Dosimetric impact of MLC positional errors on dose distribution in IMRT.

Optimizing the positional accuracy of multileaf collimators (MLC) for radiotherapy is important for dose accuracy and for reducing doses delivered to normal tissues. This study investigates dose sensitivity variations and complexity metrics of MLC positional error in volumetric modulated arc therapy and determines the acceptable ranges of MLC positional accuracy in several clinical situations. Treatment plans were generated for four treatment sites (prostate cancer, lung cancer, spinal, and brain metastases) using different treatment planning systems (TPSs) and fraction sizes. Each treatment plan introduced 0.25-2.0 mm systematic or random MLC leaf bank errors. The generalized equivalent uniform dose (gEUD) sensitivity and complexity metrics (MU/Gy and plan irregularity) were calculated, and the correlation coefficients were assessed. Furthermore, the required tolerances for MLC positional accuracy control were calculated. The gEUD sensitivity showed the highest dependence of systematic positional error on the treatment site, followed by TPS and fraction size. The gEUD sensitivities were 6.7, 4.5, 2.5, and 1.7%/mm for Monaco and 8.9, 6.2, 3.4, and 2.3%/mm (spinal metastasis, lung cancer, prostate cancer, and brain metastasis, respectively) for RayStation. The gEUD sensitivity was strongly correlated with the complexity metrics (r = 0.88-0.93). The minimum allowable positional error for MLC was 0.63, 0.34, 1.02, and 0.28 mm (prostate, lung, brain, and spinal metastasis, respectively). The acceptable range of MLC positional accuracy depends on the treatment site, and an appropriate tolerance should be set for each treatment site with reference to the complexity metric. It is expected to enable easier and more detailed MLC positional accuracy control than before by reducing dose errors to patients at the treatment planning stage and by controlling MLC quality based on complexity metrics, such as MU/Gy.

Experimental investigation of the effective point of measurement for plane-parallel chambers used in electron beam dosimetry.

In this study, the effective point of measurement (EPOM) for plane-parallel ionization chambers in clinical high-energy electron beams was determined experimentally. Previous studies have reported that the EPOM of plane-parallel chambers is shifted several tens of millimeters downstream from the inner surface of the entrance window to the cavity. These findings were based on the Monte Carlo (MC) simulation, and few experimental studies have been performed. Thus, additional experimental validations of the reported EPOMs were required. In this study, we investigated the EPOMs of three plane-parallel chambers (NACP-02, Roos and Advanced Markus) for clinical electron beams. The EPOMs were determined by comparing the measured percentage depth-dose (PDD) of the plane-parallel chambers and the PDD obtained using the microDiamond detector. The optimal shift to the EPOM was energy-dependent. The determined EPOM showed no chamber-to-chamber variation, thereby allowing the use of a single value. The mean optimal shifts were 0.104 ± 0.011, 0.040 ± 0.012, and 0.012 ± 0.009 cm for NACP-02, Roos, and Advanced Markus, respectively. These values are valid in the R50 range from 2.40 to 8.82 cm, which correspond to 6-22 MeV. Roos and Advanced Markus exhibited similar results to those of the previous studies, but NACP-02 showed a larger shift. This is probably due to the uncertainty of the entrance window of NACP-02. Therefore, it is necessary to carefully consider where the optimal EPOM is located when using this chamber.

Delivery accuracy of VMAT on two beam-matched linacs provided by accelerated go live service.

INTRODUCTION: Dosimetric accuracy is critical when a patient treated with volumetric modulated arc therapy (VMAT) is transferred to another beam-matched linac. To evaluate the performance of Accelerated Go Live (AGL) service, the measured beam characteristics and patient specific quality assurance (QA) results between two AGL-matched linacs were compared. MATERIALS AND METHODS: Two VersaHD linacs were installed using the AGL service. After the installation, the beam data such as percentage depth dose (PDD), lateral profiles and output factors for all photon beams were measured. Relative doses were also measured as a function of the multi-leaf collimator (MLC) leaf gap width. Subsequently, VMAT plans were created for prostate, pelvis, head and neck, liver, lung cancers and multiple brain metastases. Dose distributions and point doses were measured by multi-dimensional detectors and ionization chambers for patient specific quality assurance, and comparisons were made between the two linacs. RESULTS: Dose differences in PDDs were all within ± 1% except the entrance region, and the averaged gamma indices of the lateral profiles were within 0.3. The differences in doses as a function of the MLC leaf gap width between the two linacs were within ±0.5%. For all the plans, gamma passing rates were all higher than 95% with criteria of 2%/2 mm. The average and the SD of dose differences on the multi-dimensional detector between both measurements was 0.06 ± 2.12%, and the average of point dose differences was -0.03 ± 0.33%. CONCLUSION: We have evaluated the AGL performance in the context of beam characteristics and patient specific QA. It was demonstrated that the AGL service provides an accurate VMAT treatment reproducibility for many tumor sites with gamma pass rates greater than 95% under criteria of 2%/2 mm.

Mini Nutritional Assessment Short-Form as screening tool for osteoporosis in patients with chronic obstructive pulmonary disease.

BACKGROUND AND OBJECTIVES: Osteoporosis is a common complication of chronic obstructive pulmonary dis-ease (COPD). It is impractical to measure bone mineral density (BMD) in all patients with COPD. This study aimed to investigate the relationship between Mini Nutritional Assessment Short-Form (MNA-SF), a simple nutritional status questionnaire, and osteoporosis, and to determine whether it can be used as a reliable screening tool for osteoporosis in patients with COPD. METHODS AND STUDY DESIGN: Thirty-seven patients with stable COPD were enrolled in this prospective cohort study. Patients with MNA-SF scores >11 were defined as well-nourished, and those with scores of ≤11 being at risk for malnutrition. Body composition, BMD, and undercarboxylated osteocalcin (ucOC), a bone metabolism marker, were measured using bioelectrical impedance, dual energy X-ray, and electrochemiluminescence immunoassay, respectively. RESULTS: Seventeen (45.9%) were classified as at risk for malnutrition, and 13 (35.1%) had osteoporosis. Patients at risk for malnutrition had significantly more osteoporosis and higher ucOC values than well-nourished patients (p=0.007, p=0.030, respectively). Patients with osteoporosis also had significantly lower body mass index (BMI) and fat-free mass index than those without osteoporosis (p= 0.007 and p=0.005, respectively), although FEV1 % pred was not significantly different. MNA-SF (cutoff value; 11) had better sensitivity to identify the presence of osteoporosis than BMI (cutoff value; 18.5 kg/m2) (sensitivity, 0.769; specificity, 0.708; sensitivity, 0.462; specificity, 0.875, respectively). CONCLUSIONS: MNA-SF was associated with osteoporosis and bone metabolism markers in patients with COPD. MNA-SF may be a useful screening tool for osteoporo-sis in patients with COPD.

The efficacy and safety of additional treatment with short-acting muscarinic antagonist combined with long-acting beta-2 agonist in stable patients with chronic obstructive pulmonary disease: A systematic review and meta-analysis.

BACKGROUND: The rationale for additional treatment with short-acting bronchodilators combined with long-acting bronchodilators for patients with chronic obstructive pulmonary disease (COPD) is not adequately studied. METHODS: We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of a short-acting muscarinic antagonist (SAMA) therapy combined with a long-acting beta-2 agonist (LABA) in patients with stable COPD. Pulmonary function, dyspnea, health-related quality of life, exercise tolerance, physical activity, exacerbations of COPD, and adverse events during regular use were set as outcomes of interest. RESULTS: We included five controlled trials including two sets of publicly available online data without article publications for the meta-analysis. Additional use of SAMA plus LABA showed a significant improvement in the peak response in FEV1 (mean difference (MD) 98.70 mL, p < .00001), transitional dyspnea index score (MD .85, p = .02), and St George's Respiratory Questionnaire score (MD -2.00, p = .008) compared to LABA treatment. There was no significant difference in the risk of exacerbation of COPD (p = .20) and only a slight trend of increased severe adverse events (OR: 2.16, p = .08) and cardiovascular events (OR: 2.38, p = .06). CONCLUSION: Additional treatment with SAMA combined with LABA could be a feasible choice due to its efficacy and safety.

Potential patient screening for late-onset Pompe disease in suspected sleep apnea: a rationale and study design for a Prospective Multicenter Observational Cohort Study in Japan (PSSAP-J Study).

BACKGROUND: Pompe disease is an autosomal recessive disorder caused by deficiency of the acid α-glucosidase (GAA) enzyme. GAA deficiency induces progressive glycogen accumulation which leads to weakness of the respiratory muscle including the diaphragm. Pompe disease is one of the few myopathies, for which an established therapy is available. Thus, earlier detection of potential late-onset Pompe disease (LOPD) and earlier intervention would have a significant clinical impact. PURPOSE: Our hypothesis is that sleep problems including sleep disordered breathing (SDB) and clinical symptoms may indicate an early stage of LOPD since decreased respiratory muscle activity generally first presents during sleep. Thus, the aims of this prospective, multicenter observational cohort study in Japan (PSSAP-J) are to demonstrate a higher prevalence of LOPD in a sleep lab-based population (primary outcome), and to identify predictive factors for LOPD from findings in diagnostic polysomnography (PSG) and clinical symptoms (secondary outcomes). METHODS: The study design is a prospective multicenter observational cohort study. Consecutive patients who present to sleep labs due to suspected SDB for an overnight PSG will be enrolled. All patients will be measured for creatine kinase, GAA activity, and if necessary, genetic analysis of GAA. Furthermore, chest X-ray, pulmonary function test, and arterial blood gas analysis will be collected. Then, prevalence and specific findings of LOPD will be assessed. RESULT: Congenital myopathy shows a shift from slow-deep to rapid-shallow breathing during transition from wakefulness to sleep accompanying a symptom of waking with gasping (actual further results are pending). DISCUSSION: The distribution in respiratory physiology between during wakefulness and sleep specific to LOPD may provide insights into early-stage detection. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000039191, UMIN Clinical Trials Registry ( http://www.umin.ac.jp/ctr ).

Relationship Between Intermittent Hypoxia and Type 2 Diabetes in Sleep Apnea Syndrome.

Sleep apnea syndrome (SAS) is a very common disease involving intermittent hypoxia (IH), recurrent symptoms of deoxygenation during sleep, strong daytime sleepiness, and significant loss of quality of life. A number of epidemiological researches have shown that SAS is an important risk factor for insulin resistance and type 2 diabetes mellitus (DM), which is associated with SAS regardless of age, gender, or body habitus. IH, hallmark of SAS, plays an important role in the pathogenesis of SAS and experimental studies with animal and cellular models indicate that IH leads to attenuation of glucose-induced insulin secretion from pancreatic ß cells and to enhancement of insulin resistance in peripheral tissues and cells, such as liver (hepatocytes), adipose tissue (adipocytes), and skeletal muscles (myocytes). In this review, we focus on IH-induced dysfunction in glucose metabolism and its underlying molecular mechanisms in several cells and tissues related to glucose homeostasis.

[Efficient Commissioning of the Radiotherapy Treatment Planning System with the Golden Beam Data].

Commissioning of a linear accelerator (Linac) and treatment planning systems (RTPs) for clinical use is complex and time-consuming, typically 3-4 months in total. However, based on clinical needs and economics, hospitals desire early clinical starts for patients, and various studies have been conducted for shortening the preparation period. One of the methods to shorten the period is using golden beam data (GBD). The purpose of this study was to shorten the commissioning period without reducing accuracy and to simplify commissioning works while improving safety. We conducted commissioning of the RTPs before installing the Linac using GBD, and carried out verification immediately after the acceptance test. We used TrueBeam STx (Varian Medical Systems) and Eclipse (ver. 13.7, Varian Medical Systems) for RTPs and anisotropic analysis algorithm (AAA) and AcurosXB (AXB) for calculation algorithms. The difference between GBD and the measured beam data was 0.0 ± 0.2% [percentage depth dose (PDDs) ] and -0.1 ± 0.2% (Profiles) with X-ray, and -1.2 ± 1.3% (PDDs) with electrons. The difference between the calculated dose and the measured dose was 0.1 ± 0.3% (AAA) and 0.0 ± 0.3% (AXB) under homogeneous conditions, and 0.7 ± 1.4% (AAA) and 0.6 ± 1.1% (AXB) under heterogeneous conditions. We took 43 days from the end of the acceptance test to the start of clinical use. We found that the preparation period for clinical use can be shortened without reducing the accuracy, by thinning out the number of measurement items using GBD.

The effects of arousal accompanying an apneic event on blood pressure and sympathetic nerve activity in severe obstructive sleep apnea.

PURPOSE: Arousal plays an important protective role against life-threatening events by terminating the apneic events. However, arousal might also be considered as a contributor to obstructive sleep apnea (OSA) pathogenesis since ventilatory overshoot due to arousal leads to irregular breathing. Patients with OSA who have greater upper airway compensation, expressed by relatively high proportion of apneic events without arousal, could have less adverse events or consequences. Thus, our hypothesis was that the proportion of apneic events with or without arousal affects daytime systemic blood pressure and nocturnal sympathetic activity. METHODS: Subjects were consecutive 97 patients who had diagnostic polysomnography (PSG) and showed severe OSA (apnea-hypopnea index ≥ 30). The proportion of apnea-hypopneas with arousal among all apnea-hypopneas was calculated in each patient. Then, the association among the proportion of arousal accompanying apnea-hypopneas and a diagnosis of hypertension or heart rate variability during the PSG were investigated. RESULTS: The proportion of apnea-hypopneas with arousal among all apnea-hypopneas was higher in hypertensive patients (n = 47) than that in normotensive patients (n = 50) (mean ± standard deviation; 80.0 ± 12.8% vs. 73.7 ± 13.0%, p < 0.01). However, heart rate variability was not associated with the proportion of apnea-hypopneas with arousal. CONCLUSIONS: Apnea-hypopneas terminated by arousal are more often present in those with current systemic hypertension but independent of sympathetic nerve activity, compared with those whose apnea-hypopnea events do not have as many arousals. One could target an elevation in arousal threshold as a pathway for reducing daytime blood pressure.

Density scaling of phantom materials for a 3D dose verification system.

In this study, the optimum density scaling factors of phantom materials for a commercially available three-dimensional (3D) dose verification system (Delta4) were investigated in order to improve the accuracy of the calculated dose distributions in the phantom materials. At field sizes of 10 × 10 and 5 × 5 cm2 with the same geometry, tissue-phantom ratios (TPRs) in water, polymethyl methacrylate (PMMA), and Plastic Water Diagnostic Therapy (PWDT) were measured, and TPRs in various density scaling factors of water were calculated by Monte Carlo simulation, Adaptive Convolve (AdC, Pinnacle3 ), Collapsed Cone Convolution (CCC, RayStation), and AcurosXB (AXB, Eclipse). Effective linear attenuation coefficients (µeff ) were obtained from the TPRs. The ratios of µeff in phantom and water ((µeff )pl,water ) were compared between the measurements and calculations. For each phantom material, the density scaling factor proposed in this study (DSF) was set to be the value providing a match between the calculated and measured (µeff )pl,water . The optimum density scaling factor was verified through the comparison of the dose distributions measured by Delta4 and calculated with three different density scaling factors: the nominal physical density (PD), nominal relative electron density (ED), and DSF. Three plans were used for the verifications: a static field of 10 × 10 cm2 and two intensity modulated radiation therapy (IMRT) treatment plans. DSF were determined to be 1.13 for PMMA and 0.98 for PWDT. DSF for PMMA showed good agreement for AdC and CCC with 6 MV x ray, and AdC for 10 MV x ray. DSF for PWDT showed good agreement regardless of the dose calculation algorithms and x-ray energy. DSF can be considered one of the references for the density scaling factor of Delta4 phantom materials and may help improve the accuracy of the IMRT dose verification using Delta4.

Variability of breathing during wakefulness while using CPAP predicts adherence.

BACKGROUND AND OBJECTIVE: The standard therapy for obstructive sleep apnoea (OSA) is continuous positive airway pressure (CPAP) therapy. However, long-term adherence remains at ~50% despite improvements in behavioural and educational interventions. Based on prior work, we explored whether regularity of breathing during wakefulness might be a physiologic predictor of CPAP adherence. METHODS: Of the 117 consecutive patients who were diagnosed with OSA and prescribed CPAP, 79 CPAP naïve patients were enrolled in this prospective study. During CPAP initiation, respiratory signals were collected using respiratory inductance plethysmography while wearing CPAP during wakefulness in a seated position. Breathing regularity was assessed by the coefficient of variation (CV) for breath-by-breath estimated tidal volume (VT ) and total duration of respiratory cycle (Ttot). In a derivation group (n = 36), we determined the cut-off CV value which predicted poor CPAP adherence at the first month of therapy, and verified the validity of this predetermined cut-off value in the remaining participants (validation group; n = 43). RESULTS: In the derivation group, the CV for estimated VT was significantly higher in patients with poor adherence than with good adherence (median (interquartile range): 44.2 (33.4-57.4) vs 26.0 (20.4-33.2), P < 0.001). The CV cut-off value for estimated VT for poor CPAP adherence was 34.0, according to a receiver-operating characteristic (ROC) curve. In the validation group, the CV value for estimated VT >34.0 confirmed to be predicting poor CPAP adherence (sensitivity, 0.78; specificity, 0.83). CONCLUSION: At the initiation of therapy, breathing regularity during wakefulness while wearing CPAP is an objective predictor of short-term CPAP adherence.

Hypersialylation is a common feature of neurofibrillary tangles and granulovacuolar degenerations in Alzheimer's disease and tauopathy brains.

Glycosylation is one of the major post-translational modifications of proteins. The status of sialylation of the neuropathological hallmarks of various neurodegenerative disorders was investigated in this study. Here, we report the novel findings that two phosphorylated tau (p-tau)-containing structures associated with Alzheimer's disease (AD), that is, neurofibrillary tangles (NFTs) and granulovacuolar degenerations (GVDs), were hypersialylated. The NFTs, GVDs and dystrophic neurites of senile plaques (SPs) in AD hippocampi were clearly visualized by immunohistochemistry using an anti-sialic acid (SA) antibody. In contrast, the amyloid core of SPs was not sialylated at all. Interestingly, other p-tau-containing structures, that is, globose-type NFTs in progressive supranuclear palsy and Pick bodies and ballooned neurons in frontotemporal lobar degeneration with Pick bodies, were also hypersialylated. Unlike the p-tau-containing structures observed in tauopathies, the hallmarks of other neurodegenerative disorders, such as Lewy bodies in Parkinson's disease, glial cytoplasmic inclusions in multiple system atrophy, Bunina bodies, skein-like inclusions and round inclusions in amyotrophic lateral sclerosis, intranuclear inclusions in neuronal intranuclear inclusion disease and physiological bodies or granules (lipofuscin granules, corpora amylacea and melanin granules), were not immunolabeled by the anti-SA antibody. Because this antibody specifically identified NFTs and GVDs, immunostaining for sialylation represents a useful tool to screen these structures in a diagnostic setting. These results clearly indicate that the pathological hallmarks of various tauopathies are commonly hypersialylated, and that sialylation plays an important role in the process of p-tau accumulation in AD and other tauopathies.

An autopsy case of familial amyotrophic lateral sclerosis with a TARDBP Q343R mutation.

We describe a Japanese autopsy case of familial amyotrophic lateral sclerosis (FALS) with a TARDBP Q343R mutation. This male patient developed dysarthria at the age of 52 years, and bulbar symptoms progressed, with weakness and atrophy in the extremities. His mental status was normal, but he became bedridden, received artificial respiratory support at 54 years of age, and gradually acquired a locked-in state and died at 58 years of age. Microscopically, marked diffuse myelin pallor was observed in the anterolateral columns of the spinal cord. The remaining anterior horn cells contained Bunina bodies and phosphorylation-dependent transactivation response DNA-binding protein of 43 kDa (pTDP-43)-positive neuronal cytoplasmic inclusions (NCIs). Glial cytoplasmic inclusions (GCIs) were also observed. The number of ubiquitin- and p62-positive inclusions was markedly lower than that of pTDP-43-positive inclusions. NCIs and many fine dot-like pTDP-43-positive granules in the neuropil were mainly seen in the temporal and motor cortices, and striatum. NCIs were rare in hippocampal granular cells. Immunoblotting of samples from the cerebral cortex using an anti-pTDP-43 antibody was slightly different from previous TDP-43 pathological subtypes.

Evaluation of patient DVH-based QA metrics for prostate VMAT: correlation between accuracy of estimated 3D patient dose and magnitude of MLC misalignment.

The purpose of this study was to evaluate the accuracy of commercially available software, using patient DVH-based QA metrics, by investigating the correlation between estimated 3D patient dose and magnitude of MLC misalignments. We tested 3DVH software with an ArcCHECK. Two different calculating modes of ArcCHECK Planned Dose Perturbation (ACPDP) were used: "Normal Sensitivity" and "High Sensitivity". Ten prostate cancer patients treated with hypofractionated VMAT (67.6 Gy/26 Fr) in our hospital were studied. For the baseline plan, we induced MLC errors (-0.75, -0.5, -0.25, 0.25, 0.5, and 0.75 mm for each single bank). We calculated the dose differences between the ACPDP dose with error and TPS dose with error using gamma passing rates and using DVH-based QA metrics. The correlations between dose estimation error and MLC position error varied with each structure and metric. A comparison using 1%/1 mm gamma index showed that the larger was the MLC error-induced, the worse were the gamma passing rates. Slopes of linear fit to dose estimation error versus MLC position error for mean dose and D95 to the PTV were 1.76 and 1.40% mm-1, respectively, for "Normal Sensitivity", and -0.53 and -0.88% mm-1, respectively, for "High Sensitivity", showing better accuracy for "High Sensitivity" than "Normal Sensitivity". On the other hand, the slopes for mean dose to the rectum and bladder, V35 to the rectum and bladder and V55 to the rectum and bladder, were -1.00, -0.55, -2.56, -1.25, -3.53, and -1.85%mm-1, respectively, for "Normal Sensitivity", and -2.89, -2.39, -4.54, -3.12, -6.24, and -4.11% mm-1, respectively, for "High Sensitivity", showing significant better accuracy for "Normal Sensitivity" than "High Sensitivity". Our results showed that 3DVH had some residual error for both sensitivities. Furthermore, we found that "Normal Sensitivity" might have better accuracy for the DVH metric for the PTV and that "High Sensitivity" might have better accuracy for DVH metrics for the rectum and bladder. We must be willing to tolerate this residual error in clinical care.

Mini Nutritional Assessment Short-Form predicts exacerbation frequency in patients with chronic obstructive pulmonary disease.

BACKGROUND AND OBJECTIVE: Exacerbations of chronic obstructive pulmonary disease (COPD) are a major cause of morbidity, mortality and reduced health status. Thus, to predict and prevent exacerbations is essential for the management of COPD. The aims of this study were to determine whether nutritional status as assessed by the Mini Nutritional Assessment Short-Form (MNA-SF) predicts COPD exacerbation and to compare the ability of the MNA-SF to predict COPD exacerbation with that of the COPD Assessment Test (CAT). METHODS: Pulmonary function, the modified Medical Research Council (mMRC) scale and body mass index (BMI) were evaluated in 60 stable patients with COPD (mean age, 72 years; mean forced expiratory volume in 1 s (FEV1 ), 51.1% predicted). The MNA-SF and CAT were also completed. Exacerbations were recorded prospectively for 1 year after the initial assessment. RESULTS: The mean MNA-SF score was 11.4 ± 2.4 (well nourished, 51%; at risk, 37%; and malnourished, 12%). The mean CAT score was 14.4 ± 7.5 (low impact, 37%; medium impact, 38%; high impact, 20%; and very high impact, 5%). The CAT scores were significantly associated with the mMRC scale and %FEV1, but were not associated with BMI and the MNA-SF score. The exacerbation frequency was associated with the MNA-SF score but not with the CAT score. CONCLUSIONS: The MNA-SF predicts COPD exacerbation independently of the CAT.

Distribution of bone mineral content is associated with body weight and exercise capacity in patients with chronic obstructive pulmonary disease.

BACKGROUND: Although low bone mineral density is highly prevalent in patients with chronic obstructive pulmonary disease (COPD), the distribution of the reduced bone mass has not been fully elucidated. OBJECTIVES: To determine regional bone mass loss in patients with COPD and investigate whether the change in distribution may be associated with body weight loss and functional capacity. METHODS: Body mass index (BMI) was assessed, and height squared indices were derived for the bone mineral content index (BMCI) of the arms, legs and trunk by dual-energy X-ray absorptiometry in 45 male patients with COPD and 12 age- and sex-matched control subjects. Pulmonary function tests were performed, and maximal oxygen uptake (VO2max) was measured. RESULTS: The BMCI was lower in the total bone, legs and trunk of patients with COPD than in control subjects, although the BMCI in the arms was similar between the groups. BMI correlated significantly with the BMCI in all 3 segments. Bone mineral content (BMC) in the trunk, expressed as a percentage of total BMC (BMC trunk/total BMC), correlated significantly with BMI. The BMCI in the trunk was closely related with VO2max but not with airflow limitation. CONCLUSIONS: There was a regional difference in BMC reduction, but a predominant reduction of bone mass in the trunk was not associated with the severity of airflow limitation but rather with body weight loss and exercise intolerance. These data suggest that body weight loss and exercise intolerance are important risk factors for vertebral fracture in patients with COPD.

The impact of obstructive sleep apnea and nasal CPAP on circulating adiponectin levels.

PURPOSE: Although obstructive sleep apnea syndrome (OSAS) is known to be an important risk factor for cardiovascular diseases, the mechanism behind this association has not been fully elucidated. Transendothelial migration of monocytes mediated by adhesion molecules is a crucial step in the pathogenesis of atherosclerosis. We investigated the effect of hypoxic stress on plasma adiponectin and tumor necrosis factor-α (TNF-α) levels and whether adiponectin and TNF-α modulate adhesion molecules in patients with OSAS. METHODS: In 22 patients, plasma adiponectin and TNF-α levels and serum concentrations of soluble intercellular adhesion molecule-1 (sICAM-1) were determined early in the morning after polysomnography and after nasal continuous positive airway pressure (nCPAP) treatment. RESULTS: Plasma adiponectin levels were inversely correlated with the apnea-hypopnea index (AHI) (r = -0.582, p < 0.005) and % time in SpO2 <90 % (r = -0.539, p < 0.01) but not with the body mass index (BMI). TNF-α levels were positively correlated with the AHI (r = 0.462, p < 0.05) and BMI (r = 0.452, p < 0.05). Serum sICAM-1 levels were inversely correlated with plasma adiponectin levels (r = -0.476, p < 0.05) but not with TNF-α levels. Although plasma TNF-α levels decreased after overnight nCPAP treatment (p < 0.05), plasma adiponectin levels increased after long-term nCPAP (3 months) treatment (p < 0.02) in ten patients. CONCLUSIONS: Our findings suggest that reduced adiponectin and elevated TNF-α levels in plasma are associated with OSAS-induced hypoxic stress. Decreased adiponectin levels are associated with sICAM-1 levels.

Effects of environment light during sleep on autonomic functions of heart rate and breathing.

PURPOSE: Poor sleep hygiene including sleeping in the daytime or with the lights on at night is discovered during the assessment of many sleep disorders including sleep apnea. The aim of this study was to investigate whether environmental light affected autonomic control of heart rate, sleep-disordered breathing (SDB), and/or breathing patterning. METHODS: Seventeen non-obese healthy volunteers without witnessed snoring and apneas were recruited. Studies were performed at home using a type 3 portable monitor combined with actigraphy for sleep-wake timing, using a randomly assigned, crossover between dark, or 1,000 lx of fluorescent lighting environment. The outcomes were low-frequency power divided by high-frequency power (LF/HF ratio) in the analysis of heart rate variability, the apnea-hypopnea index (AHI), and ventilatory pattern variability before and after sleep onset between environments. RESULTS: The LF/HF ratio and AHI were both significantly higher in light as compared to dark. Before sleep onset, the coefficient of variation (CV) for breath-to-breath tidal volume representing breathing irregularity tended to be higher in light than in dark environment. The CV values for tidal volume after sleep onset were significantly decreased compared with before sleep onset in both sleep environments. Mutual information of the ventilatory pattern was significantly lower before sleep onset than after sleep onset, only in the light environment. CONCLUSIONS: Sleeping in the light has effects like that of a stressor as it is associated with neuroexcitation, SDB, and resting breathing irregularity in healthy volunteers. These findings may be relevant to many sleep disorders associated with poor sleep hygiene.

Cytoplasmic TDP-43 accumulation in cells of the adrenal medulla in individuals with or without amyotrophic lateral sclerosis.

The transactive response DNA-binding protein of 43 kDa (TDP-43) is normally located predominantly in the nucleus, whereas pathological TDP-43 is mostly found in the cytoplasm. Cytoplasmic TDP-43 accumulation has not yet been reported in normal general organs. In our preliminary study, paraffin sections of the general organs of individuals with or without amyotrophic lateral sclerosis (ALS) were immunostained with antibodies against TDP-43 and phosphorylated TDP-43 (pTDP-43). Diffuse and granular immunostaining pattern of TDP-43 and pTDP-43 were observed frequently in the cytoplasm of renal tubular cells, and less frequently in the cells of several organs; however, the majority of these immunoreactivities were nonspecific biotin reactions. Conversely, many TDP-43-positive and pTDP-43-negative cytoplasmic accumulations were observed in the adrenal medulla in every individual (with or without ALS). Skein-like or round inclusions were not observed. The cells in the adrenal medulla were well preserved, and the cytoplasmic TDP-43 accumulations were frequent in the cells of all routine autopsy cases without loss of nuclear TDP-43 immunostaining; therefore, we considered that this was a physiological phenomenon. This is the first study that demonstrated the cytoplasmic accumulation of TDP-43 in routinely autopsied cases.

Assessment and management of continuous positive airway pressure therapy in patient with obstructive sleep apnea.

Obstructive sleep apnea (OSA) causes excessive daytime sleepiness, impaired daytime functioning, and an increased risk of cardiovascular diseases. Continuous positive airway pressure (CPAP) is a highly effective therapy for moderate to severe OSA. Although CPAP adherence is commonly assessed using a 4-hthreshold, determining the optimal usage time based on clinical outcomes is crucial. While subjective sleepiness often improves with ≥4 h of CPAP usage, an extended duration (≥6 h) may be necessary to impact objective sleepiness. CPAP demonstrated a modest yet clinically meaningful dose-dependent effect on lowering blood pressure. For patients seeking antihypertensive benefits from CPAP therapy, the goal should extend beyond 4 h of use to maximize the therapeutic impact. Recognizing individual variations in sleep duration and responses to CPAP therapy is essential. The adoption of 'individualized goals for CPAP use,' outlining target times for specific outcomes, should also consider an individual's total sleep duration, including periods without CPAP. The impact of CPAP on clinical outcomes may vary, even with the same duration of CPAP use, depending on the period without CPAP use, particularly during the first or second half of sleep. Patients who remove or initiate CPAP midway or have a low CPAP usage frequency may require different forms of guidance. Tailoring patient education to address CPAP usage patterns may be necessary to enhanced satisfaction, self-efficacy, and adherence to therapy. Management of CPAP treatment should be personalized to meet individual needs and adapted based on specific response patterns for achieving treatment efficacy.