and Q258X, exhibited no steroidogenesis enhancing activity. However, the M225T mutant retained some steroidogenic activity. The patient with the M225T mutation had late onset of this disorder and some capacity to secrete testosterone in response to hCG. These findings suggest: (i) that the Q258X mutation can be used as a genetic marker for the screening of Japanese for lipoid CAH, (ii) that the C-terminus of StAR plays an important role in the protein's activity and (iii) that there are differences in the extent of functional impairment of the testis and ovaries in lipoid CAH.

Full duplex transmission operation of a 2.45-GHz asynchronous spread spectrum using a SAN convolver.

An asynchronous spread spectrum (SS) modem in the 2.45-GHz band has been implemented using an efficient ZnO-SiO(2)-Si surface acoustic wave (SAW) convolver. The modem, which can operate under full duplex transmission is based on a direct-sequence/code-shift-keying (DS/CSK) method for the modulation. Pseudonoise (PN) codes are chosen from a preferred pair of m-sequences of period 127, and the code rate is 14 MHz. The demodulation is carried out asynchronously, utilizing the coherent correlation characteristics of the SAW convolver. The main interference caused by a transmitted signal in the modem itself is effectively reduced by an RF isolator and the SS process gain. Adequate self-jamming rejection capability has been confirmed; a bit error rate of 10(-6) is observed at -78.3 dB of a desired-to-undesired-signal ratio using an artificial transmission line.

Interstitial deletion of the long arm of chromosome 11: report of a case and review of the literature.

A 12-month-old female infant with developmental delay, growth retardation, and dysmorphic features including dolichocephaly, telecanthus, ptosis, flat nasal bridge, anteverted nares, high-arched palate, carp-shaped mouth, micro-retrognathia, and low-set and posteriorly rotated ears was found to have an interstitial deletion of chromosome 11 involving bands q14-q22. Immunoblot analysis of her fibroblasts revealed a normal amount of mitochondrial acetoacetyl-coenzyme A thiolase, of which gene locus has been assigned to chromosome 11q22.3-q23.1. This result suggested that the region around the boundary of 11q22.3-q23.1 was intact in this patient.

Vitamin D and vitamin D dependency.

Administration of large doses of vitamin D2 brought about a marked increase of 25-hydroxyvitamin D in both the patients with vitamin D dependency and hypophosphatemic vitamin D-resistant rickets. During the administration of vitamin D2, increment of 1,25-dihydroxyvitamin D was marked in hypophosphatemic vitamin D-resistant rickets, but far smaller in vitamin D dependency. In the latter, however, the 1,25-dihydroxyvitamin D reached the level close to the normal adult values. 1 alpha-hydroxyvitamin D3 was found 50 approximately 100 times as effective as vitamin D2 in 2 patients with vitamin D dependency (optimum maintenance dose: 0.05 micrograms/kg/day). It was concluded that 1 alpha-hydroxylation in the renal tubules is markedly defective in the patients with vitamin D dependency, but that a large dose of vitamin D2 is able to cause a definite increase in serum concentration of 1,25-dihydroxyvitamin D resulting in improvement of the rickets.

Biological activity of 1-alpha-hydroxy vitamin D3 in vitamin D dependency.

The biological activity of 1(OH) vitamin D3 was evaluated in 2 cases of vitamin D dependency. For the improvement of serum chemistry and increment of urinary excretion of calcium 1(OH) vitamin D3 was 500--1000 times more active than vitamin D2. The administration of 0.05 microg/kg/day and 0.1 microg/kg/day of 1(OH) vitamin D3 were equally effective to keep the serum chemistry within normal limits. However, urinary excretion of calcium increased to an abnormal height on 0.1 microg/kg/day of 1(OH) vitamin D3. On the other hand, administration of 0.05 microg/kg/day of 1(OH) vitamin D3 kept both serum level and urinary excretion of calcium normal. It is suggested that 0.05 microg/kg/day is close to the optimum requirement of 1(OH) vitamin D3 in vitamin D dependency and this should correspond to the essential requirement of 1(OH) vitamin D3 in man.