Recently, de novo KIF1A mutations were identified in patients with intellectual disability, spasticity and cerebellar atrophy and/or optic nerve atrophy. In this study, we analyzed a total of 62 families, including 68 patients with genetically unsolved childhood cerebellar atrophy, by whole-exome sequencing (WES). We identified five de novo missense KIF1A mutations, including only one previously reported mutation (p.Arg316Trp). All the mutations are located in the motor domain of KIF1A. In all patients, initial symptom onset was during the infantile period, and included developmental delay in three patients and gait disturbance in two. Thereafter, they showed gait disturbances, exaggerated deep tendon reflexes, cerebellar symptoms and cerebellar atrophy on brain magnetic resonance imaging. Four patients showed lower limb spasticity, upper limb clumsiness and visual disturbances. Nerve conduction study revealed peripheral neuropathy in three patients. This study further delineates clinical features of de novo KIF1A mutations. Genetic testing of KIF1A should be considered in children with developmental delay, cerebellar atrophy and pyramidal features.

We examined therapeutic gene transfer of human hepatocyte growth factor (hHGF) to alveolar septa in mouse bleomycin-induced lung fibrosis using macroaggregated albumin-polyethylenimine complex (MAA-PEI). Intravenous administration of MAA-PEI along with 1 microg pCAG.hHGF to C57BL/6 mice increased the uptake of plasmids into alveolar capillary endothelial cells and epithelial cells, prolonged hHGF expression in the lung, and induced a level of hHGF expression equal to that seen with 10 microg of hHGF-expression plasmids alone. The exogenous source of hHGF gene expression increased the endogenous mouse HGF in the lungs and significantly decreased TNF-alpha, IL-6, and collagen synthesis after bleomycin injury. Because GFP-labeled bone marrow-derived stem cells after bleomycin injury were reduced in number by HGF, the primary mechanism of HGF is likely to be the prevention of apoptosis, as has been suggested by in vitro experiments. This novel HGF gene transfer method to alveolar septa with nonstimulatory MAA-PEI conjugates may have promising clinical applications.

Purpose Reactive FDG uptake in the axillary lymph nodes (ALN) and deltoid muscle (DM) after COVID-19 mRNA vaccination has been recognized, although the actual situation in the Japanese population remains unknown. To determine the incidence of reactive FDG uptake and its contributing factors, we retrospectively studied a cohort of subjects who were vaccinated at our hospital. Methods Whole-body FDG-PET/CT examinations performed in 237 subjects out of 240 subjects with a definite history of COVID-19 vaccination (BNT162b2; BioNTech-Pfizer) were analyzed. Positivity and SUVmax of FDG uptake in the ALN and DM ipsilateral to vaccination, various subject characteristics, and the grade of the pathological FDG-PET/CT findings were evaluated using a multivariate analysis. Results FDG uptake in the ALN and DM ipsilateral to vaccination was seen in about 60% of the subjects even soon (0–4 days) after the first vaccination, with percentages reaching 87.5% and 75.0%, respectively, after the second vaccination. DM uptake had almost disappeared at around 2 weeks, while ALN uptake persisted for 3 weeks or longer. A multivariate analysis showed that a short duration since vaccination, a younger age, a female sex, and a low FDG-PET/CT grade (minimal pathological FDG uptake) contributed significantly to positive ALN uptake, while a short duration since vaccination and a female sex were the only significant contributors to positive DM uptake. This study is the first to identify factors contributing to positive FDG uptake in ALN and DM after COVID-19 vaccination. Conclusion A high incidence of FDG uptake in ALN and DM was observed after vaccination. ALN uptake seemed to be associated with a younger age, a female sex, and minimal pathological FDG uptake. After vaccination, an acute inflammatory reaction in DM followed by immune reaction in ALN linked to humoral immunity may be speculated.

BackgroundRecent studies have suggested that microvascular and macrovascular diseases are associated with coronary events.ObjectiveTo test the hypothesis that asymptomatic coronary heart disease (CHD) may be present in many patients with diabetes with vascular complications.DesignFrom April 2009 to August 2010, the authors conducted a cross-sectional study to assess the prevalence of asymptomatic CHD among patients with type 2 diabetes with vascular complications at a national diabetes centre in Japan. Eligibility criteria included patients with type 2 diabetes with no known CHD and one or more of the following four criteria: (1) proliferative diabetic retinopathy or after photocoagulation; (2) estimated glomerular filtration rate <30 ml/min/1.73 m2 or an estimated glomerular filtration rate <45 ml/min/1.73 m2 plus albuminuria; (3) peripheral arterial disease; and (4) cerebrovascular disease. Each patient underwent a stress single-photon emission computed tomography; patients with myocardial perfusion abnormalities then underwent coronary angiography.ResultsA total of 1008 patients with type 2 diabetes were screened, and 122 eligible patients consented to participate. Stress single-photon emission computed tomography revealed myocardial perfusion abnormalities in 96 (79%) patients. Of the 112 patients who completed the study protocol, 59 (53%) had asymptomatic CHD with ≥50% diameter stenosis. Additionally, 35 (31%) patients had multivessel disease or left main disease, and 42 (38%) had a coronary artery with ≥75% diameter stenosis. In the multivariate logistic-regression analysis to identify coronary risk factors associated with asymptomatic CHD, the only significant predictor was male sex (OR 6.18; 95% CI 2.30 to 16.64; p<0.001).ConclusionsAsymptomatic CHD with ≥50% diameter stenosis and myocardial perfusion abnormalities was detected in more than half of the patients with type 2 diabetes with vascular complications.

Abstract. Toll-like receptors (TLRs) are important pathogenassociated molecular pattern recognition receptors involved in initiating immune responses. The adaptor protein Myd88 adaptor-like (Mal), involved in signaling downstream of TLRs, plays a crucial role in mediating NF-κB activation. The association of Mal polymorphisms with allergic diseases has not previously been defined. The objective of this study was to detect polymorphisms in the Mal gene and to investigate their association with allergic diseases. Mal gene polymorphisms were genotyped in 310 subjects. The functional effects of Mal variants were analyzed in vitro. One Mal polymorphism, c.303 G>A (Q101Q), was found at a significantly lower frequency in atopic dermatitis patients (p=0.016). Q101Q is in linkage disequilibrium with -103 A>G (rs1893352) and c.539 c>T (S180L) (rs8177374) in the HapMap database. The A allele of -103 A>G showed significantly reduced transcription of Mal compared with the G allele. In addition, three rare variants were identified in this study, c.394 G>A (E132K), c.428 G>A (R143Q) and c.570 G>c (E190d), and were shown to lead to loss-of-function of Mal. It is possible that gene polymorphisms in Mal could affect atopic dermatitis by influencing the innate immune system. We show that Q101Q, which is in linkage disequilibrium with -103 A>G and S180L, may play a protective role against atopic dermatitis. Furthermore, we propose that loss-of-function variants of Mal could predispose individuals to atopic dermatitis or other immunological disorders.