Differential effects of long- and short-term exposure to PM2.5 on accelerating telomere shortening: from in vitro to epidemiological studies.

Exposure to air pollutants has been associated with DNA damage and increases the risks of respiratory diseases, such as asthma and COPD; however short- and long-term effects of air pollutants on telomere dysfunction remain unclear. We investigated the impact of short- and long-term exposure to fine particulate matter with an aerodynamic diameter below 2.5 µm (PM2.5) on telomere length in human bronchial epithelial BEAS-2B cells, and assessed the potential correlation between PM2.5 exposure and telomere length in the LIGHTS childhood cohort study. We observed that long-term, but not short-term, PM2.5 exposure was significantly associated with telomere shortening, along with the downregulation of human telomerase reverse transcriptase (hTERT) mRNA and protein levels. Moreover, long-term exposure to PM2.5 induced proinflammatory cytokine secretion, notably interleukin 6 (IL-6) and IL-8, triggered subG1 cell cycle arrest, and ultimately caused cell death. Long-term exposure to PM2.5 upregulated the LC3-II/ LC3-I ratio but led to p62 protein accumulation in BEAS-2B cells, suggesting a blockade of autophagic flux. Moreover, consistent with our in vitro findings, our epidemiological study found significant association between annual average exposure to higher PM2.5 and shortening of leukocyte telomere length in children. However, no significant association between 7-day short-term exposure to PM2.5 and leukocyte telomere length was observed in children. By combining in vitro experimental and epidemiological studies, our findings provide supportive evidence linking potential regulatory mechanisms to population level with respect to long-term PM2.5 exposure to telomere shortening in humans.

Hyperbaric Oxygen Therapy Adjuvant Chemotherapy and Radiotherapy through Inhibiting Stemness in Glioblastoma.

Glioblastoma multiforme (GBM) is the most common and deadliest primary brain tumor in adults. Despite the advances in GBM treatment, outcomes remain poor, with a 2-year survival rate of less than 5%. Hyperbaric oxygen (HBO) therapy is an intermittent, high-concentration, short-term oxygen therapy used to increase cellular oxygen content. In this study, we evaluated the effects of HBO therapy, alone or combined with other treatment modalities, on GBM in vitro and in vivo. In the in vitro analysis, we used a 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to assess the effects of HBO therapy alone, a colony formation assay to analyze the effects of HBO therapy combined with radiotherapy and with temozolomide (TMZ), and a neurosphere assay to assess GBM stemness. In the in vivo analysis, we used immunohistochemical staining and in vivo bioluminescence imaging to assess GBM stemness and the therapeutic effect of HBO therapy alone or combined with TMZ or radiotherapy, respectively. HBO therapy did not affect GBM cell viability, but it did reduce the analyzed tumors' ability to form cancer stem cells. In addition, HBO therapy increased GBM sensitivity to TMZ and radiotherapy both in vitro and in vivo. HBO therapy did not enhance tumor growth and exhibited adjuvant effects to chemotherapy and radiotherapy through inhibiting GBM stemness. In conclusion, HBO therapy shows promise as an adjuvant treatment for GBM by reducing cancer stem cell formation and enhancing sensitivity to chemotherapy and radiotherapy.

Hyperbaric Oxygen Therapy as a Novel Approach to Modulating Macrophage Polarization for the Treatment of Glioblastoma.

Glioblastoma multiforme (GBM) is a highly aggressive brain cancer with a poor prognosis despite current treatments. This is partially attributed to the immunosuppressive environment facilitated by tumor-associated macrophages, which predominantly underlie the tumor-promoting M2 phenotype. This study investigated the potential of hyperbaric oxygen (HBO) therapy, traditionally used to treat conditions such as decompression sickness, in modulating the macrophage phenotype toward the tumoricidal M1 state and disrupting the supportive tumor microenvironment. HBO has direct antiproliferative effects on tumor cells and reduces hypoxia, which may impair angiogenesis and tumor growth. This offers a novel approach to GBM treatment by targeting the role of the immune system within the tumor microenvironment. The effects of HBO on macrophage polarization and GBM cell viability and apoptosis were evaluated in this study. We detected that HBO promoted M1 macrophage cytokine expression while decreasing GBM cell viability and increasing apoptosis using GBM cell lines and THP-1-derived macrophage-conditioned media. These findings suggest that HBO therapy can shift macrophage polarization toward a tumoricidal M1 state. This can improve GBM cell survival and offers a potential therapeutic strategy. In conclusion, HBO can shift macrophages from a tumor-promoting M2 phenotype to a tumoricidal M1 phenotype in GBM. This can facilitate apoptosis and, in turn, improve treatment outcomes.

Association between MIF gene polymorphisms and carotid artery atherosclerosis.

Atherosclerosis is a chronic inflammatory disorder. Macrophage migration inhibitory factor (MIF) is a potent cytokine that plays an important role in the regulation of immune responses. Polymorphisms including five- to eight-repeat CATT variants ((CATT)(5-8)) and G-173C in the promoter region of the MIF gene are associated with altered levels of MIF gene transcription. The purpose of the study is to investigate the relationship between promoter polymorphisms of the MIF gene and the severity of carotid artery atherosclerosis (CAA). The severity of CAA was assessed in 593 individuals with a history of ischemic stroke by using sonographic examination, and the MIF promoter polymorphisms of these individuals were genotyped. The carriage of (CATT)7 (compared to genotypes composed of (CATT)5, (CATT)6, or both), carriage of C allele (compared to GG), and carriage of the haplotype (CATT)7-C (compared to genotypes composed of (CATT)5-G, (CATT)6-G, or both) were significantly associated with an increase in the severity of CAA. We conclude that polymorphisms in the MIF gene promoter are associated with CAA severity in ischemic stroke patients. These genetic variants may serve as markers for individual susceptibility to CAA.

Sleep quality and daytime sleepiness in patients with epilepsy.

PURPOSE: Poor sleep quality and excessive daytime sleepiness (EDS) are common complaints of patients with epilepsy (PWE). This study aimed to evaluate possible predisposing factors for EDS and subjective sleep quality in PWE. METHODS: One hundred and seventeen PWE were enrolled and 30 healthy volunteers were recruited as controls. EDS was evaluated by the Epworth Sleepiness Scale (ESS) while the Pittsburg Sleep Quality Index (PSQI) was designed to evaluate overall sleep quality. Clinical baseline data and possible risk factors for sleep disturbances were included in the statistical analysis. RESULTS: Twenty percent of PWE (23/117) and 7% of healthy controls (2/30) had excessive daytime sleepiness (p = 0.007). PWE had significantly higher PSQI total scores (6.5 ± 3.8 vs. 3.7 ± 2.9), sleep latency (1.2 ± 0.8 vs. 0.6 ± 0.7) and sleep efficiency (0.8 ± 1.0 vs. 0.0 ± 0.2) scores than the controls (all p < 0.001). A significantly higher prevalence of poor sleep quality was found in the partial seizure, non-seizure-free, and polytherapy groups (all p < 0.05). Multivariate analysis showed that poor seizure control was the strongest independent risk factor for poor sleep quality (OR = 2.43, 95% CI = 1.15-5.15, p = 0.02). CONCLUSION: EDS and poor sleep quality are common in PWE and are closely related to partial epilepsy, poor seizure control, and polytherapy. These relationships must be addressed in order to provide the best management of sleep disturbance in such patients.

Star fruit intoxication in a patient with moderate renal insufficiency presents as a posterior reversible encephalopathy syndrome.

PURPOSE: Star fruit has been reported to contain neurotoxins that often cause severe neurological complications in patients with uremia or severe chronic renal insufficiency. However, the occurrence of neurotoxicity in patients with mild or moderate renal insufficiency has rarely been mentioned. CASE REPORT: A 67-year-old woman who had diabetes mellitus and moderate renal insufficiency presented with acute onset of hiccups and nausea two hours after ingestion of one fresh star fruit. She further presented with progressively incoherent speech, echolalia and bizarre behavior. On the next day, her consciousness level declined to deep coma and she experienced two seizures. Brain magnetic resonance imaging examinations revealed a focal cerebral lesion over the left occipital area. The clinical symptoms recovered and the brain lesion reversed after emergency hemodialysis. CONCLUSION: The clinicians should be aware that star fruit intoxication must be considered when patients with a chronic renal disease, even mild or moderate chronic renal insufficiency, present with unexplained neurological or psychiatric symptoms. Emergency hemodialysis or other replacement therapies may be required for the management of acute star fruit intoxication.

The relation between plasma homocysteine level and cardiovascular risk factors in cerebral ischemia.

PURPOSE: Hyperhomocysteinemia (HHcy) is associated with a higher risk of cerebral ischemia and other vascular thrombosis. Homocysteine is greatly influenced by a broad spectrum of physiological and pathological conditions but the confounding factor for HHcy is unknown in our population, especially in normocreatininemic individuals. It is our aim in this study to elucidate the relation between homocysteine and cardiovascular risk factors, and also describe the distribution of plasma homocysteine level in cerebral ischemia patients with normal serum creatinine level. METHODS: A retrospective study was conducted to understand the frequency of HHcy in cerebral ischemia patients, and the confounding cardiovascular risk factors in HHcy. Patients were classified into two groups by their plasma homocysteine levels; group I patients were those whose level was > or = 12 microM/L whereas group II < 12 microM/L. RESULTS: A total of 218 patients were enrolled. Their plasma homocysteine level ranged from 3.57 to 46.37 microM/L (mean: 10.01 +/- 5.03 microM/L). Group I included 45 patients whereas group II 173 patients. The frequency of hypertension, diabetes mellitus and cardiac disease, as well as age, aminotransferases, total cholesterol, triglyceride, albumin, hematocrit, hemoglobin and leucocyte count did not differ between group I and II patients, except serum creatinine level was higher in group I patients (p < 0.01). Serum creatinine level correlated directly to and was an independent predictor for the plasma homocysteine level. CONCLUSIONS: HHcy is common in our cerebral ischemia patients. Since renal function is a determinant for HHcy even in normocreatininemic patients, as a cardiovascular risk factor which detriments the renal function, it should be regularly monitored as HHcy is amenable for treatment.

Ictal paralysis with tonic eye gazing mimicking a pontine infarction.

PURPOSE: Concomitant positive and negative motor phenomena in a single seizure have not been reported before. METHOD: We used an extensive history review, neurological examination, EEG, MRI and SPECT study to demonstrate a rare combination of motor presentations as an ictal phenomenon. RESULT: A 64-year-old male was brought to the emergency room with dizziness, progressive drowsiness and left hemiparesis. A spontaneous eye deviation to the left side with nystagmus was observed. A right pontine lesion was tentatively diagnosed. However, a focal motor seizure of the patient's left face and limbs occurred 3.5h later. A brain MRI revealed a high signal in the right amygdala, hippocampus and thalamus, instead of the pons. An EEG showed periodic epileptic discharges in the right posterior temporal parietal region. Regional hyperperfusion was found by brain SPECT. The level of consciousness improved dramatically after adequate phenytoin treatment. CONCLUSION: A posterior temporal-parietal seizure can present with a prolonged ictal paralysis, a positive ocular nystagmoid deviation and an altered level of consciousness. The EEG is essential for a correct diagnosis, especially with a negative or an unexplainable MRI study. The SPECT has an additional role for the differential diagnosis.

Vigabatrin-attributable visual field defects in patients with intractable partial epilepsy.

INTRODUCTION: Vigabatrin (VGB) is implicated to cause visual field defects. We estimated the prevalence, described the characteristics and investigated the risk factors of VGB-attributable visual field defects. METHODS: Patients with intractable partial epilepsy under VGB add-on treatment received static perimetric examinations. Visual field charts were reviewed and interpreted using a three-grade system. Clinical features and therapeutic courses were analyzed for possible risk factors. RESULTS: Visual field defects in at least one eye were detected in 27 (79%) of 34 patients. In the subgroup of 27 patients with both eyes reliably tested, 16 (59%) had bilateral defect, among whom seven were severely involved and showed nasally dominant, crescent or concentric defect. Five patients had unilateral visual field defects. Four out of the 27 affected patients reported blurred vision. No statistically significant differences were noted between patients with and without visual field defects in terms of gender, age, duration or etiology of the epilepsy, and duration, maximum daily dose, or cumulative dose of VGB. CONCLUSIONS: There was a high prevalence of VGB-attributable visual field defects. No risk factors could be identified. Routine initial and regular follow-up of visual field examination, especially that focusing within a range of central fixation to 60 degrees, should be performed in patients on VGB.

The relationship of leukoaraiosis and the clinical severity of vascular Parkinsonism.

Vascular Parkinsonism (VP) is referred to as secondary Parkinsonian syndrome. It occurs with lacunar state or sub-cortical white matter micro-angiopathy and is highly associated with vascular risk factors and leukoaraiosis, also known as cerebral white matter lesions (WML). This study aimed to assess the prevalence of different vascular risk factors and WML in patients with VP, and their impact on clinical features. Sixty-two consecutive VP patients (70.2 ± 9.2 years) were evaluated for clinical severity using the Unified Parkinson's Disease Rating Scale (UPDRS). WML was assessed and scored on fluid-attenuated inversion recovery T2-weighted (FLAIR) magnetic resonance imaging (MRI). Cerebro-vascular risk factors, WML severity, and the UPDRS for clinical disability were analyzed statistically. There were no associations between WML score and age, sex, hypertension, diabetes, previous stroke, cardiac disease, cigarette smoking, or serum levels of cholesterol and triglyceride. The WML score positively correlated with UPDRS part I (p = 0.035) and part III (p = 0.041) scores. After adjustments for age, gender, stroke history, and use of levodopa, the WML score was associated with the UPDRS total (p = 0.020), part I (p = 0.012), part II (p = 0.039), and part III (p = 0.019) scores. The severity of WML is not associated with conventional vascular risk factors in VP patients but is significantly correlated with the UPDRS total and all sub-scores, which suggests that disruption of the cortico-sub-cortical circuits may lead to impaired mentation, behavior and mood, activities of daily living, and motor performance in these patients.

Risk factors of hyperammonemia in patients with epilepsy under valproic acid therapy.

Hyperammonemia has been reported to be associated with patients who receive valproic acid (VPA) therapy. This study aimed to determine the risk factors for hyperammonemia in patients with epilepsy treated with VPA. One hundred and fifty-eight adult patients with epilepsy aged older than 17 years who received VPA therapy were enrolled into this study. Blood samples were taken during the interictal state and analyzed for the blood level of ammonia. Statistical analysis was conducted between different groups of patients. The results showed that the frequency of hyperammonemia associated with VPA therapy was 27.8% (ammonia level >93 µg/dL), and 5.1% of the patients had severe hyperammonemia (ammonia level >150 µg/dL). The blood ammonia level was significantly correlated with the dosage of VPA and the plasma concentration of VPA. An increase of 1 mg in the dosage of VPA increased the risk of hyperammonemia by 0.1%. In addition, combination treatment with liver enzyme inducing antiepileptic drugs (AEDs) and antipsychotic drugs increased the risk of hyperammonemia. In conclusion, the use of VPA in adult patients with epilepsy was associated with a dose-dependent increase in blood concentrations of ammonia. Combination treatment with liver enzyme-inducing AEDs and antipsychotic drugs increased the risk of VPA-induced hyperammonemia. Most of the patients with VPA-induced hyperammonemia were asymptomatic; however, if patients taking VPA present with symptoms such as nausea, fatigue, somnolence, ataxia, and consciousness disturbance, the blood ammonia level should be measured.

Risk factors of oxcarbazepine-induced hyponatremia in patients with epilepsy.

OBJECTIVES: To determine the risk factors for hyponatremia in patients with epilepsy treated with oxcarbazepine (OXC). METHODS: Seventy-three adult patients with epilepsy aged older than 17 years who received OXC therapy were enrolled in this study. Patients who had hyponatremia due to any etiology before OXC therapy and patients receiving OXC therapy for nonepileptic disorders were excluded from this study. The baseline level of serum sodium of the patients was measured before the OXC therapy. During OXC therapy, serum sodium levels were measured at least once per 3 months. RESULTS: The frequency of hyponatremia (Na+, ≤ 134 mEq/L) was 24.7% (n = 18) in patients with OXC therapy, and 8.2% (n = 6) of the patients had severe hyponatremia (Na+, ≤ 128 mEq/L). The degree of decline in serum sodium concentration was significantly negatively correlated with the dosage of OXC. An increase of 1 mg in the dosage of OXC increased the risk of hyponatremia by 0.2%. Moreover, increasing the number of combination antiepileptic drugs increased the risk of hyponatremia. CONCLUSIONS: Higher dosages of OXC and the number of combination antiepileptic drugs may increase the risk of OXC-induced hyponatremia in patients with epilepsy. Most patients are asymptomatic, but if symptoms of hyponatremia, such as headache, general malaise, gait disturbance, and somnolence, are suspected, the serum sodium level should be measured; it may be necessary to decrease the OXC dose or to discontinue the drug.

Association of plasma homocysteine concentration with cerebral white matter hyperintensity on magnetic resonance images in stroke patients.

BACKGROUND: Homocysteine (Hcy) has been recognized as a risk factor for atherosclerosis. White matter hyperintensity (WMH) on MRI has been regarded as a hallmark for cerebral small vascular disease. The study is to investigate the relationship between plasma Hcy level and WMH on a hospital-based cohort of Taiwanese stroke patients. METHODS AND RESULTS: A total of 352 consecutive stroke patients (64.7+/-11.2 years) were included. Severity of WMH was semi-quantitatively evaluated with a scoring system. The top WMH score tertile was defined as severe white matter change (sv-WMH). Associations between Hcy tertile levels and sv-WMH were examined, adjusting for demographics and atherosclerosis risk factors. Subjects in the top Hcy tertile (>10.25 micromol/L) had higher WMH scores and prevalence of sv-WMH than those in the middle and in the bottom tertile. The adjusted odds ratio of having sv-WMH was 2.04 (95% confidence interval 1.20-3.47, p=0.008) for the top Hcy level tertile than for the lower two tertiles combined. CONCLUSION: Hcy is a risk factor for cerebral white matter lesion in stroke patients. Even mild hyperhomocysteinemia can significantly increase severity of cerebral microangiopathy.

Transient global amnesia-like episode due to mistaken intake of zolpidem: drug safety concern in the elderly.

OBJECTIVE: Chronic insomnia is a common phenomenon among the elderly. Inaccurate handling and use of hypnotics in the elderly has become an important issue in patient safety. Older people who self-medicate often have a high risk for medication errors. METHODS AND RESULTS: We described here the case of a 65-year-old woman who experienced recurrent transient anterograde amnesia, anxiety, bewilderment, and repetitive questioning that lasted for 2 to 3 hours after erroneously taking zolpidem. This mistake was due to the similarity in appearance between zolpidem and her newly prescribed anticholesterol drug, ezetimibe. CONCLUSIONS: History of medication, particularly as regards hypnotics, should be carefully reviewed when a patient presents with transient global amnesia-like symptoms. The inadvertent use of drugs may be an underrecognized phenomenon among the elderly who self-medicate. When prescribing a new drug to elderly patients, especially hypnotics, physicians and pharmacists should educate them and their families about the proper use of these medications for their own safety.

Magnetic resonance imaging and single-photon emission computed tomography changes in hypoglycemia-induced chorea.

We present two case studies, one of generalized chorea and one of hemichorea, both after severe hypoglycemia episodes. Both cases showed hyperperfusion in their SPECT scans. The MRI and SPECT findings serve as clues regarding the role of basal ganglion dysfunction associated with chorea.

Spontaneous intracranial hypotension in a patient with reversible pachymeningeal enhancement and brain descent.

A 56-year-old woman presented with severe orthostatic headache in association with nausea and vomiting. Lumbar puncture for the patient revealed significantly low cerebrospinal fluid pressure (CSF) and the clinical diagnosis of intracranial hypotension syndrome was made. An initial gadolinium-enhanced brain magnetic resonance imaging (MRI) disclosed diffuse meningeal enhancement as well as brain sagging. No definite CSF leakage was found using radionuclide cisternography. Her headaches abated with proper usage of analgesics, strict bed rest, and intravenous hydration. Follow-up neuroimaging studies showed partially resolved meningeal enhancement 2 months after treatment and complete resolution 6 months after treatment. The temporal changes found on MRI suggest that the pachymeningeal enhancement is reversible in patients with spontaneous intracranial hypotension. Moreover, proliferation of meninges is likely to be responsible for this type of delayed resolution phenomenon.