Level of Amyloid-ß (Aß) Binding Leading to Differential Effects on Resting State Functional Connectivity in Major Brain Networks.

INTRODUCTION: Amyloid-ß protein (Aß) is one of the biomarkers for Alzheimer's disease (AD). The recent application of interhemispheric functional connectivity (IFC) in resting-state fMRI has been used as a non-invasive diagnostic tool for early dementia. In this study, we focused on the level of Aß accumulated and its effects on the major functional networks, including default mode network (DMN), central executive network (CEN), salience network (SN), self-referential network (SRN) and sensory motor network (SMN). METHODS: 58 participants (27 Hi Aß (HiAmy) and 31 low Aß (LowAmy)) and 25 healthy controls (HC) were recruited. [18F]flutemetamol PET/CT was performed for diseased groups, and MRI scanning was done for all participants. Voxel-by-voxel correlation analysis was done for both groups in all networks. RESULTS: In HiAmy, IFC was reduced in all networks except SN. A negative correlation in DMN, CEN, SRN and SMN suggests high Aß related to IFC reduction; However, a positive correlation in SN suggests high Aß related to an increase in IFC. In LowAmy, IFC increased in CEN, SMN, SN and SRN. Positive correlation in all major brain networks. CONCLUSION: The level of Aß accumulated demonstrated differential effects on IFC in various brain networks. As the treatment to reduce Aß plaque deposition is available in the market, it may be an option for the HiAmy group to improve their IFC in major brain networks.

The fractional amplitude of low-frequency fluctuations signals related to amyloid uptake in high-risk populations-A pilot fMRI study.

Background: Patients with type 2 diabetes mellitus (T2DM) and subjective cognitive decline (SCD) have a higher risk to develop Alzheimer's Disease (AD). Resting-state-functional magnetic resonance imaging (rs-fMRI) was used to document neurological involvement in the two groups from the aspect of brain dysfunction. Accumulation of amyloid-ß (Aß) starts decades ago before the onset of clinical symptoms and may already have been associated with brain function in high-risk populations. However, this study aims to compare the patterns of fractional amplitude of low-frequency fluctuations (fALFF) maps between cognitively normal high-risk groups (SCD and T2DM) and healthy elderly and evaluate the association between regional amyloid deposition and local fALFF signals in certain cortical regions. Materials and methods: A total of 18 T2DM, 11 SCD, and 18 healthy elderlies were included in this study. The differences in the fALFF maps were compared between HC and high-risk groups. Regional amyloid deposition and local fALFF signals were obtained and further correlated in two high-risk groups. Results: Compared to HC, the altered fALFF signals of regions were shown in SCD such as the left posterior cerebellum, left putamen, and cingulate gyrus. The T2DM group illustrated altered neural activity in the superior temporal gyrus, supplementary motor area, and precentral gyrus. The correlation between fALFF signals and amyloid deposition was negative in the left anterior cingulate cortex for both groups. In the T2DM group, a positive correlation was shown in the right occipital lobe and left mesial temporal lobe. Conclusion: The altered fALFF signals were demonstrated in high-risk groups compared to HC. Very early amyloid deposition in SCD and T2DM groups was observed to affect the neural activity mainly involved in the default mode network (DMN).

Incremental diagnostic value of 18F-Fluetemetamol PET in differential diagnoses of Alzheimer's Disease-related neurodegenerative diseases from an unselected memory clinic cohort.

To evaluate the incremental diagnostic value of 18F-Flutemetamol PET following MRI measurements on an unselected prospective cohort collected from a memory clinic. A total of 84 participants was included in this study. A stepwise study design was performed including initial analysis (based on clinical assessments), interim analysis (revision of initial analysis post-MRI) and final analysis (revision of interim analysis post-18F-Flutemetamol PET). At each time of evaluation, every participant was categorized into SCD, MCI or dementia syndromal group and further into AD-related, non-AD related or non-specific type etiological subgroup. Post 18F-Flutemetamol PET, the significant changes were seen in the syndromal MCI group (57%, p < 0.001) involving the following etiological subgroups: AD-related MCI (57%, p < 0.01) and non-specific MCI (100%, p < 0.0001); and syndromal dementia group (61%, p < 0.0001) consisting of non-specific dementia subgroup (100%, p < 0.0001). In the binary regression model, amyloid status significantly influenced the diagnostic results of interim analysis (p < 0.01). 18F-Flutemetamol PET can have incremental value following MRI measurements, particularly reflected in the change of diagnosis of individuals with unclear etiology and AD-related-suspected patients due to the role in complementing AD-related pathological information.

Factors Associated with Development of New Joint Contractures in Long-Term Care Residents.

OBJECTIVE: Limb contractures are associated with poor outcomes and quality of life in long-term care (LTC) residents. This study examined the rate of developing new joint contracture in the LTC residents and associated risk factors to formulate effective interventions in this critical but understudied area. DESIGN: This is an observational study with data obtained from the Hong Kong Longitudinal Study on LTC Residents between 2005 and 2016. SETTING AND PARTICIPANTS: Trained assessors (nurses, social workers, and therapists) used the Minimum Data Set Resident Assessment Instrument (MDS-RAI 2.0) to collect the data of the residents from 9 residential LTC facilities. MEASURES: Limb contractures were defined as a functional limitation in the range of motion involving the upper or lower limbs. Primary outcomes included annual prevalence of joint contractures and factors that were associated with the development of new joint contractures. RESULTS: We analyzed the data for 1914 older residents (674 males, mean age 83.4 years). During the first 5 years since admission, the annual prevalence of upper limb contractures increased from 29.8% to 36.5%, and lower limb contractures increased from 41.5% to 57.4%. Overall, the increment of the prevalence rate of joint contractures per year ranged from 0.7% to 3.2% for the upper limbs and 0.3% to 6.0% per year for the lower limbs. Impaired mobility, presence of neurologic diseases, and older age were the leading independent risk factors for the development of new joint contractures. CONCLUSIONS AND IMPLICATIONS: Joint contractures are highly prevalent among residents admitted to the LTC facilities, and many residents develop new contractures during the first 5 years of their admission. Immobility appears to be the main modifiable risk factor. Further studies are needed to identify potential strategies to prevent new contractures in this vulnerable group.

Diagnostic Efficacy of Voxel-Mirrored Homotopic Connectivity in Vascular Dementia as Compared to Alzheimer's Related Neurodegenerative Diseases-A Resting State fMRI Study.

Previous studies have demonstrated that functional connectivity (FC) of different brain regions in resting state function MRI were abnormal in patients suffering from mild cognitive impairment (MCI) and Alzheimer's disease (AD) when comparing to healthy controls (HC) using seed based, independent component analysis (ICA) or small world network techniques. A new technique called voxel-mirrored homotopic connectivity (VMHC) was used in the current study to evaluate the value of interhemispheric functional connectivity (IFC) as a diagnostic tool to differentiate vascular dementia (VD) from other Alzheimer's related neurodegenerative diseases. Eighty-three participants were recruited from the university hospital memory clinic. A multidisciplinary panel formed by a neuroradiologist and two geriatricians classified the participants into VD (13), AD (16), MCI (29), and HC (25) based on clinical history, Montreal Cognitive Assessment Hong Kong version (HK­MoCA) neuropsychological score, structural MRI, MR perfusion, and 18-F Flutametamol (amyloid) PET-CT findings of individual subjects. We adopted the calculation method used by Kelly et al. (2011) and Zuo et al. (2010) in obtaining VMHC maps. Specific patterns of VMHC maps were obtained for VD, AD, and MCI to HC comparison. VD showed significant reduction in VMHC in frontal orbital gyrus and gyrus rectus. Increased VMHC was observed in default mode network (DMN), executive control network (ECN), and the remaining salient network (SN) regions. AD showed a reduction of IFC in all DMN, ECN, and SN regions; whereas MCI showed VMHC reduction in vSN, and increased VMHC in DMN and ECN. When combining VMHC values of relevant brain regions, the accuracy was improved to 87%, 92%, and 83% for VD, AD, and MCI from HC, respectively, in receiver operating characteristic (ROC) analysis. Through studying the VMHC maps and using VMHC values in relevant brain regions, VMHC can be considered as a reliable diagnostic tool for VD, AD, and MCI from HC.

Heterogeneity of Amyloid Binding in Cognitively Impaired Patients Consecutively Recruited from a Memory Clinic: Evaluating the Utility of Quantitative 18F-Flutemetamol PET-CT in Discrimination of Mild Cognitive Impairment from Alzheimer's Disease and Other Dementias.

BACKGROUND: With the more widespread use of 18F-radioligand-based amyloid-ß (Aß) PET-CT imaging, we evaluated Aß binding and the utility of neocortical 18F-Flutemetamol standardized uptake value ratio (SUVR) as a biomarker. OBJECTIVE: 18F-Flutemetamol SUVR was used to differentiate 1) mild cognitive impairment (MCI) from Alzheimer's disease (AD), and 2) MCI from other non-AD dementias (OD). METHODS: 109 patients consecutively recruited from a University memory clinic underwent clinical evaluation, neuropsychological test, MRI and 18F-Flutemetamol PET-CT. The diagnosis was made by consensus of a panel consisting of 1 neuroradiologist and 2 geriatricians. The final cohort included 13 subjective cognitive decline (SCD), 22 AD, 39 MCI, and 35 OD. Quantitative analysis of 16 region-of-interests made by Cortex ID software (GE Healthcare). RESULTS: The global mean 18F-Flutemetamol SUVR in SCD, MCI, AD, and OD were 0.50 (SD-0.08), 0.53 (SD-0.16), 0.76 (SD-0.10), and 0.56 (SD-0.16), respectively, with SUVR in SCD and MCI and OD being significantly lower than AD. Aß binding in SCD, MCI, and OD was heterogeneous, being 23%, 38.5%, and 42.9% respectively, as compared to 100% amyloid positivity in AD. Using global SUVR, ROC analysis showed AUC of 0.868 and 0.588 in differentiating MCI from AD and MCI from OD respectively. CONCLUSION: 18F-Flutemetamol SUVR differentiated MCI from AD with high efficacy (high negative predictive value), but much lower efficacy from OD. The major benefit of the test was to differentiate cognitively impaired patients (either SCD, MCI, or OD) without AD-related-amyloid-pathology from AD in the clinical setting, which was under-emphasized in the current guidelines proposed by Amyloid Imaging Task Force.

Diurnal Cortisol Slope Mediates the Association Between Affect and Memory Retrieval in Older Adults With Mild Cognitive Impairment: A Path-Analytical Study.

BACKGROUND: Memory deficits are linked to dysfunctional HPA axis activity and negative affect in older adults. This study evaluated the mediating effect of the diurnal cortisol pattern on the relationship between affect and memory in older people with mild cognitive impairment (MCI). METHODS: This longitudinal study recruited 189 Chinese older adults with MCI from elderly centers in Hong Kong. The participants completed assessments of affect, salivary cortisol, and digit spans at baseline; neurocognitive assessments on verbal fluency, memory retrieval, and digit spans at 6-month follow-up; and instrumental activities of daily living (IADL) at 1-year follow-up. Structural equation modeling examined the direct and indirect effects of negative affect on memory and IADL via diurnal cortisol pattern. RESULTS: Controlling for covariates, negative affect significantly predicted flattened diurnal cortisol slopes (ß = 0.17, p < 0.05) but not memory or IADL (p = 0.23 - 0.91) directly. Diurnal cortisol slopes negatively predicted memory retrieval (ß = -0.20, p < 0.05), which in turn positively predicted IADL (ß = 0.22, p < 0.01). The indirect effect from negative affect to IADL via cortisol slope and memory retrieval was significant and negative (αßγ = -0.05, 95% bootstrapped CI = -0.248 to -0.001). DISCUSSION: The present study established certain temporal linkages among affect and cortisol slopes at baseline, memory retrieval at 6 months, and functional decline 1 year later in older adults with MCI. Flattened diurnal cortisol slopes might mediate the detrimental effects of negative affect on memory retrieval and functioning across 1 year.

Psychophysiological Effects of Dance Movement Therapy and Physical Exercise on Older Adults With Mild Dementia: A Randomized Controlled Trial.

OBJECTIVES: Dementia interferes with older adults' functioning in cognitive, daily, psychosocial, and neuroendocrine domains. The present study examined the psychophysiological effects of dance movement therapy (DMT) and physical exercise for older adults with dementia. METHODS: This randomized controlled trial recruited 204 older adults diagnosed with mild dementia into the DMT, exercise, or waitlist control group. Both DMT and exercise interventions had similar intensity and comprised 24 hr of intervention that spanned over 12 weeks. All participants completed self-report questionnaires on psychosocial well-being, daily functioning, neurocognitive assessments, and salivary cortisol measures at baseline and 3 follow-up measurements more than 1 year. RESULTS: The DMT group showed significant decreases in depression, loneliness, and negative mood (d = 0.33-0.42, p < .05) and improved daily functioning (d = 0.40, p < .01) and diurnal cortisol slope (d = 0.30, p < .01). The effects on daily functioning and cortisol slope remained at 1-year follow-up. The exercise group of matched intensity showed no significant effects on the outcomes. DISCUSSION: The study findings support the potential utility of DMT as a multifaceted intervention for improving various aspects of functioning in older adults with declining cognitive abilities. The lack of beneficial effects for our exercise intervention and long-term DMT effects highlights the need to maintain persistent levels of exercise with adequate intensity and duration.

Minimal clinically important difference of the EORTC QLQ-CIPN20 for worsening peripheral neuropathy in patients receiving neurotoxic chemotherapy.

CONTEXT/OBJECTIVES: This is the first study to determine the minimal clinically important difference (MCID) of the European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire-CIPN twenty-item scale (EORTC QLQ-CIPN20), a validated instrument designed to elicit cancer patients' experience of symptoms and functional limitations related to chemotherapy-induced peripheral neuropathy. METHODS: Cancer patients receiving neurotoxic chemotherapy completed EORTC QLQ-CIPN20 and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity [FACT/GOG-NTX] at baseline, second cycle of chemotherapy (T2, n = 287), and 12 months after chemotherapy (T3, n = 191). Anchor-based approach used the validated FACT/GOG-NTX neurotoxicity (Ntx) subscale to identify optimal MCID cutoff for deterioration. Distribution-based approach used one-third standard deviation (SD), half SD, and one standard error of measurement of the total EORTC QLQ-CIPN20 score. RESULTS: There was a moderate correlation between the change scores of the Ntx subscale and sensory and motor subscales of QLQ-CIPN20 (T2: r = - 0.722, p < 0.001 and r = - 0.518, p < 0.001, respectively; T3: r = - 0.699; p < 0.001 and r = - 0.523, p < 0.001, respectively). The correlation between the change scores of the Ntx subscale and the QLQ-CIPN20 autonomic subscale was poor (T2: r = - 0.354, p < 0.001; T3: r = 0.286, p < 0.001). Based on the MCID derived using distribution-based method, the MCID for the QLQ-CIPN20 sensory subscale was 2.5-5.9 (6.9% to 16.4% of the subdomain score) and for motor subscale was 2.6-5.0 (8.1%-15.6% of the subdomain score). CONCLUSION: The MCID for the EORTC QLQ-CIPN20 established using distribution-based approaches was 2.5-5.9 for the sensory subscale and 2.6-5.0 for the motor subscale. When noted in assessments even with small change in scores, clinicians can be alerted for appropriate intervention.

Are we mis-estimating chemotherapy-induced peripheral neuropathy? Analysis of assessment methodologies from a prospective, multinational, longitudinal cohort study of patients receiving neurotoxic chemotherapy.

BACKGROUND: There are inconsistencies in the literature regarding the prevalence and assessment of chemotherapy-induced peripheral neuropathy (CIPN). This study explored CIPN natural history and its characteristics in patients receiving taxane- and platinum-based chemotherapy. PATIENTS AND METHODS: Multi-country multisite prospective longitudinal observational study. Patients were assessed before commencing and three weekly during chemotherapy for up to six cycles, and at 6,9, and 12 months using clinician-based scales (NCI-CTCAE; WHO-CIPN criterion), objective assessments (cotton wool test;10 g monofilament); patient-reported outcome measures (FACT/GOG-Ntx; EORTC-CIPN20), and Nerve Conduction Studies. RESULTS: In total, 343 patients were recruited in the cohort, providing 2399 observations. There was wide variation in CIPN prevalence rates using different assessments (14.2-53.4%). Prevalence of sensory neuropathy (and associated symptom profile) was also different in each type of chemotherapy, with paclitaxel (up to 63%) and oxaliplatin (up to 71.4%) showing the highest CIPN rates in most assessments and a more complex symptom profile. Peak prevalence was around the 6-month assessment (up to 71.4%). Motor neurotoxicity was common, particularly in the docetaxel subgroup (up to 22.1%; detected by NCI-CTCAE). There were relatively moderately-to-low correlations between scales (rs = 0.15,p < 0.05-rs = 0.48 p < 0.001), suggesting that they measure different neurotoxicity aspects from each other. Cumulative chemotherapy dose was not associated with onset and course of CIPN. CONCLUSION: The historical variation reported in CIPN incidence and prevalence is possibly confounded by disagreement between assessment modalities. Clinical practice should consider assessment of motor neuropathy for neurotoxic chemotherapy. Current scales may not be all appropriate to measure CIPN in a valid way, and a combination of scales are needed.

Psychometric validation of Fuld Object Memory Evaluation in older adults with cognitive impairments.

OBJECTIVES: Mild cognitive impairment (MCI) refers to an early but abnormal state of cognitive impairment with minimal functional impairment. The present study aimed to evaluate the validity of Fuld Object Memory Evaluation (FOME) as a measure of episodic memory function. METHOD: The study sample included 204 Chinese older adults with cognitive impairments. The participants completed five recall trials and a delayed trial in FOME, neurocognitive measures on digit spans and trail making, and daily functioning. Discriminative power of FOME to differentiate between MCI and dementia was inspected via receiver operating characteristic curve analysis. RESULTS: FOME showed good test-retest reliability and convergent validity with digit spans and trail making. Controlling for gender, age, and education, lower levels of FOME total retrieval, verbal fluency, and daily functioning significantly predicted a higher likelihood of dementia compared to MCI. The optimal cut-off scores for total retrieval, verbal fluency, and daily functioning to differentiate dementia were 37/38 (77% sensitivity and 83% specificity), 28/29 (85% sensitivity and 72% specificity), and 14/15 (92% sensitivity and 78% specificity), respectively, in the younger subgroup. The corresponding figures were 34/35 (69% sensitivity and 76% specificity) and 27/28 (92% sensitivity and 62% specificity), and 11/12 (74% sensitivity and 80% specificity), respectively, in the older subgroup. CONCLUSION: The findings support the FOME as a valid assessment tool of episodic memory function in older Chinese adults. The combined use of FOME and daily functioning is recommended to distinguish persons with dementia from MCI.

Converting MMSE to MoCA and MoCA 5-minute protocol in an educationally heterogeneous sample with stroke or transient ischemic attack.

BACKGROUND: The Montreal Cognitive Assessment (MoCA) is psychometrically superior over the Mini-mental State Examination (MMSE) for cognitive screening in stroke or transient ischemic attack (TIA). It is free for clinical and research use. The objective of this study is to convert scores from the MMSE to MoCA and MoCA-5-minute protocol (MoCA-5 min) and to examine the ability of the converted scores in detecting cognitive impairment after stroke or TIA. METHODS: A total of 904 patients were randomly divided into training (n = 623) and validation (n = 281) samples matched for demography and cognition. MMSE scores were converted to MoCA and MoCA-5 min using (1) equipercentile method with log-linear smoothing and (2) Poisson regression adjusting for age and education. Receiver operating characteristics curve analysis was used to examine the ability of the converted scores in differentiating patients with cognitive impairment. RESULTS: The mean education was 5.8 (SD = 4.6; ranged 0-20) years. The entire spectrum of MMSE scores was converted to MoCA and MoCA-5 min using equipercentile method. Relationship between MMSE and MoCA scores was confounded by age and education, and a conversion equation with adjustment for age and education was derived. In the validation sample, the converted scores differentiated cognitively impaired patients with area under receiver operating characteristics curve 0.826 to 0.859. CONCLUSION: We provided 2 methods to convert scores from the MMSE to MoCA and MoCA-5 min based on a large sample of patients with stroke or TIA having a wide range of education and cognitive levels. The converted scores differentiated patients with cognitive impairment after stroke or TIA with high accuracy.

Factors Associated With the Trend of Physical and Chemical Restraint Use Among Long-Term Care Facility Residents in Hong Kong: Data From an 11-Year Observational Study.

BACKGROUND: Negative effects of restraint use have been well-documented. However, the prevalence of restraints use has been high in long-term care facilities in Hong Kong compared with other countries and this goes against the basic principles of ethical and compassionate care for older people. The present study aimed to review the change in the prevalence of physical and chemical restraint use in long-term care facilities (LTCFs) over a period of 11 years in Hong Kong and to identify the major factors associated with their use. METHODS: This is an observational study with data obtained from the Hong Kong Longitudinal Study on LTCF Residents between 2005 and 2015. Trained assessors (nurses, social workers, and therapists) used the Minimum Data Set Resident Assessment Instrument to collect the data from 10 residential LTCFs. Physical restraint was defined as the use of any of the following: full bedside rails on all open sides of bed, other types of bedside rails used, trunk restraint, limb restraint, or the use of chair to prevent rising during the past 7 days. Chemical restraint was defined as the use of any of the following medications: antipsychotic, antianxiety, or hypnotic agents during past 7 days, excluding elder residents with a diagnosis of psychiatric illness. OUTCOMES: Annual prevalence of restraint use over 11 years and factors that were associated with the use of physical and chemical restraints. RESULTS: We analyzed the data for 2896 older people (978 male individuals, mean age = 83.3 years). Between 2005 and 2015, the prevalence of restraint use was as follows: physical restraint use increased from 52.7% to 70.2%; chemical restraint use increased from 15.9% to 21.78%; and either physical or chemical restraint use increased from 57.9% to 75.7%. Physical restraint use was independently associated with older age, impaired activities of daily living or cognitive function, bowel and bladder incontinence, dementia, and negative mood. Chemical restraint use was independently associated with older age, falls, bladder incontinence, use of feeding tube, dementia, poor cognitive function, delirium, behavioral problems, and negative mood. The increasing time-trend of physical but not chemical restraint use remained significant after adjusting for other factors as mentioned above (coefficient = 0.092, P < .001). CONCLUSIONS: Use of physical and chemical restraint was highly prevalent among LTCF residents in Hong Kong, with an increasing trend over a period of 11 years, especially targeting the most physically and cognitively frail older people. Appropriate healthcare staff education and policy change are urgently needed to ensure personal care that is characterized by respect, dignity, empathy, and compassion for the older generation.

MiR-30 Family Potentially Targeting PI3K-SIAH2 Predicted Interaction Network Represents a Novel Putative Theranostic Panel in Non-small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) comprises about 84% of all lung cancers. Many treatment options are available but the survival rate is still very low due to drug resistance. It has been found that phosphoinositide-3-kinase (PI3K) affects sensitivity to tyrosine kinase inhibitors (TKIs), including gefitinib and erlotinib. Expression level of seven in absentia homolog 2 (SIAH2), an E3 ubiquitin-protein ligase, is upregulated in NSCLC and correlated with tumor grade. However, the relationship between PI3K and SIAH2 remains unclear and therefore it is not known whether they can act as treatment co-targets and theranostic dual markers for overcoming TKI resistance. It is worthy to note that PI3K and SIAH2 are potentially regulated by a common group of microRNAs in miR-30 family. Our bioinformatics analyses showed upregulated SIAH2 expression in NSCLC based on mass spectrometry data, explored its indirect interaction with PI3K and predicted their targeting microRNAs in common. We have also explored the potential role of miR-30 family in the modulation of PI3K-SIAH2 interaction in NSCLC.

Prognostic value of alcohol consumption and some other dietary habits for survival in a cohort of Chinese men with lung cancer.

BACKGROUND: Alcohol consumption and some other dietary habits are thought to be associated with lung cancer incidence. However, the effects of these habits on lung cancer prognosis have been studied rarely. The purpose of this study was to address these gaps in knowledge. METHODS: We studied a cohort of 1052 Chinese men in Hong Kong who were diagnosed with primary lung cancer. Cox proportional hazards models were used to determine the prognostic values of consumption of alcohol, fresh fruits or vegetables, meat, and fried or preserved food. RESULTS: Compared with never drinkers, men who drank alcohol 1-3 days per week had a more favorable lung cancer prognosis (hazard ratio [HR]: 0.82, 95% confidence interval [CI] 0.68-0.97); however, this survival advantage was not significant in men who drank alcohol more frequently (HR: 0.91, 95% CI 0.73-1.14). Compared with men who consumed preserved or fried food only occasionally, men who consumed these foods frequently had a higher risk of lung cancer mortality (HR: 1.20, 95% CI 1.00-1.42). CONCLUSIONS: Occasional consumption of alcohol was a favorable survival factor for Chinese men with lung cancer. However, this survival benefit did not exist for frequent drinkers of alcohol. Chinese men with lung cancer who were frequent consumers of fried or preserved food had a worse prognosis than those who consumed these foods only occasionally.

The impact of single versus double blastocyst transfer on pregnancy outcomes: A prospective, randomized control trial.

OBJECTIVE: To determine if elective single blastocyst transfer (e-SBT) compromises pregnancy outcomes compared to double blastocyst transfer (DBT) in patients with favorable reproductive potential. METHODS: This Randomized Control Trial included 50 patients with SBT (Group 1) and 50 patients with DBT (Group 2). All women were <35 years and had favorable reproductive potential. Randomization criterion was two good quality blastocysts on day 5. Patients who did not get pregnant or who miscarried underwent subsequent frozen cycles with transfer of two blastocysts (if available) in both groups. RESULTS: No significant difference was observed in the majority of the demographic data, infertility etiology, ovarian stimulation characteristics and embryology data between the two groups. There was a significantly lower clinical pregnancy (61.2% vs 80.0%), and delivery (49.0% vs 70.0%) rates, but no difference in implantation (59.2% vs 54.0%), miscarriage, or ectopic pregnancy rates between Group 1 and Group 2, respectively. There was a significantly higher multiple pregnancy rate in Group 2 (35.0%) compared to Group 1 (0%) [P=0.000]. When fresh and first frozen cycles were combined, there was a significantly lower cumulative clinical pregnancy (77.6% vs 96.0%, P=0.007) and delivery (65.3% vs 86.0%, P=0.016) rates in Group 1 compared to Group 2 respectively. CONCLUSIONS: In patients with favorable reproductive potential, although e-SBT appears to reduce clinical pregnancy and live-birth rates, excellent pregnancy outcomes are achieved. Clinicians must weigh the benefits of DBT against the risk associated with multiple pregnancies in each specific patient before determining the number of blastocysts to be transferred.

Mechanistic study of TRPM2-Ca(2+)-CAMK2-BECN1 signaling in oxidative stress-induced autophagy inhibition.

Reactive oxygen species (ROS) have been commonly accepted as inducers of autophagy, and autophagy in turn is activated to relieve oxidative stress. Yet, whether and how oxidative stress, generated in various human pathologies, regulates autophagy remains unknown. Here, we mechanistically studied the role of TRPM2 (transient receptor potential cation channel subfamily M member 2)-mediated Ca(2+) influx in oxidative stress-mediated autophagy regulation. On the one hand, we demonstrated that oxidative stress triggered TRPM2-dependent Ca(2+) influx to inhibit the induction of early autophagy, which renders cells more susceptible to death. On the other hand, oxidative stress induced autophagy (and not cell death) in the absence of the TRPM2-mediated Ca(2+) influx. Moreover, in response to oxidative stress, TRPM2-mediated Ca(2+) influx activated CAMK2 (calcium/calmodulin dependent protein kinase II) at levels of both phosphorylation and oxidation, and the activated CAMK2 subsequently phosphorylated BECN1/Beclin 1 on Ser295. Ser295 phosphorylation of BECN1 in turn decreased the association between BECN1 and PIK3C3/VPS34, but induced binding between BECN1 and BCL2. Clinically, acetaminophen (APAP) overdose is the most common cause of acute liver failure worldwide. We demonstrated that APAP overdose also activated ROS-TRPM2-CAMK2-BECN1 signaling to suppress autophagy, thereby causing primary hepatocytes to be more vulnerable to death. Inhibiting the TRPM2-Ca(2+)-CAMK2 cascade significantly mitigated APAP-induced liver injury. In summary, our data clearly demonstrate that oxidative stress activates the TRPM2-Ca(2+)-CAMK2 cascade to phosphorylate BECN1 resulting in autophagy inhibition.

Characterizing the malignancy and drug resistance of cancer cells from their membrane resealing response.

In this report, we showed that two tumor cell characteristics, namely the malignancy and drug-resistance status can be evaluated by their membrane resealing response. Specifically, membrane pores in a number of pairs of cancer and normal cell lines originated from nasopharynx, lung and intestine were introduced by nano-mechanical puncturing. Interestingly, such nanometer-sized holes in tumor cells can reseal ~2-3 times faster than those in the corresponding normal cells. Furthermore, the membrane resealing time in cancer cell lines exhibiting resistance to several leading chemotherapeutic drugs was also found to be substantially shorter than that in their drug-sensitive counterparts, demonstrating the potential of using this quantity as a novel marker for future cancer diagnosis and drug resistance detection. Finally, a simple model was proposed to explain the observed resealing dynamics of cells which suggested that the distinct response exhibited by normal, tumor and drug resistant cells is likely due to the different tension levels in their lipid membranes, a conclusion that is also supported by direct cortical tension measurement.

Antiepileptic drugs for the primary and secondary prevention of seizures after intracranial venous thrombosis.

BACKGROUND: Intracranial venous thrombosis (ICVT) commonly presents with seizures in the acute period, and some people may develop recurrent seizures in the long term. The prophylactic use of antiepileptic drugs (AEDs) for the management of post-ICVT seizures is controversial, and there is currently no consensus on the optimal management of post-ICVT seizures. This is an updated version of the Cochrane review first published in theCochrane Database of Systematic Reviews 2006, Issue 3. OBJECTIVES: To assess the effects of AEDs for the primary and secondary prevention of seizures related to ICVT.(1) For the question of primary prevention, we aimed to examine whether AEDs reduce the likelihood of seizures in people who have had an ICVT but have not had a seizure.(2) For the question of secondary prevention, we aimed to examine whether AEDs reduce the likelihood of further seizures in people who have had an ICVT and at least one seizure. SEARCH METHODS: For the latest update, we searched the Cochrane Epilepsy Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO), and MEDLINE (Ovid 1946 onwards) to 20 April 2015, and we checked the reference lists of articles retrieved from the searches. SELECTION CRITERIA: We planned to include all randomised and quasi-randomised controlled trials in which participants with a diagnosis of ICVT were assigned to a treatment group (that is, receiving at least one AED) or control group (receiving placebo or no drug). DATA COLLECTION AND ANALYSIS: Both review authors independently screened and assessed the methodological quality of the studies. If studies had been included in the review, one review author would have extracted the data and another would have checked the extracted data. MAIN RESULTS: No relevant studies were found. AUTHORS' CONCLUSIONS: There is no evidence to support or refute the use of antiepileptic drugs for the primary or secondary prevention of seizures related to intracranial venous thrombosis. Well-designed randomised controlled trials are urgently needed to inform practice. Since the last version of this review no new studies have been found.