Differences in cough strength, respiratory function, and physical performance in older adults with and without low swallowing function in the repetitive saliva swallowing test.

[Purpose] In older adults, the risk of aspiration pneumonia increases because of coexisting factors such as age-related decline in swallowing function, inefficient cough, reduced respiratory function, and poor physical performance. This study aimed to investigate the differences in cough strength, respiratory function, and physical performance in community-dwelling ambulatory older adults with and without low swallowing function. [Participants and Methods] In 225 community-dwelling ambulatory older adults, swallowing function (the repetitive saliva swallowing test, RSST), cough strength (peak cough flow), lung function (forced vital capacity, forced expiratory volume in 1 second/forced vital capacity), respiratory muscle strength (maximum inspiratory and expiratory pressures), and physical performance (30-second chair stand test and Timed Up and Go test) were evaluated. Participants with low swallowing function in RSST (low RSST group) were compared to age- and sex-matched participants without low swallowing function (control group). [Results] Peak cough flow and maximum inspiratory and expiratory pressures were significantly lower in the low RSST group (n=14) than the control group (n=14). [Conclusion] These preliminary results suggest that community-dwelling ambulatory older adults with low swallowing function in RSST might have lower cough and respiratory muscle strength, even if they have relatively preserved lung function and physical performance.

Intellectual disability and abnormal cortical neuron phenotypes in patients with Bloom syndrome.

Bloom syndrome (BS) is a rare autosomal recessive disorder characterized by genomic instability that leads to various complications, including cancer. Given the low prevalence of BS in Japan, we conducted a nationwide survey. We recruited eight patients with BS, three of whom exhibited intellectual disability. The 631delCAA mutation in the BLM gene was detected in 9 out of 16 alleles. To investigate neuronal development in patients with BS, we generated induced pluripotent stem cells derived from one of these patients (BS-iPSCs). We examined the phenotypes of the induced cortical neurons derived from the generated BS-iPSCs using a previously reported protocol; the generated BS-iPSCs showed an approximately 10-times higher frequency of sister-chromatid exchange (SCE) than the control iPSCs. Immunocytochemistry revealed shorter axons and higher proliferative potential in BS-iPSC-derived cortical neurons compared with control iPSCs. To our knowledge, our study is the first to clarify the abnormality of the cortical neuron phenotypes derived from patients with BS. Our findings may help identify the pathogenesis of neuronal differentiation in BS and aid in the development of novel therapeutic agents.

Effects of Cough Training and Inspiratory Muscle Training on Cough Strength in Older Adults: A Randomized Controlled Trial.

PURPOSE: While the need for preventive strategies to reduce the incidence of aspiration pneumonia has been indicated, it is also important to investigate effective training methods to improve cough function, which is associated with the development of aspiration pneumonia. This study aimed to investigate whether a 4-week home-based unsupervised cough training (CT) or inspiratory muscle training (IMT) program was effective in improving cough strength in older adults. METHODS: Fifty-three ambulatory older adults without airflow limitations were randomly assigned to one of three groups: a CT group (n = 18), an IMT group (n = 18), or a control group (n = 17). The CT and IMT groups performed home-based unsupervised training with a device for 4 weeks. Cough strength (cough peak flow), forced vital capacity, and respiratory muscle strength were assessed at the 4-week and 16-week follow-up. Intention-to-treat analyses were performed to investigate differences between the three groups using linear mixed models. RESULTS: At the 4-week follow-up, the CT group showed significant increases in cough peak flow and forced vital capacity compared with the control group, while the IMT group showed significant increases in inspiratory muscle strength compared with the cough training and control groups. At the 16-week follow-up, the CT group showed a significant increase in cough peak flow compared with the IMT group. CONCLUSION: These preliminary results suggest that a 4-week home-based CT program may have short-term effectiveness in improving cough peak flow in ambulatory older adults. TRIAL REGISTRATION: This trial was registered on UMIN-CTR on 01/05/2018 (UMIN000031656).

Rothmund-Thomson syndrome investigated by two nationwide surveys in Japan.

BACKGROUND: Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disorder characterized by poikiloderma of the face, small stature, sparse scalp hair, juvenile cataract, radial aplasia, and predisposition to cancers. Due to the rarity of RTS, the situation of patients with RTS in Japan has not been elucidated. METHODS: In 2010 and 2020, following the results of a primary questionnaire survey, a secondary questionnaire survey on RTS was conducted nationwide to investigate the number of RTS cases and their associated skin lesions, bone lesions, other clinical features, and quality of life in Japan. RESULTS: In 2010 and 2020, 10 and eight patients with RTS were recruited, respectively. Skin lesions such as poikiloderma, erythema, pigmentation, and abnormal scalp hair were observed in almost all cases. Bone lesions were observed in four cases in the 2010 and 2020 surveys, respectively. Two cases had mutations in the RECQL4 gene in the 2020 survey. CONCLUSIONS: Two nationwide surveys have shown the actual situation of patients with RTS in Japan. Cutaneous and bone manifestations are important for the diagnosis of RTS. However, many patients have no RECQL4 mutations. The novel causative gene of RTS should be further elucidated.

Threshold dose of cow's milk in sensitization to casein higher than those of casein and ß-lactoglobulin in children with cow's milk allergy.

BACKGROUND: Recent treatment for food allergies involves the intake of allergy-causing foods at doses lower than the threshold dose determined by the oral food challenge (OFC). For a more successful treatment, it is necessary to identify a biomarker to establish safer doses of allergens in foods consumed at home. OBJECTIVE: In this study, we aim to investigate whether the pattern of sensitization to cow's milk (CM) is related to the threshold dose of CM. METHODS: Fifty patients with sensitization to casein (casein-specific IgE titer ≥ 0.7 UA/ml) and who have undergone the CM OFC test from July 2013 to July 2015 were enrolled. They were examined for the presence or absence of sensitization to ß-lactoglobulin (BLG) (BLG-specific IgE ≥ 0.7 UA/ml). They were divided into two groups, namely, the only-casein-specific IgE-positive (C) group, and both casein- and BLG-specific IgE-positive (C + B) group. RESULTS: The C group had 26 patients and the C + B group had 24. Both the CM- and casein-specific IgE titers were higher in the C + B group than in the C group. The positivity rates determined from OFC test results were 53.8 and 87.5%, and the threshold doses of CM were 88.7 and 31.1 ml in the C and C + B groups, respectively. In patients with low casein-specific IgE titers (≤ 10 UA/ml), the C + B group showed a significantly lower threshold dose of CM than the C group. CONCLUSIONS: Our results suggest that children with CM allergy sensitized to casein alone have a higher threshold dose than those sensitized to both casein and BLG.

Association of respiratory function with physical performance, physical activity, and sedentary behavior in older adults.

[Purpose] The associations between respiratory function, physical performance, physical activity, and sedentary behavior in older adults remain to be elucidated. This study aimed to investigate the associations of lung volume and respiratory muscle strength with physical performance, physical activity, and sedentary behavior in older adults. [Participants and Methods] In 62 ambulatory community-dwelling older adults, lung volumes (forced vital capacity and forced expiratory volume in 1s), respiratory muscle strength (maximum inspiratory and expiratory muscle pressures), physical performance (Timed Up and Go test and 30 s chair stand test), physical activity (steps and locomotive and non-locomotive physical activity), and sedentary behavior (percent sedentary time) were assessed. [Results] The percent sedentary time, 30-s chair stand test performance, and non-locomotive moderate-to-vigorous physical activity were independently associated with forced vital capacity, maximum inspiratory pressure, and maximum expiratory pressure, respectively. [Conclusion] The preliminary findings suggest that lung volumes and respiratory muscle strength may be differently affected by physical performance, physical activity, and sedentary behavior in ambulatory older adults.

The Protective Effects of Levetiracetam on a Human iPSCs-Derived Spinal Muscular Atrophy Model.

Spinal muscular atrophy (SMA) is an inherited disease characterized by progressive motor neuron death and subsequent muscle weakness and is caused by deletion or mutation of survival motor neuron (SMN) 1 gene. Protecting spinal motor neuron is an effective clinical strategy for SMA. The purpose of this study was to investigate the potential effect of an anti-epileptic drug levetiracetam on SMA. In the present study, we used differentiated spinal motor neurons (MNs) from SMA patient-derived induced pluripotent stem cells (SMA-iPSCs) to investigate the effect of levetiracetam. Levetiracetam promoted neurite elongation in SMA-iPSCs-MNs. TUNEL-positive spinal motor neurons were significantly reduced by levetiracetam in SMA-iPSCs-MNs. In addition, the expression level of cleaved-caspase 3 was decreased by levetiracetam in SMA-iPSCs-MNs. Furthermore, levetiracetam improved impaired mitochondrial function in SMA-iPSCs-MNs. On the other hand, levetiracetam did not affect the expression level of SMN protein in SMA-iPSCs-MNs. These findings indicate that levetiracetam has a neuroprotective effect for SMA.

A path analysis of the interdependent relationships between life space assessment scores and relevant factors in an elderly Japanese community.

[Purpose] This study aimed to examine the direct and indirect effects of factors influencing the risk of life space assessment using path analysis. [Participants and Methods] A sample of 212 elderly residents (at least 65 years old) with no clear indications of cognitive dysfunction, visual impairment, and physical dysfunction were recruited for the study. Data on these factors were collected from the participants at a community gathering using measures of life space assessment, skeletal muscle mass, lower extremity muscle strength, mobility, cognitive function, and fear of falling. Correlational and path analyses were used to investigate the relationships between these variables. [Results] The final path model satisfied the requisite statistical criteria, and subsequently, the relationships between the physiological and psychological factors associated with life space assessment were structured and represented visually. Age, skeletal muscle mass, fear of falling, and mobility had a direct effect on life space assessment, whereas lower extremity muscle strength and cognitive function affected it indirectly. [Conclusion] In this study, direct and indirect effects of physiological and psychological factors related to risk of life space assessment of the elderly were clarified using path analysis.

A Docosahexaenoic Acid-Derived Pro-resolving Agent, Maresin 1, Protects Motor Neuron Cells Death.

Maresin 1 is a novel pro-resolving mediator derived from docosahexaenoic acid (DHA), with potent anti-inflammation effects against several animal models, including brain ischemia, sepsis, and lung fibrosis. However, its effect against motor neuron cell death is still not investigated. Therefore, we investigated the effects of maresin 1 on several stress-induced motor neuron cell death. Maresin 1 suppressed combinatorial stress which was evoked by superoxide dismutase 1 (SOD1)G93A and serum-free, -induced motor neuron cells death in a concentration-dependent manner, and had a stronger neuroprotective effective than DHA. Maresin 1 also had neuroprotective effects against transactivation response DNA-binding protein (TDP)-43A315T and serum-free stress, H2O2, and tunicamycin-induced cell death. Maresin 1 reduced the reactive oxygen species (ROS) production caused by SOD1G93A or TDP-43A315T. Moreover, maresin 1 suppressed the NF-κB activation induced by SOD1G93A and serum-free stress. These data indicate that maresin 1 has motor neuron protective effects against several stresses by reduction of ROS production or attenuation of the NF-κB activation. Maresin 1 also had neuroprotective effects against H2O2, and tunicamycin-induced cell death in a concentration-dependent manner. Finally, maresin 1 ameliorated the motor function deficits of spinal muscular atrophy model in which endoplasmic reticulum stress was upregulated. Thus, maresin 1 may be beneficial to protect against motor neuron diseases.

T-cell epitope-containing hypoallergenic ß-lactoglobulin for oral immunotherapy in milk allergy.

BACKGROUND: Optimally hydrolyzed ß-Lactoglobulin (ßLg) is a promising milk oral immunotherapy (OIT) candidate with respect to showing reduced B-cell reactivity but retaining the T-cell epitope. To demonstrate that an edible hypoallergenic ßLg hydrolysate containing the T-cell epitope is suitable for OIT. We tested how chymotrypsin affected the retention of the T-cell epitope of ßLg when preparing ßLg hydrolysates using food-grade trypsin. METHODS: We investigated the effect of chymotrypsin activity on the formation of the T-cell epitope-containing peptide of ßLg (ßLg102-124 ) and prepared an edible ßLg hydrolysate containing ßLg102-124 using screened food-grade trypsins. B-cell reactivity was determined using immunoassays in which ELISA was performed with anti-ßLg rabbit IgG and Western blotting was performed with a milk-specific IgE antiserum. RESULTS: In ßLg hydrolysis performed by varying the activity of trypsin and chymotrypsin, chymotrypsin activity inhibited the formation of ßLg102-124 with an increase in hydrolysis time in a dose-dependent manner. ßLg102-124 was generated by two of five food-grade trypsins used at a ratio of 1:50 (w/w, enzyme/substrate) for 20 h at 40°C. The edible ßLg hydrolysate retained ßLg102-124 and showed a reduction in molecular weight distribution and antigenicity against IgG and IgE. CONCLUSIONS: Chymotrypsin activity inhibited the formation of ßLg102-124 in the trypsin hydrolysate of ßLg. This ßLg trypsin hydrolysate is a novel candidate for peptide-based OIT in cow's milk allergy for safely inducing desensitization.

Indocyanine green lymphography and lymphaticovenous anastomosis for generalized lymphatic dysplasia with pleural effusion and ascites in neonates.

BACKGROUND: The fatality rate of generalized lymphatic dysplasia (GLD) with chylous pleural effusion and ascites is particularly high when it persists over a prolonged period. The purpose of this report was to determine the utility of indocyanine green (ICG) lymphography and lymphaticovenous anastomosis (LVA) in GLD with chylous pleural effusion and ascites in neonates. METHODS: We tested the lymphatic function in the 4 extremities for 8 GLD neonate patients using ICG lymphography, and on the basis of the results, we performed LVA for 5 of them. LVA was performed at the extremities under general anesthesia using incisions <1 cm in length. The outcome of LVA was evaluated with the amount of ascites discharged from thoracostomy tube or abdominal tube, except for 1 patient who had no drainage tube. RESULTS: In all cases, ICG lymphography showed varying degrees of dermal backflow in the limbs with lymphostasis. After LVA surgery, effusion stopped in 2 cases and decreased in 1 case. In the cases where effusion stopped, backflow as observed with ICG lymphography was minimal, and in the case where effusion decreased but did not stop, backflow was moderate. CONCLUSIONS: The application of ICG and LVA could possibly be used to diagnose and treat lymphatic pleural effusion or ascites.

New scale to assess breathing movements of the chest and abdominal wall: preliminary reliability testing.

[Purpose] Physical examinations for chest movements by inspection and palpation are poorly reproducible. This study aimed to investigate the inter-rater reliability of a new breathing movement scale for patients with respiratory diseases, in clinical practice. [Subjects and Methods] Twenty-six patients with respiratory diseases were enrolled. BMS measurements were obtained during quiet breathing for 13 patients and during deep breathing for the other 13 patients. The BMS used to assess QB and DB movements of the upper chest, lower chest, and abdomen was based on a scale of -1 to 8. Scale values were measured while in the supine position using a pen-sized breathing movement-measuring device used by two raters during the same session. Scale values at five observation points and total values were recorded. A weighted Kappa coefficient and percentage agreement were used to assess inter-rater reliability with this BMS. [Results] The weighted Kappa coefficients during quiet and deep breathing had substantial to excellent strength of agreement (0.63-1.00) with percentage agreements of 31-100%. [Conclusion] Our results provide preliminary evidence to support the reliability of breathing movement scale measurements to assess breathing movements and chest and abdominal mobility for patients with respiratory diseases.

A complement factor B mutation in a large kindred with atypical hemolytic uremic syndrome.

PURPOSE: Gain-of-function mutations in complement factor B (CFB) were recently identified in patients with atypical hemolytic uremic syndrome (aHUS), but are extremely rare. Our purpose is to describe a large kindred with aHUS associated with a CFB mutation and to further understand CFB-mutated aHUS patients. METHODS AND RESULTS: We report a large kindred in which 3 members had aHUS. This kindred revealed that 9 of 12 members, including 2 affected patients, had persistent activation of the alternative pathway with low complement component 3 and that those 9 members showed a CFB mutation (c.1050G > C, p.Lys350Asn) in exon 8. This missense mutation was heterozygous in 8 of them and homozygous in only one. From structural studies, this mutation is shown to be located in close proximity to the Mg2-binding site within a von Willebrand factor type A domain of CFB, resulting in a gain-of-function effect of CFB and predisposition to aHUS. At present, 2 of the 3 members with aHUS have maintained normal renal function for a long-term period. CONCLUSIONS: This kindred illustrates that a CFB mutation (c.1050G > C, p.Lys350Asn) can result in aHUS. In the future, phenotype-genotype correlations and outcome in CFB-mutated aHUS patients need to be further investigated by accumulation of a number of cases.

In vitro analysis of the functional effects of an NLRP3 G809S variant with the co-existence of MEFV haplotype variants in atypical autoinflammatory syndrome.

PURPOSE: Hereditary periodic fever syndromes have been considered monogenic diseases. However, some recent reports have described patients with co-existence of recurrent fever responsible genes. This study assessed whether a rare variant, found in Japanese children showing atypical autoinflammatory syndrome, located in the leucine-rich repeat domain of Nod-like receptor family, pyrin domain containing 3 (NLRP3) with co-existence of Mediterranean fever (MEFV) haplotype variants may contribute to a proinflammatory phenotype using a systematic approach. METHODS: Cytokine production in serum or from peripheral blood monocytes was measured by ELISA. DNA sequence analysis of genes including NLRP3, MEFV, mevalonate kinase (MVK), and tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A) were performed on patient samples. In vitro functional assays determined the effects of the NLRP3 variants and pyrin using NF-κB activation and speck formation assays. RESULTS: A heterozygous genetic variant of NLRP3, G809S, was found in samples from both patients. Additionally the previously reported heterozygous MEFV variants (P369S-R408Q or E148Q-P369S-R408Q) were also detected in both patients. Serum IL-1ra and sTNFR1 levels increased in the attack phase of the disease in both patients. The production levels of IL-1ß from monocytes isolated from both cases were elevated following LPS and IFN-γ stimulation. The NLRP3 G809S variant demonstrated no increase of NF-κB activity following monosodium urate stimulation, whereas it significantly increased speck formation by interacting with apoptosis-associated speck-like protein with caspase recruitment domain. CONCLUSIONS: The phenotype of atypical autoinflammatory disease in patients could be modified by a synergistic effect with two other variants of autoinflammatory-associated genes.

Peripheral blood stem cell transplantation in a significant body weight difference between a smaller donor and a larger recipient: a case report.

Allogeneic peripheral blood stem cell transplantation (PBSCT) is becoming a common transplantation procedure in children. However, few benefits have been reported, in particular in regard to the choice of small children as donors for larger recipients. We report a case of relapsed acute myeloid leukemia (body weight 52 kg and blood type O) who underwent allogeneic PBSCT from his smaller human leukocyte antigen-matched brother (body weight 29.9 kg and blood type A).

Total IgE at 6 months predicts remittance or persistence of atopic dermatitis at 14 months.

Some patients with infantile atopic dermatitis (AD) achieve remission around 1 year old, but in others it persists. The difference between them is unclear. We performed a birth cohort study to find the markers predicting the outcome of infantile AD. We followed up a cohort (n = 314) from birth to 14 months of age, and cord blood was taken from the participants. Some of them (n = 144) had a physical examination and a blood test at 6 and 14 months of age. The subjects who had AD at 6 months (n = 34) were divided into two groups, named the transient group (those who had no AD at 14 months of age; n = 16) and the persistent group (those who still had AD at 14 months of age; n = 18). Then, laboratory data were compared between these two groups. Percentage of CD8 in cord blood lymphocytes and total IgE at 6 months of age in the persistent group was significantly higher than those of the transient group. The area under the curves of a receiver operating characteristic analysis were 0.792 (p = 0.007) and 0.722 (p = 0.027). In the persistent group, total IgE, percentages of T-helper (Th) 2 and phytohemagglutinin-induced IL-4 production from peripheral blood mononuclear cells at 14 months of age were also significantly higher than those of the transient group. Thus Th2 polarization in the persistent group was confirmed. In clinical use, total IgE at 6 months of age is the most useful predictive marker to know the outcome of infantile AD. The clinical trial registration ID is UMIN000002926.

Effect of Maternal Egg Intake During the Early Neonatal Period and Risk of Infant Egg Allergy at 12 Months Among Breastfeeding Mothers: A Randomized Clinical Trial.

Importance: Egg introduction in infants at age 4 to 6 months is associated with a lower risk of immunoglobulin E-mediated egg allergy (EA). However, whether their risk of EA at age 12 months is affected by maternal intake of eggs at birth is unknown. Objective: To determine the effect of maternal egg intake during the early neonatal period (0-5 days) on the development of EA in breastfed infants at age 12 months. Design, Setting, and Participants: This multicenter, single-blind (outcome data evaluators), randomized clinical trial was conducted from December 18, 2017, to May 31, 2021, at 10 medical facilities in Japan. Newborns with at least 1 of 2 parents having an allergic disease were included. Neonates whose mothers had EA or were unable to consume breast milk after the age of 2 days were excluded. Data were analyzed on an intention-to-treat basis. Interventions: Newborns were randomized (1:1) to a maternal egg consumption (MEC) group, wherein the mothers consumed 1 whole egg per day during the first 5 days of the neonate's life, and a maternal egg elimination (MEE) group, wherein the mothers eliminated eggs from their diet during the same period. Main Outcomes and Measures: The primary outcome was EA at age 12 months. Egg allergy was defined as sensitization to egg white or ovomucoid plus a positive test result in an oral food challenge or an episode of obvious immediate symptoms after egg ingestion. Results: Of the 380 newborns included (198 [52.1%] female), 367 (MEC: n = 183; MEE: n = 184) were followed up for 12 months. On days 3 and 4 after delivery, the proportions of neonates with ovalbumin and ovomucoid detection in breast milk were higher in the MEC group than in the MEE group (ovalbumin: 10.7% vs 2.0%; risk ratio [RR], 5.23; 95% CI, 1.56-17.56; ovomucoid: 11.3% vs 2.0%; RR, 5.55; 95% CI, 1.66-18.55). At age 12 months, the MEC and MEE groups did not differ significantly in EA (9.3% vs 7.6%; RR, 1.22; 95% CI, 0.62-2.40) or sensitization to egg white (62.8% vs 58.7%; RR, 1.07; 95% CI, 0.91-1.26). No adverse effects were reported. Conclusions and Relevance: In this randomized clinical trial, EA development and sensitization to eggs were unaffected by MEC during the early neonatal period. Trial Registration: UMIN Clinical Trials Registry: UMIN000027593.