Feasibility study of multimodal imaging for redox status and glucose metabolism in tumor.

Understanding the tumor redox status is important for efficient cancer treatment. Here, we noninvasively detected changes in the redox environment of tumors before and after cancer treatment in the same individuals using a novel compact and portable electron paramagnetic resonance imaging (EPRI) device and compared the results with glycolytic information obtained through autoradiography using 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG). Human colon cancer HCT116 xenografts were used in the mice. We used 3-carbamoyl-PROXYL (3CP) as a paramagnetic and redox status probe for the EPRI of tumors. The first EPRI was followed by the intraperitoneal administration of buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis, or X-ray irradiation of the tumor. A second EPRI was performed on the following day. Autoradiography was performed after the second EPRI. After imaging, the tumor sections were evaluated by histological analysis and the amount of reducing substances in the tumor was measured. BSO treatment and X-ray irradiation significantly decreased the rate of 3CP reduction in tumors. Redox maps of tumors obtained from EPRI can be compared with tissue sections of approximately the same cross section. BSO treatment reduced glutathione levels in tumors, whereas X-ray irradiation did not alter the levels of any of the reducing substances. Comparison of the redox map with the autoradiography of [18F]FDG revealed that regions with high reducing power in the tumor were active in glucose metabolism; however, this correlation disappeared after X-ray irradiation. These results suggest that the novel compact and portable EPRI device is suitable for multimodal imaging, which can be used to study tumor redox status and therapeutic efficacy in cancer, and for combined analysis with other imaging modalities.

Comprehensive Analysis of a Japanese Pedigree with Biallelic ACAGG Expansions in RFC1 Manifesting Motor Neuronopathy with Painful Muscle Cramps.

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is an autosomal recessive multisystem neurologic disorder caused by biallelic intronic repeats in RFC1. Although the phenotype of CANVAS has been expanding via diagnostic case accumulation, there are scant pedigree analyses to reveal disease penetrance, intergenerational fluctuations in repeat length, or clinical phenomena (including heterozygous carriers). We identified biallelic RFC1 ACAGG expansions of 1000 ~ repeats in three affected siblings having sensorimotor neuronopathy with spinocerebellar atrophy initially presenting with painful muscle cramps and paroxysmal dry cough. They exhibit almost homogeneous clinical and histopathological features, indicating motor neuronopathy. Over 10 years of follow-up, painful intractable muscle cramps ascended from legs to trunks and hands, followed by amyotrophy and subsequent leg pyramidal signs. The disease course combined with the electrophysical and imagery data suggest initial and prolonged hyperexcitability and the ensuing spinal motor neuron loss, which may progress from the lumbar to the rostral anterior horns and later expand to the corticospinal tract. Genetically, heterozygous ACAGG expansions of similar length were transmitted in unaffected family members of three successive generations, and some of them experienced muscle cramps. Leukocyte telomere length assays revealed comparatively shorter telomeres in affected individuals. This comprehensive pedigree analysis demonstrated a non-anticipating ACAGG transmission and high penetrance of manifestations with a biallelic state, especially motor neuronopathy in which muscle cramps serve as a prodromal and disease progress marker. CANVAS and RFC1 spectrum disorder should be considered when diagnosing lower dominant motor neuron disease, idiopathic muscle cramps, or neuromuscular hyperexcitability syndromes.

Large-Scale Moth-Eye-Structured Roll Mold Fabrication Using Sputtered Glassy Carbon Layer and Transferred Moth-Eye Film Characterization.

Currently, there is high demand for the development of a highly mass-producible technology for manufacturing moth-eye-structured films with an antireflection function. Conventional moth-eye-structured films have been produced by roll-to-roll (RTR) ultraviolet nanoimprint lithography (UV-NIL) using porous alumina, but the process of manufacturing the roll mold with aluminum is both complicated and time-consuming. To solve this problem, we proposed a sputtering process for forming a thin film of glassy carbon on a roll substrate and fabricated a moth-eye structure through the irradiation of oxygen plasma. A glassy carbon (GC) moth-eye-structure roll mold with a uniform reflectance of less than 0.1% over a length of 1560 mm was fabricated following this method. In addition, a superhydrophobic moth-eye-structured film was produced by RTR UV-NIL using the proposed roll mold, which exhibited a reflectance of 0.1%. In this study, a moth-eye-structure roll using porous alumina was compared with a film transferred from it. The GC moth-eye-structure roll mold was found to be superior in terms of antireflection, water repellency, and productivity. When the proposed large-area GC moth-eye-structured film was applied to window glass, significant anti-reflection and water-repellent functionalities were obtained.

Electron Paramagnetic Resonance Implemented with Multiple Harmonic Detections Successfully Maps Extracellular pH In Vivo.

Extracellular acidification indicates a metabolic shift in cancer cells and is, along with tissue hypoxia, a hallmark of tumor malignancy. Thus, non-invasive mapping of extracellular pH (pHe) is essential for researchers to understand the tumor microenvironment and to monitor tumor response to metabolism-targeting drugs. While electron paramagnetic resonance (EPR) has been successfully used to map pHe in mouse xenograft models, this method is not sensitive enough to map pHe with a moderate amount of exogenous pH-sensitive probes. Here, we show that a modified EPR system achieves twofold higher sensitivity by using the multiple harmonic detection (MHD) method and improves the robustness of pHe mapping in mouse xenograft models. Our results demonstrate that treatment of a mouse xenograft model of human-derived pancreatic ductal adenocarcinoma cells with the carbonic anhydrase IX (CAIX) inhibitor U-104 delays tumor growth with a concurrent tendency toward further extracellular acidification. We anticipate that EPR-based pHe mapping can be expanded to monitor the response of other metabolism-targeting drugs. Furthermore, pHe monitoring can also be used for the development of improved metabolism-targeting cancer treatments.

Endothelial ganglioside GM3 regulates angiogenesis in solid tumors.

Cancer cells require oxygen and nutrients for growth, making angiogenesis one of the essential components of tumor growth. Gangliosides, constituting membrane lipid rafts, regulate intracellular signal transduction and are involved in the malignancy of cancer cells. While endothelial cells, as well as cancer cells, express vast amounts of gangliosides, the precise function of endothelial gangliosides in angiogenesis remains unclear. In this study, we focused on gangliosides of vascular endothelial cells and analyzed their functions on tumor angiogenesis. In human breast cancer, GM3 synthase was highly expressed in vascular endothelial cells as well as immune cells. Angiogenesis increased in GM3S-KO mice. In BAEC, RNA interference of GM3S showed increased cellular invasion and oxidative stress tolerance through activation of ERK. In the breast cancer model, GM3-KO mice showed an increase in tumor growth and angiogenesis. These results suggest that the endothelial ganglioside GM3 regulates tumor angiogenesis by suppressing cellular invasion and oxidative stress tolerance in endothelial cells.

Association with Ambient Air Pollutants and School Absence Due to Sickness in Schoolchildren: A Case-Crossover Study in a Provincial Town of Japan.

The effect of ambient air pollutants and Asian dust (AD) on absence from school due to sickness has not been well researched. By conducting a case-crossover study, this study investigated the influence of ambient air pollutants and desert sand dust particles from East Asia on absence from school due to sickness. From November 2016 to July 2018, the daily cases of absence due to sickness were recorded in five elementary schools in Matsue, Japan. During the study period, a total of 16,915 absence cases were recorded, which included 4865 fever cases and 2458 cough cases. The relative risk of overall absence in a 10-µg/m3 increment of PM2.5 and a 0.1-km-1 of desert sand dust particles from East Asia were found with 1.28 (95%CI: 1.15-1.42) and 2.15 (1.04-4.45) at lag0, respectively. The significant influence of PM2.5 persisted at lag5 and that of desert sand dust particles at lag2. NO2 had statistically significant effects at lag2, lag3, and lag4. However, there was no evidence of a positive association of Ox and SO2 with absence from school. These results suggested that PM2.5, NO2, and AD increased the risk of absence due to sickness in schoolchildren.

Lipid-soluble polyphenols from sweet potato exert antitumor activity and enhance chemosensitivity in breast cancer.

Polyphenols are abundant in vegetables and fruit. They have been shown to have various antitumor, antioxidant, and anti-inflammatory effects. Here, we extracted the lipid-soluble fraction of polyphenols from fermented sweet potato (Ipomoea batatas). These lipid-soluble polyphenols mainly contained caffeic acid derivatives with strong antioxidant ability, which we hypothesized to affect diseases for which oxidative stress is a factor, such as cancer. We therefore investigated the antitumor and chemo-sensitizing effects of lipid-soluble polyphenols on E0771 murine breast cancer cells. The lipid-soluble polyphenols accumulated in the cells' cytoplasm due to its high lipophilicity, and reduced reactive oxygen species through its strong antioxidant activity. The lipid-soluble polyphenols also arrested the cell cycle at G0/G1 by suppressing Akt activity, and enhanced the cytotoxicity of anticancer agents. In this model, lipid-soluble polyphenols inhibited tumor growth and enhanced the efficacy of chemotherapy drugs. These results suggest the potential of lipid-soluble polyphenols as a functional food to support cancer therapy.

Ent-kaurane-type diterpenoids from Isodonis Herba activate human hair follicle dermal papilla cells proliferation via the Akt/GSK-3ß/ß-catenin transduction pathway.

A methanol extract from Isodonis Herba demonstrated significant proliferative effect on human hair follicle dermal papilla cells (HFDPC, % of control: 150.0 ± 2.0% at 20 µg/mL, p < 0.01). From the extract, 14 ent-kaurane-type diterpenoids (1-14), two abietane-type diterpenoids (15 and 16) and four triterpenoids (17-20) were isolated. Among the isolates, enmein (1, 160.9 ± 3.0% at 20 µM, p < 0.01), isodocarpin (2, 169.3 ± 4.9% at 5 µM, p < 0.01), nodosin (4, 160.5 ± 12.4% at 20 µM, p < 0.01), and oridonin (8, 165.4 ± 10.6% at 10 µM, p < 0.01) showed the proliferative effects. The principal component enmein (1) activated the expression of vascular endothelial growth factor (VEGF) mRNA, upregulated the production of VEGF and increased levels of phospho-Akt, phospho-GSK-3ß, and ß-catenin accumulation in HFDPC, which could be the mechanism of these activate proliferation activity.

Rapid Treatment of Acute Ischemic Stroke Using a Computed Tomography-Based Reperfusion Protocol: The Reality of a Local Community Hospital with Limited Resources.

Objective: In patients with acute ischemic stroke (AIS), prognosis strongly depends on the onset-to-recanalization time. The Ishinomaki protocol for rapid recanalization has been used since October 2017. This protocol determines the indication for reperfusion therapy based on computed tomography (CT)/three-dimensional CT angiography (3DCTA) findings and intends to reduce the onset-to-recanalization time. We aimed to compare the outcomes before and after protocol introduction. Methods: Our hospital is the only thrombectomy-capable center in Ishinomaki, Tome, and Kesennuma medical area. Before protocol introduction (April 2014-June 2016), both CT and magnetic resonance imaging were performed to determine the indications for intravenous (IV) recombinant tissue-plasminogen activator (rt-PA) or mechanical thrombectomy within 6 hours of disease onset. However, after protocol introduction (from October 2017), plain CT and 3DCTA were used. We collected data on patients who underwent mechanical thrombectomy and/or IV rt-PA before (n = 13) and after (n = 34) the protocol introduction. The required time from onset to door (OTD), door to needle (DTN), needle to puncture (NTP), puncture to recanalization (PTR), and door to recanalization (DTR) were compared before and after protocol introduction. Furthermore, thrombolysis in cerebral infarction (TICI) grades and modified Rankin scale (mRS) scores at discharge were compared. Results: The outcomes before and after protocol introduction were as follows: OTD: 105 ± 73.8 (mean ± standard deviation) vs. 120 ± 68.1 min (p = 0.376, Mann-Whitney U test); DTN: 62.9 ± 15.9 vs. 41 ± 17 min (p <0.01); NTP: 112 ± 69.8 vs. 39.9 ± 33.7 min (p <0.01); PTR: 87.9 ± 45.4 vs. 52.5 ± 27.9 min (p <0.01); and DTR, 230 ± 69.9 vs. 110 ± 40.3 min (p <0.0001). Before and after protocol introduction, the proportion of patients with TICI grade 2b-3, mRS score of 0-2 at discharge, and mRS score of 5-6 were 54% vs. 50% (p = 0.815, Fisher's exact test), 23% vs. 21% (p = 0.854), and 15% vs. 50% (p = 0.046), respectively. Conclusion: The Ishinomaki protocol reduced the mean DTR time by 120 min. The reduction in treatment time was due to the change in CT-based recanalization and collaboration with emergency physicians and paramedics. There was no increase in good outcomes, but there was a significant increase in poor outcomes at discharge. Patients who could not be salvaged were indicated for reperfusion therapy as CT and 3DCTA cannot detect the ischemic core.

Tumor hypoxia regulates ganglioside GM3 synthase, which contributes to oxidative stress resistance in malignant melanoma.

BACKGROUND: Tumor hypoxia drastically changes cancer phenotypes, including angiogenesis, invasion, and cell death. Gangliosides are sialic acid-containing glycosphingolipids that are ubiquitously distributed on plasma membranes and are involved in many biological processes, such as the endoplasmic reticulum stress response and apoptosis. In this study, we investigated the regulation and function of glycosphingolipids, which associate with lipid raft on mammalian plasma membranes under hypoxic condition. METHODS: B16F10 melanoma cells were subjected to chemical hypoxia and low pO2 condition, and the effect of hypoxia on expression of GM3 synthase were analyzed. Cellular resistance to oxidative stress was analyzed in GM3S-KO B16F10 cells. RESULTS: Hypoxia treatment decreased the expression of ganglioside GM3 synthase (GM3S; ST3GAL5), which synthesizes the common substrate of ganglioside biosynthesis. RNA interference of hypoxia inducible factor 1 subunit alpha (HIF-1α) inhibited hypoxia-induced GM3S suppression. Additionally, GM3S deficiency increased cellular resistance to oxidative stress and radiation therapy via upregulation of ERK. CONCLUSIONS: Altered synthesis of glycosphingolipids downstream of HIF-1α signaling increased the resistance of melanoma cells to oxidative stress. Furthermore, GM3 has important role on cellular adaptive response to hypoxia. GENERAL SIGNIFICANCE: This study indicates that tumor hypoxia regulates therapy-resistance via modulation of ganglioside synthesis.

Levetiracetam improves symptoms of multiple chemical sensitivity: Case report.

Multiple chemical sensitivity (MCS) is a disorder of unknown etiology with no effective treatment. Many clinicians accept that a diagnosis of somatic symptoms disorder (SSD) is an appropriate diagnostic category for MCS. We found that administration of levetiracetam improved recurrent symptoms of MCS in a patient. A 23-year-old female presented with recurrent multiple symptoms of musculoskeletal, airway or mucous membrane, heart/chest-related, gastrointestinal, cognitive, affective, neuromuscular, head-related, and skin-related induced by exposure to diesel or gas engine exhaust, tobacco smoke, insecticide, gasoline, paint or paint thinner, cleaning products, fragrances, tar or asphalt, nail polish or hairspray, and new furnishings. Gastrointestinal, cognitive, and skin-related symptoms were precipitated by some food additives. She suffered partial seizures from the age of 17 years, and was diagnosed with right parietal lobe epilepsy. Administration of levetiracetam (250 mg/day) eliminated her MCS symptoms. Levetiracetam reduces the release of presynaptic neurotransmitter including glutamate by binding to presynaptic vesicle protein. A recent study established the presence of glutamatergic overactivation in somatization disorder, a form of SSD. Our case may indicate that a subset of patients with SSD have glutamatergic overactivation, which levetiracetam can normalize. J. Med. Invest. 64: 296-298, August, 2017.

Differences in sleep architecture between left and right temporal lobe epilepsy.

To investigate whether seizure lateralization affects sleep macrostructure in patients with left and right temporal lobe epilepsy (TLE), as rapid eye movement (REM) sleep is shorter in patients with right hemispheric cerebral infarction than with left. We retrospectively analyzed data from 16 patients with TLE (6 men and 10 women aged 34.9 ± 11.4 years) who underwent polysomnography as well as long-term video electroencephalography. Ten patients were diagnosed with left TLE and six patients with right TLE. Sleep stages and respiratory events were scored based on the American Academy of Sleep Medicine criteria. Sleep and respiratory parameters were compared between the patient groups. Percentage of REM stage sleep was significantly (p < 0.05) lower in patients with left TLE (median 8.8 %, interquartile range 5.5-13.8 %) than in patients with right TLE (median 17.0 %, interquartile range 14.1-18.3 %). The other parameters showed no significant differences. Shorter REM sleep in patients with left TLE sharply contrasts with the previous report of shorter REM sleep in patients with right cerebral infarction. Laterality of the irritative epileptic focus versus destructive lesion may have different effects on the sleep macrostructures.

Brain Metabolic Changes of Cervical Dystonia with Spinocerebellar Ataxia Type 1 after Botulinum Toxin Therapy.

We occasionally observe long-term remission of cervical dystonia after several botulinum toxin treatments. However, botulinum toxin transiently acts on neuromuscular junctions. We herein report that a cervical dystonia patient with spinocerebellar ataxia type 1 could have long-term remission as a result of the depression of hypermetabolism in the bilateral putamen and primary sensorimotor cortex after botulinum toxin therapy. We suggest that botulinum toxin impacts the central nervous system, causing prolonged improvement through the normalization of basal ganglia circuits in addition to its effects at neuromuscular junctions.

Development and validation of a predictive model of failed stepping-down of inhaled corticosteroids in adult asthmatics.

BACKGROUND: Asthma guidelines suggest stepping-down of inhaled corticosteroids (ICSs) when asthma is stable. OBJECTIVE: To determine outcomes of stepping-down and prediction of outcome after stepping-down of ICSs in controlled adult asthma. METHODS: We performed a retrospective study on 21-81 year-old hospital-based outpatients with asthma in Japan. Protocol for stepping-down of ICSs was performed according to the GINA guideline. Failure/success of stepping-down is judged as occurring exacerbation or not for stepping-down of ICSs. Multiple logistic regression analysis was used to develop a prediction model for failed stepping-down, and then was validated by the leave-one-out cross-validation method. Our model of prediction score was calculated using receiver-operating characteristic area under the curve (AUC) analysis. The Nelson-Aalen curve demonstrated time to failure of stepping-down of ICSs. RESULTS: A total of 126 patients with asthma attempted the stepping-down of ICSs according to the guideline. Of patients with follow-up, 97 (77.0%) of stepping-down attempts were successful. Using multivariate logistic regression analysis, comorbidity with rhinitis/rhinosinusitis and phlegm grade were independent predictors of failed stepping-down of ICSs, with odds ratios of 3.8 (95% confidence interval, 1.04-13.3; P=0.04) and 1.3 (95% confidence interval, 1.01-11.5; P=0.04), respectively. These variables were then used to build a prediction score in terms of the prediction of failed stepping-down events. When the two variables were added to form the prediction score, the discriminative power of scores calculated by the prediction model using the AUC was 0.75 (range: 0.62-0.88) for naïve prediction and 0.72 (range: 0.60-0.86) after cross-validation. In the time-to-failure models, cumulative hazard ratio of failed stepping-down have fixed 1 year after stepping-down. CONCLUSION: Our results suggest that comorbidity with rhinitis/rhinosinusitis and phlegm grade are imperative to predict failed stepping-down of ICSs in controlled patients with adult asthma.

Differences in the effects of Asian dust on pulmonary function between adult patients with asthma and those with asthma-chronic obstructive pulmonary disease overlap syndrome.

BACKGROUND: Asian dust (AD) exposure exacerbates pulmonary dysfunction in patients with asthma. Asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS), characterized by coexisting symptoms of asthma and chronic obstructive pulmonary disease, is considered a separate disease entity. Previously, we investigated the effects of AD on pulmonary function in adult patients with asthma. Here, we present the findings of our further research on the differences in the effects of AD exposure on pulmonary function between patients with asthma alone and those with ACOS. METHODS: Between March and May 2012, we conducted a panel study wherein we monitored daily peak expiratory flow (PEF) values in 231 adult patients with asthma. These patients were divided into 190 patients with asthma alone and 41 patients with ACOS in this study. Daily AD particle levels were measured using light detection and ranging systems. Two heavy AD days (April 23 and 24) were determined according to the Japan Meteorological Agency definition. A linear mixed model was used to estimate the association between PEF and AD exposure. RESULTS: Increments in the interquartile range of AD particles (0.018 km(-1)) led to PEF changes of -0.50 L/min (95% confidence interval, -0.98 to -0.02) in patients with asthma alone and -0.11 L/min (-0.11 to 0.85) in patients with ACOS. The PEF changes after exposure to heavy AD were -2.21 L/min (-4.28 to -0.15) in patients with asthma alone and -2.76 L/min (-6.86 to 1.35) in patients with ACOS. In patients with asthma alone, the highest decrease in PEF values was observed on the heavy AD day, with a subsequent gradual increase over time. CONCLUSION: Our results suggest that the effects of AD exposure on pulmonary function differ between patients with asthma alone and ACOS, with the former exhibiting a greater likelihood of decreased pulmonary function after AD exposure.

Association between pulmonary function and daily levels of sand dust particles assessed by light detection and ranging in schoolchildren in western Japan: A panel study.

BACKGROUND: An important aspect of sand dust emissions in association with respiratory disorders is the quantity of particulate matter. This is usually expressed as particulate matter less than 10 µm (PM10) and 2.5 µm (PM2.5). However, the composition of PM10 and PM2.5 varies. Light detection and ranging is used to monitor sand dust particles originating in East Asian deserts and distinguish them from air pollution aerosols. The objective of this study was to investigate the association between the daily levels of sand dust particles and pulmonary function in schoolchildren in western Japan. METHODS: In this panel study, the peak expiratory flow (PEF) of 399 schoolchildren was measured daily from April to May 2012. A linear mixed model was used to estimate the association of PEF with the daily levels of sand dust particles, suspended particulate matter (SPM), and PM2.5. RESULTS: There was no association between the daily level of sand dust particles and air pollution aerosols, while both sand dust particles and air pollution aerosols had a significant association with SPM and PM2.5. An increment of 0.018 km(-1) in sand dust particles was significantly associated with a decrease in PEF (-3.62 L/min; 95% confidence interval, -4.66 to -2.59). An increase of 14.0 µg/m(3) in SPM and 10.7 µg/m(3) in PM2.5 led to a significant decrease of -2.16 L/min (-2.88 to -1.43) and -2.58 L/min (-3.59 to -1.57), respectively, in PEF. CONCLUSIONS: These results suggest that exposure to sand dust emission may relate to pulmonary dysfunction in children in East Asia.

High frequency oscillations are less frequent but more specific to epileptogenicity during rapid eye movement sleep.

OBJECTIVE: We hypothesized that high frequency oscillations (HFOs) are differently suppressed during rapid eye movement sleep (REM) between epileptogenic and less epileptogenic cortices, and that the suppressive effect can serve as a specific marker of epileptogenicity. METHODS: Intracranial electroencephalography (EEG) was recorded in 13 patients with drug-resistant epilepsy. HFOs between 80 and 200Hz were semi-automatically detected from total 15-min EEG epochs each for REM and slow wave sleep (SWS). z-Score of HFO occurrence rate was calculated from the baseline rate derived from non-epileptogenic cortex. Intracranial electrodes were labeled as REM dominant HFO (RdH) if REM z-score was greater than SWS z-score or as SWS dominant HFO (SdH) if SWS z-score was greater than REM z-score. Relationship of electrode location to the area of surgical resection was compared between RdH and SdH electrodes. RESULTS: Out of 1070 electrodes, 101 were defined as RdH electrodes and 115 as SdH electrodes. RdH electrodes were associated with the area of resection in patients with postoperative seizure freedom (P<0.001), but not in patients without seizure freedom. CONCLUSIONS: HFOs near the epileptogenic zone are less suppressed during REM. SIGNIFICANCE: The less suppressive effect of REM may provide a specific marker of epileptogenicity.

Association of Sand Dust Particles with Pulmonary Function and Respiratory Symptoms in Adult Patients with Asthma in Western Japan Using Light Detection and Ranging: A Panel Study.

Light detection and ranging (LIDAR) can estimate daily volumes of sand dust particles from the East Asian desert to Japan. The objective of this study was to investigate the relationship between sand dust particles and pulmonary function, and respiratory symptoms in adult patients with asthma. One hundred thirty-seven patients were included in the study. From March 2013 to May 2013, the patients measured their morning peak expiratory flow (PEF) and kept daily lower respiratory symptom diaries. A linear mixed model was used to estimate the correlation of the median daily levels of sand dust particles, symptoms scores, and PEF. A heavy sand dust day was defined as an hourly concentration of sand dust particles of >0.1 km(-1). By this criterion, there were 8 heavy sand dust days during the study period. Elevated sand dust particles levels were significantly associated with the symptom score (0.04; 95% confidence interval (CI); 0.03, 0.05), and this increase persisted for 5 days. There was no significant association between PEF and heavy dust exposure (0.01 L/min; 95% CI, -0.62, 0.11). The present study found that sand dust particles were significantly associated with worsened lower respiratory tract symptoms in adult patients with asthma, but not with pulmonary function.

[Clinical characteristics of four patients with temporal lobe epilepsy associated with elevated anti-GAD antibodies].

Anti-glutamic acid decarboxylase (GAD) antibodies are known to be associated with insulin-dependent diabetes mellitus (IDDM), stiff-person syndrome, and other neurological symptoms including temporal lobe epilepsy (TLE), known as autoimmune epilepsy. We treated four patients with TLE who had elevated titers of serum anti-GAD antibody (anti-GAD-Ab), higher than 100 U/ml. Three of the four patients started to have epileptic seizures in their 5th or 6th decade. Characteristic symptoms suggesting encephalitis or encephalopathy were absent at onset of these symptoms, which led to delayed diagnosis. All four patients developed two or three of cerebellar ataxia, neuropsychological impairment, and IDDM, by several years or decades after onset of TLE, even after seizure freedom in two patients. These abnormalities were indicators for suspecting the involvement of anti-GAD-Ab in the pathogenesis. Anti-GAD-Ab levels in the cerebrospinal fluid (CSF) were measured, which detected elevated CSF/serum anti-GAD-Ab ratio (≥ 1.0), suggesting intrathecal anti-GAD-Ab synthesis, in three of the four patients. The TLE symptoms were somewhat prolonged, but three of the four patients eventually achieved seizure freedom after immunotherapies with combinations of two or three anti-epileptic drugs. Serum anti-GAD Ab is recommended to be measured in patients with middle-aged onset TLE. Moreover, immune-modulating therapies including steroid pulse and intravenous immunoglobulin therapies could have ameliorated neurological complications, even in the chronic phase.