Development and validation of equations for predicting appendicular skeletal muscle mass in male patients with head and neck cancer and normal hydration status.

OBJECTIVE: Muscle mass is typically assessed by abdominal computed tomography, magnetic resonance imaging, and dual-energy x-ray absorptiometry. However, these tests are not routinely performed in patients with head and neck cancer (HNC), making sarcopenia assessment difficult. The aim of this study was to develop and validate equations for predicting appendicular skeletal muscle mass (ASM) from data obtained in daily medical practice, with bioelectrical impedance analysis (BIA)-measured appendicular skeletal muscle mass (BIA-ASM) as a reference. METHODS: This cross-sectional study included 103 men with HNC who were randomly placed into development and validation groups. The prediction equations for BIA-ASM were developed by multiple regression analysis and validated by Bland-Altman analyses. The estimated skeletal muscle mass index (eSMI) was also statistically evaluated to discriminate the cutoff value for BIA-measured SMI according to the Asian Working Groups for Sarcopenia. RESULTS: Two practical equations, which included 24-h urinary creatinine excretion volume (24hUCrV), handgrip strength (HGS), body weight (BW), and body height (BHt), were developed: ASM (kg) = -39.46 + (3.557 × 24hUCrV [g]) + (0.08872 × HGS [kg]) + (0.1263 × BW [kg]) + (0.2661 × BHt [cm]) if available for 24hUCrV (adjusted R2 = 0.8905), and ASM (kg) = -42.60 + (0.1643 × HGS [kg]) + (0.1589 × BW [kg]) + (0.2807 × BHt [cm]) if not (adjusted R2 = 0.8589). ASM estimated by these two equations showed a significantly strong correlation with BIA-ASM (R > 0.900). Bland-Altman analyses showed a good agreement, and eSMI accuracy was high (>80%) in both equations. CONCLUSIONS: These two equations are a valid option for estimating ASM and diagnosing sarcopenia in patients with HNC in all facilities without special equipment.

Muscle mass, quality, and strength; physical function and activity; and metabolic status in cachectic patients with head and neck cancer.

BACKGROUND & AIMS: Cancer cachexia is commonly associated with poor prognosis in patients with head and neck cancer (HNC). However, its pathophysiology and treatment are not well established. The current study aimed to assess the muscle mass/quality/strength, physical function and activity, resting energy expenditure (REE), and respiratory quotient (RQ) in cachectic patients with HNC. METHODS: This prospective cross-sectional study analyzed 64 patients with HNC. Body composition was measured via direct segmental multifrequency bioelectrical impedance analysis, and muscle quality was assessed using echo intensity on ultrasonography images. Muscle strength was investigated utilizing handgrip strength and isometric knee extension force (IKEF). Physical function was evaluated using the 10-m walking speed test and the five times sit-to-stand (5-STS) test. Physical activity was examined using a wearable triaxial accelerometer. REE and RQ were measured via indirect calorimetry. These parameters were compared between the cachectic and noncachectic groups. RESULTS: In total, 23 (36%) patients were diagnosed with cachexia. The cachectic group had a significantly lower muscle mass than the noncachectic group. Nevertheless, there was no significant difference in terms of fat between the two groups. The cachectic group had a higher quadriceps echo intensity and a lower handgrip strength and IKEF than the noncachectic group. Moreover, they had a significantly slower normal and maximum walking speed and 5-STS speed. The number of steps, total activity time, and time of activity (<3 Mets) did not significantly differ between the two groups. The cachectic group had a shorter time of activity (≥3 Mets) than the noncachectic group. Furthermore, the cachectic group had a significantly higher REE/body weight and REE/fat free mass and a significantly lower RQ than the noncachectic group. CONCLUSIONS: The cachectic group had a lower muscle mass/quality/strength and physical function and activity and a higher REE than the noncachectic group. Thus, REE and physical activity should be evaluated to determine energy requirements. The RQ was lower in the cachectic group than that in the noncachectic group, indicating changes in energy substrate. Further studies must be conducted to examine effective nutritional and exercise interventions for patients with cancer cachexia.

Association of phase angle with muscle function and prognosis in patients with head and neck cancer undergoing chemoradiotherapy.

OBJECTIVES: The aims of this study were to investigate the correlation of phase angle (PhA) with other parameters (e.g., muscle mass/quality/strength and physical function), assess the prognostic relevance of prechemoradiotherapy (CRT) PhA, and suggest a reference value of PhA in Asian patients with head and neck cancer (HNC). METHODS: Ninety-six patients with HNC who underwent CRT were divided into two groups- maintained-PhA group and low-PhA group-according to the PhA 25th percentile values by sex. Pretreatment PhA was measured using direct segmental multifrequency bioelectrical impedance analysis, and muscle quality was assessed using echo intensity in ultrasound images. Correlation of PhA with other parameters was investigated, and between-group differences with respect to adverse events, treatment interruption, and 3-y survival were assessed. RESULTS: PhA showed a positive correlation with isometric knee extension force (R = 0.710), handgrip strength (R = 0.649), skeletal muscle mass index (R = 0.620), and maximum gait speed (R = 0.543; P < 0.001). PhA showed a negative correlation with echo intensity (R = -0.439) and five times sit-to-stand test (R = -0.505; P < 0.01). The low-PhA group had a higher incidence of severe anemia (52% in low-PhA versus 17% in maintained-PhA), aspiration (17 versus 1%), radiotherapy interruption (17 versus 3%), and poor 3-y survival (47 versus 81%) than the maintained-PhA group (P < 0.05). CONCLUSION: PhA was correlated with muscle mass/quality/strength, and physical function. Low PhA was associated with severe adverse events, treatment interruption, and shorter survival. These findings suggested that 4.6° for men and 4° for women may be useful as prognostic reference values in Asian patients with HNC.

Development of receptive vocabulary and verbal intelligence in Japanese children with unilateral hearing loss.

OBJECTIVE: In the past, it was believed that unilateral hearing loss has a minimal impact on the speech and language development in children. However, several studies have suggested that some school-age children with unilateral hearing loss have learning impairments in language. In the present study, we first examined whether preschool-age children with unilateral severe-to-profound hearing loss (UHL) have delays in the development of receptive vocabulary and verbal intelligence. In the follow-up study, we tested the children again after school admission. The objective of the present study was to reveal the development of receptive vocabulary and verbal intelligence from preschool to school years in children with UHL. METHODS: Fifteen Japanese preschool-age children with UHL and a control group of 20 age-matched Japanese children with bilateral normal hearing (NH), who were examined because articulation disorder was suspected, were enrolled in this study. The development of receptive vocabulary and verbal intelligence was evaluated using the Picture Vocabulary Test-Revised (PVT-R) and the Wechsler Intelligence Scale, respectively. The present retrospective study was approved by the Committee for Medical Ethics of Tokushima University Hospital (#3801). RESULTS: The scaled score (SS) of the PVT-R and verbal intelligence quotient (VIQ)/verbal comprehension index (VCI), but not performance intelligence quotient/perceptual reasoning index in children with UHL were significantly lower than those in the control children with NH at preschool-age. The SS of the PVT-R and VIQ/VCI in children with UHL significantly improved after school admission. In the subgroup analysis, the SS of the PVT-R in the lower receptive vocabulary group of children with UHL at preschool-age was significantly increased after school admission, but the SS in the normal and higher receptive vocabulary group of children with UHL at preschool-age were still around the standardized mean of SS after school admission. CONCLUSION: These findings suggest that the development of receptive vocabulary and verbal intelligence was delayed in preschool-age children with UHL and that most of them caught up to exhibit normal language ability after school admission.

Effects of vocal nodules on acoustic characteristics of voice in children†:†an acoustic analysis of voice.

Objective : In the present study, an attempt was made to evaluate the acoustic characteristics of voice in pediatric patients with vocal nodules using acoustic analysis of voice. Methods : Thirty-five pediatric patients with vocal nodules and 32 control children without dysphonia were enrolled in this study. Their voice samples were analyzed using the Multi-Dimensional Voice Program. Acoustic parameters of voice, such as pitch period perturbation quotient (PPQ), amplitude perturbation quotient (APQ), and noise-to-harmonic ratio (NHR), were measured. Results : In phonation at a loudness of over 80 dBA, the PPQ, APQ, and NHR values of the voice significantly increased in children with vocal nodules than in the control children without dysphonia. The sensitivities and specificities of PPQ, APQ, and NHR for prediction of vocal nodules in children were 62.86% and 84.38%, 74.29% and 75.00%, and 31.43% and 93.75%, respectively. Discussion : The present findings suggest that vocal nodules affect vocal fold vibration, resulting in impaired control of pitch and loudness leading to increased noise components. NHR could be used to evaluate the efficacy of treatment, such as voice rehabilitation, in pediatric patients with vocal nodules because of its high specificity for prediction of vocal nodules in children. J. Med. Invest. 68 : 276-279, August, 2021.

Reversible Hearing Impairment Due to Inferior Colliculi Compression by a Pineal Glial Cyst.

Pineal glial cysts associated with bilateral hearing impairment are very rare. Here, we present the case of a 13-year-old boy with a pineal cyst, which caused severe bilateral hearing impairment persisting from 6 years of age. When the patient was 6 years old, the bilateral hearing acuity was about 40 dB on audiometry. Upon admission to our otolaryngology department, his audiogram revealed a bilateral worsening of the hearing acuity (80 dB). Magnetic resonance imaging (MRI) revealed an abnormal pineal cyst with tectal compression from the left with hardly normal bilateral brainstem auditory evoked potentials (BAEPs). We obtained informed consent for exploratory surgery and employed the right occipital transtentorial approach for pineal cyst removal. Based on histological examination, we diagnosed a glial cyst of the pineal gland. At 12 months postoperatively, the patient's hearing improved, showing a bilateral hearing acuity of 40 dB on audiometry. Since the auditory pathway has both crossed and uncrossed fibers at the upper pons and midbrain level, compression at the lateral lemniscus or inferior colliculus level can cause bilateral hearing impairment. In the present case, there was a possible slow pineal cyst growth that eventually compressed the upper pons to the midbrain, lateral lemniscuses, or inferior colliculi from the left side, this eventually led to bilateral hearing impairment. These findings indicate that surgery can improve hearing acuity in patients with a pineal cyst associated with progressive hearing impairment.

Effects of FM system fitted into the normal hearing ear orcartilage conduction hearing aid fitted into the affected ear on speech-in-noise recognition in Japanese children with unilateral congenital aural atresia.

The effects of FM system fitted into the normal hearing ear (NHE) or a cartilage conduction hearing aid (CCHA) fitted into the affected ear (AE) on the speech recognition ability in noise were examined in children with unilateral congenital aural atresia (UCAA). In children with bilateral normal hearing (BNH), speech recognition score (SRS) was significantly decreased in the noisy environment of -5 dB signal-to-noise ratio (SNR), compared with those in quiet. In children with UCAA, SRS was significantly decreased in noisy environments of 0 and -5 dB SNR, compared with those in quiet. In noisy environments of 0 and -5 dB SNR, SRS in children with UCAA was significantly decreased, compared those in children with BNH. In the noisy environment of -5 dB SNR, SRS in UCAA children aided by FM system fitted into NHE was significantly better than those in unaided children in the same group. In the noisy environment of 0 dB SNR, SRS in UCAA children aided by CCHA into AE tended to be higher than those in unaided children in the same group. FM system and CCHA can be recommended as an audiological management for the improvement of speech recognition in children with UCHL in classrooms. J. Med. Invest. 67 : 134-138, February, 2020.

Effects of FM system fitted into normal hearing ear on speech-in-noise recognition in Japanese school-aged children with unilateral severe-to-profound hearing loss.

OBJECTIVES: We examined speech recognition ability of elementary school-aged Japanese children with unilateral hearing loss under noisy environments and then examined the effects of the FM system fitted into their normal hearing ear on their speech recognition ability. METHODS: Twelve children with severe-to-profound sensorineural hearing loss and ten age-matched children with bilateral normal hearing received speech recognition test in quiet and noisy environments. Other nine children with severe-to-profound sensorineural hearing loss received speech recognition test with or without the FM receiver fitted to the normal hearing ear in quiet and noisy environments. RESULTS: Signal-to-noise ratio (SNR) in Japanese elementary school classrooms was estimated to be -6.9 dB at a preferential seat. In noisy environment of -5 dB SNR similar to working classrooms, the correct rates of speech recognition test in children with unilateral hearing loss were significantly lower, compared with those in children with bilateral normal hearing. In the noisy environment, the correct rates in children aided by the FM system with unilateral hearing loss were significantly better, compared with unaided ones. CONCLUSION: The results suggested that the FM system is recommended as an audiological management for improvement of speech recognition of children with unilateral hearing loss in noisy classrooms. J. Med. Invest. 65:216-220, August, 2018.

The first Japanese patient with mandibular hypoplasia, deafness, progeroid features and lipodystrophy diagnosed via POLD1 mutation detection.

Mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome is a rare autosomal dominant disorder caused by heterozygous POLD1 mutations. To date, 13 patients affected by POLD1 mutation-caused MDPL have been described. We report a clinically undiagnosed 11-year-old male who noted joint contractures at 6 years of age. Targeted exome sequencing identified a known POLD1 mutation [NM_002691.3:c.1812_1814del, p.(Ser605del)] that diagnosed him as the first Japanese/East Asian MDPL case.

Congenital dacryocystoceles controlled by nCPAP via nasal mask in a neonate.

Congenital dacryocystocele is a relatively rare type of nasolacrimal duct obstruction that may induce respiratory distress during the early neonatal period. We encountered a case of bilateral congenital dacryocystoceles with intranasal cysts in a premature infant delivered at 34 weeks of gestation. The patient developed symptoms of respiratory failure immediately after birth, but no ophthalmologic symptoms. Treatment with nasal continuous positive airway pressure via a nasal mask, instead of a nasal prong, effectively relieved the symptoms. Early diagnosis and appropriate treatment are critical for infants with nasal obstruction.

Air-bone gap estimated with multiple auditory steady-state response in young children with otitis media with effusion.

OBJECTIVE: Multiple auditory steady-state responses (ASSRs) to air- and bone-conduction stimuli were recorded in young children with otitis media with effusion (OME). After treatment for OME, differences between pre-treatment bone-conduction ASSR levels and post-treatment conditioned orientation reflex (COR) or air-conduction ASSR levels were examined, and compared with ASSR-estimated air-bone gap (ABG) before treatment. METHODS: Navigator Pro with Master was used to assess the threshold of air- and bone-conduction ASSR in both ears at 500Hz, 1000Hz, 2000Hz and 4000Hz. For bone-conduction ASSR, RadioEar B-71 bone-vibrator placed on the mastoid was used with white-noise masking on the contralateral ear. RESULTS: After ventilation tube placement, the thresholds of COR got closer to those of pre-treatment bone-conduction ASSR in young children with OME. Moreover, post-treatment air-conduction ASSR thresholds also got closer to those of pre-treatment bone-conduction ASSR. The differences between pre-treatment bone-conduction ASSR thresholds and post-treatment COR or air-conduction ASSR thresholds became much smaller than ASSR-estimated ABG before treatment. CONCLUSION: These findings suggest that bone-conduction ASSR can assess the normal or near normal cochlear sensitivity in young children with conductive hearing loss. It is also suggested that ASSR-estimated ABG can be used clinically to predict their accurate ABG.

Quest for anti-inflammatory substances using IL-1ß-stimulated gingival fibroblasts.

BACKGROUND: We have previously reported that azulene-related compounds, and alkaline extract of Sasa senanensis Rehder potently inhibited nitric oxide (NO) production by lipopolysaccharide (LPS)-stimulated mouse macrophages. We investigated here whether they can inhibit pro-inflammatory cytokine production, by activated human gingival fibroblast (HGF). MATERIALS AND METHODS: HGF was established from the periodontal tissues of extracted tooth. Viable cell number was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Production of Prostaglandin E(2) (PGE(2)) and cytokines was determined by enzyme immunoassay, and enzyme-linked immunosorbent assay, respectively. RESULTS: Interleukin (IL)-1ß did not inhibit, but rather slightly stimulated the growth of HGF cells. IL-1ß stimulated the production of PGE(2), IL-6, IL-8 and monocyte chemotactic protein-1 very potently, but not that of nitric oxide and tumor necrosis factor-α. Native LPS and synthetic lipid A from E. coli and P. gingivalis was much less stimulatory. Dexamethasone, not indomethacin, was an efficient inhibitor of IL-8 production. Among five azulene-related compounds, benzo[b]cyclohepta[e][1,4]thiazine most potently inhibited the IL-8 production by HGF cells, as well as NO production by activated RAW264.7 cells. The alkaline extract of Sasa senanensis Rehder significantly inhibited IL-8 production, without affecting the cell viability. CONCLUSION: The present system may be applicable for use in the search for anti-gingivitis substances.

Hormetic and UV-protective effects of azulene-related compounds.

BACKGROUND: We have previously reported a possible anti-inflammatory activity of azulene-, tropolone- and azulenequinone-related compounds. To further pursue the newly discovered biological activity of these compounds, five compounds that inhibited nitric oxide production by activated macrophages were investigated for their possible hormetic and anti-radiation effects. MATERIALS AND METHODS: Viable cell number of human oral normal cells (gingival fibroblast, pulp cell and periodontal ligament fibroblast) and three oral squamous cell carcinoma cell lines on treatment with various concentrations of each azulene-related compound was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Apoptosis induction was monitored by caspase-3 activation and DNA fragmentation. RESULTS: Among five compounds, only benzo[b]cyclohepta[e][1,4]thiazine slightly stimulated the growth of all three normal cell types, but not tumor cell lines, at concentrations slightly higher than cytotoxic concentrations. Using a newly established evaluation system for UV-induced cellular damage, we found that this compound slightly but significantly protected the cells from UV-induced cellular injury, and its effect was synergistically enhanced by sodium ascorbate. CONCLUSION: These data suggest the possible application of benzo[b]cyclohepta[e][1,4]thiazine in UV protection therapy.

Sialic acid-mimic peptides as hemagglutinin inhibitors for anti-influenza therapy.

Influenza is an infectious disease caused by the influenza virus, and each year many people suffer from this disease. Hemagglutinin (HA) in the membrane of type A influenza viruses recognizes sialylglycoconjugate receptors on the host cell surface at an initial step in the infection process; consequently, HA inhibitors are considered potential candidates for antiviral drugs. We identified peptides that bind to receptor-binding sites through a multiple serial selection from phage-displayed random peptide libraries. Using the HA of the H1 and H3 strains as target proteins, we obtained peptides that bind to both HAs. The binding affinities of peptides for these HAs were improved by secondary and tertiary selections from the corresponding sublibraries. A docking simulation suggested that, similar to sialic acid, the peptides are recognized by the receptor-binding site in HA, which indicates that these peptides mimic the sialic acid structure. N-stearoyl peptides inhibited infections by the A/Puerto Rico/8/34 (H1N1) and A/Aichi/2/68 (H3N2) strains of influenza virus. Such HA-inhibitors are promising candidates for novel antiviral drugs.

Establishment of an immortalized cell line from a precancerous lesion of lung adenocarcinoma, and genes highly expressed in the early stages of lung adenocarcinoma development.

Atypical adenomatous hyperplasia (AAH) is classified as a precancerous lesion of lung adenocarcinoma. We established an immortalized AAH cell line (PL16T) and a human non-neoplastic bronchial epithelial cell line (PL16B) from the same patient by transfection with the gene for SV40 large T antigen. The expression profile of PL16T was compared with that of PL16B by the suppression subtractive hybridization method. From 704 selectively hybridized clones, we finally selected 25 fragments of mRNA that showed transcription levels more than three times higher in PL16T than in PL16B. Thirteen (52%) and eight (32%) of them encoded tumor-associated calcium signal transducer 2 (TACSTD2) and S100 calcium binding protein A2 (S100A2), respectively. The high transcription of TACSTD2 and S100A2 in PL16T was confirmed by in situ hybridization. In normal lung tissue, both TACSTD2 and S100A2 were expressed at very low levels, but seven and five of 14 AAH were positive for TACSTD2 and S100A2, respectively. The frequency of TACSTD2 positivity was increased in 16 of 22 bronchioloalveolar carcinomas (BAC) and adenocarcinoma with mixed subtype with BAC component (mixed BAC). Positivity for S100A2 occurred in four of 22 BAC and mixed BAC. The abnormal transcription of TACSTD2 and S100A2 are thought to be unique molecular markers of the preinvasive stage of lung adenocarcinoma.

Potentiation of ATP-induced currents due to the activation of P2X receptors by ubiquitin carboxy-terminal hydrolase L1.

Mammalian neuronal cells abundantly express a de-ubiquitinating isozyme, ubiquitin carboxy-terminal hydrolase L1 (UCH L1). Loss of UCH L1 function causes dying-back type of axonal degeneration. However, the function of UCH L1 in neuronal cells remains elusive. Here we show that overexpression of UCH L1 potentiated ATP-induced currents due to the activation of P2X receptors that are widely distributed in the brain and involved in various biological activities including neurosecretion. ATP-induced inward currents were measured in mock-, wild-type or mutant (C90S)-UCH L1-transfected PC12 cells under the conventional whole-cell patch clamp configuration. The amplitude of ATP-induced currents was significantly greater in both wild-type and C90S UCH L1-transfected cells, suggesting that hydrolase activity was not involved but increased level of mono-ubiquitin might play an important role. The increased currents were dependent on cAMP-dependent protein kinase (PKA) and Ca2+ and calmodulin-dependent protein kinase (CaMKII) but not protein kinase C. In addition, ATP-induced currents were likely to be modified via dopamine and cyclic AMP-regulated phosphoprotein (DARPP-32) that is regulated by PKA and phosphatases. Our finding shows the first evidence that there is a relationship between UCH L1 and neurotransmitter receptor, suggesting that UCH L1 may play an important role in synaptic activity.

Recombinant human serotonin 5A receptors stably expressed in C6 glioma cells couple to multiple signal transduction pathways.

Human serotonin 5A (5-HT5A) receptors were stably expressed in undifferentiated C6 glioma. In 5-HT5A receptors-expressing cells, accumulation of cAMP by forskolin was inhibited by 5-HT as reported previously. Pertussis toxin-sensitive inhibition of ADP-ribosyl cyclase was also observed, indicating a decrease of cyclic ADP ribose, a potential intracellular second messenger mediating ryanodine-sensitive Ca2+ mobilization. On the other hand, 5-HT-induced outward currents were observed using the patch-clamp technique in whole-cell configuration. The 5-HT-induced outward current was observed in 84% of the patched 5-HT5A receptor-expressing cells and was concentration-dependent. The 5-HT-induced current was inhibited when intracellular K+ was replaced with Cs+ but was not significantly inhibited by typical K+ channel blockers. The 5-HT-induced current was significantly attenuated by 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) in the patch pipette. Depleting intracellular Ca2+ stores by application of caffeine or thapsigargin also blocked the 5-HT-induced current. Blocking G protein, the inositol triphosphate (IP3) receptor, or pretreatment with pertussis toxin, all inhibited the 5-HT-induced current. IP3 showed a transient increase after application of 5-HT in 5-HT5A receptor-expressing cells. It was concluded that in addition to the inhibition of cAMP accumulation and ADP-ribosyl cyclase activity, 5-HT5A receptors regulate intracellular Ca2+ mobilization which is probably a result of the IP3-sensitive Ca2+ store. These multiple signal transduction systems may induce complex changes in the serotonergic system in brain function.