Shou-En Lu

Sleep-disordered breathing advances cognitive decline in the elderly

Objective: To examine whether the presence of sleep-disordered breathing (SDB) is associated with an earlier age at mild cognitive impairment (MCI) or Alzheimer disease (AD)-dementia onset in participants from the Alzheimers Disease Neuroimaging Initiative (ADNI) cohort. We also examined whether continuous positive airway pressure (CPAP) use is associated with delayed onset of cognitive decline. Methods: From the ADNI cohort, 3 subsets with progressively stringent criteria were created in a step-wise manner. Age at MCI or AD-dementia onset was the main outcome variable. Analyses were performed separately for each subset in untreated SDB+ vs SDB− and untreated SDB+ vs CPAP+ groups. Chi-square and t tests were performed to examine between-group differences. Survival analyses were performed using the Kaplan–Meier method, compared by the log-rank test, and assessed by multivariate Cox regression adjusting for potential confounders. Results: SDB+ patients had a younger age at MCI onset in all subsets (MC1: 72.63 vs 83.67; MC2: 72.15 vs 83.45; MC3: 77.40 vs 89.89; p < 0.01). SDB+ patients had a younger age at AD-dementia onset only in our most conservative subset (AC3: 83.46 vs 88.13; p < 0.05). In a combined outcome analysis, SDB+ patients had a younger age at onset to MCI or AD-dementia in all subsets. In subsets 1 and 2, CPAP use delayed the age at MCI onset (CMC1: 72.63 vs 82.10; CMC2: 72.11 vs 82.10; p < 0.01). Conclusions: Consistent with our hypothesis, the presence of SDB was associated with an earlier age at cognitive decline. Our findings in CPAP+ participants suggest that CPAP treatment of SDB may delay progression of cognitive impairment.

Psychiatric Disorders and Asthma Outcomes Among High-risk Inner-city Patients

Objective: The purpose of this study was to examine the rate of psychiatric disorders among patients attending an ethnically diverse, inner-city asthma clinic for an initial visit and assess the association between psychiatric disorders and asthma morbidity. Methods: A semistructured psychological interview was conducted to assess for psychiatric diagnoses. A pulmonary physician, who was blind to psychiatric disorder, established diagnosis of asthma based on national guidelines. Results: Sixty-four percent of 85 participants received at least 1 psychiatric diagnosis. The pulmonary physician rated patients with a psychiatric disorder as achieving fewer goals (M = 2.3 ± 1.3) for asthma control than patients without a psychiatric disorder (M = 3.6 ± 1.5, p = .0002). Patients with a psychiatric diagnosis more frequently reported an emergency room visit for asthma during the past 6 months (OR = 4.89; 95% CI, 1.76–13.39) and greater use of short-acting β2-agonist medication (M = 1.5 ± 0.9 canisters per month) than patients without a psychiatric diagnosis (M = 0.9 ± 0.8, p = .003). These findings were independent of demographics, health insurance, and asthma severity. No differences emerged between patients with and without a mental disorder on percent predicted FEV1. Patients with a psychiatric disorder reported a higher severity level for asthma symptoms than the severity level indicated by their pulmonary function in comparison to patients without a psychiatric diagnosis (OR = 3.52; 95% CI, 1.23–10.10). Health insurance appeared to be a confounding factor in this relationship. Conclusion: A high rate of psychiatric disorders was found among inner-city asthma patients. Psychiatric diagnoses were associated with greater perceived impairment from asthma but not objective measurement of pulmonary function. ER = emergency room; MDI = metered-dose inhaler; NHLBI = National Heart Lung and Blood Institute; PHQ = Patient Health Questionnaire; SCID-IV = Structured Clinical Interview for DSM-IV; SES = socioeconomic status.

The interaction between sleep-disordered breathing and apolipoprotein E genotype on cerebrospinal fluid biomarkers for Alzheimer's disease in cognitively normal elderly individuals

Previous studies have suggested a link between sleep disordered breathing (SDB) and dementia risk. In the present study, we analyzed the relationship between SDB severity, cerebrospinal fluid (CSF) Alzheimers disease-biomarkers, and the ApoE alleles. A total of 95 cognitively normal elderly participants were analyzed for SDB severity, CSF measures of phosphorylated-tau (p-tau), total-tau (t-tau), and amyloid beta 42 (Aβ-42), as well as ApoE allele status. In ApoE3+ subjects, significant differences were found between sleep groups for p-tau (F[df2] = 4.3, p = 0.017), and t-tau (F[df2] = 3.3, p = 0.043). Additionally, among ApoE3+ subjects, the apnea and/or hypopnea with 4% O2-desaturation index was positively correlated with p-tau (r = 0.30, p = 0.023), t-tau (r = 0.31, p = 0.021), and Aβ-42 (r = 0.31, p = 0.021). In ApoE2+ subjects, the apnea and/or hypopnea with 4% O2-desaturation index was correlated with lower levels of CSF Aβ-42 (r = -0.71, p = 0.004), similarly to ApoE4+ subjects where there was also a trend toward lower CSF Aβ-42 levels. Our observations suggest that there is an association between SDB and CSF Alzheimers disease-biomarkers in cognitively normal elderly individuals. Existing therapies for SDB such as continuous positive airway pressure could delay the onset to mild cognitive impairment or dementia in normal elderly individuals.

Influence of Acute Epinephrine Infusion on Endotoxin Induced Parameters of Heart Rate Variability: A Randomized Controlled Trial

Objective:To determine whether the acute anti-inflammatory influence of epinephrine (EPI) extends to changes in heart rate variability (HRV) induced by the prototypical inflammatory stimulus, endotoxin (lipopolysaccharide [LPS]). Summary Background Data:HRV reflects fluctuating cardiac autonomic inputs and is acutely reduced during the systemic inflammation induced by LPS as well as during severe critical illnesses such as sepsis and traumatic injury. While EPI may diminish proinflammatory cytokine release, it is unknown whether this net anti-inflammatory activity extends to HRV. Methods:Healthy volunteers (n = 17) were randomized to either saline + LPS (2 ng/kg) or LPS + antecedent EPI infusion (30 ng/kg/min) from −3 to 6 hours relative to LPS. HRV and blood samples were obtained before EPI and LPS as well as hourly afterward. Plasma cytokines were measured by ELISA. Statistical analysis was by repeated measures analysis of variance. This study was registered at Clinicaltrials.gov and is listed under the following ID number: NCT00753402. Results:LPS acutely influenced all measured parameters of HRV including standard deviation of the average beat to beat intervals over a 5-minute period, percentage of interval differences of successive interbeat intervals greater than 50 milliseconds and square root of the mean squared differences, high frequency (HF), low frequency, low frequency/HF, and very low frequency (all P < 0.01). EPI infusion reduced the inflammatory cytokine response to LPS as measured by decreased TNF&agr;, IL-6, and IL-8 (P < 0.01). Relative to the saline + LPS group, antecedent EPI infusion was associated with further reductions in parameters of HRV measuring vagal/parasympathetic activity including, percentage of interval differences of successive interbeat intervals greater than 50 milliseconds, square root of the mean squared differences, and HF (P < 0.05). Conclusion:Prior EPI exposure exerts anti-inflammatory influences but also may reduce vagus nerve activity. Hence, acute EPI administration may be protective against early inflammatory challenges but diminish vagal nerve responsiveness to subsequent stimuli.

Shorter interpuff interval is associated with higher nicotine intake in smokers with schizophrenia

BACKGROUND People with schizophrenia are frequent and heavy smokers. METHODS The objective of this study was to measure serum nicotine levels and ad libitum smoking behavior for 24+2h using the CReSS micro topography device in 75 smokers with schizophrenia (SCZ) and compare these to 86 control smokers (CON) without mental illness. Mean values of repeatedly measured topography variables were compared using three-level nested linear models to adjust for between subject differences and the double nested data. RESULTS Smokers with SCZ smoked more cigarettes in the 24h period and took an average of 2.8 more puffs per cigarette than CON (p<0.001). The time between puffs, or interpuff interval (IPI), was shorter in SCZ by an average of 6.5s (p<0.001). The peak flow rate was higher in SCZ by an average of 4.9 ml/s (p<0.05). Smokers with SCZ spent an average of 1.0 min less time smoking a single cigarette vs. CON (p<0.001). Smokers with SCZ also had shorter IPI and more puffs per cigarette in an analysis of first cigarette of the day. For all subjects, a decrease in IPI by 1s was associated with an increase in serum nicotine of 0.19 ng/ml and in cotinine of 5.01 ng/ml (both p<0.05). After controlling for diagnosis group, higher craving scores on QSU Factor 2 (urgent desire to smoke) were associated with shorter IPI. DISCUSSION Smokers with schizophrenia demonstrate more intense cigarette puffing that is associated with greater nicotine intake. This pattern may provide insight into other heavily dependent smokers.

Interaction between sleep-disordered breathing and apolipoprotein E genotype on cerebrospinal fluid biomarkers for Alzheimer's disease in cognitively normal elderly individuals.

Previous studies have suggested a link between sleep disordered breathing (SDB) and dementia risk. In the present study, we analyzed the relationship between SDB severity, cerebrospinal fluid (CSF) Alzheimers disease-biomarkers, and the ApoE alleles. A total of 95 cognitively normal elderly participants were analyzed for SDB severity, CSF measures of phosphorylated-tau (p-tau), total-tau (t-tau), and amyloid beta 42 (Aβ-42), as well as ApoE allele status. In ApoE3+ subjects, significant differences were found between sleep groups for p-tau (F[df2] = 4.3, p = 0.017), and t-tau (F[df2] = 3.3, p = 0.043). Additionally, among ApoE3+ subjects, the apnea and/or hypopnea with 4% O2-desaturation index was positively correlated with p-tau (r = 0.30, p = 0.023), t-tau (r = 0.31, p = 0.021), and Aβ-42 (r = 0.31, p = 0.021). In ApoE2+ subjects, the apnea and/or hypopnea with 4% O2-desaturation index was correlated with lower levels of CSF Aβ-42 (r = -0.71, p = 0.004), similarly to ApoE4+ subjects where there was also a trend toward lower CSF Aβ-42 levels. Our observations suggest that there is an association between SDB and CSF Alzheimers disease-biomarkers in cognitively normal elderly individuals. Existing therapies for SDB such as continuous positive airway pressure could delay the onset to mild cognitive impairment or dementia in normal elderly individuals.

Long-Term Bone Marrow Suppression During Postoperative Chemotherapy in Rectal Cancer Patients After Preoperative Chemoradiation Therapy

PURPOSE/OBJECTIVE(S) To quantify ensuing bone marrow (BM) suppression during postoperative chemotherapy resulting from preoperative chemoradiation (CRT) therapy for rectal cancer. METHODS AND MATERIALS We retrospectively evaluated 35 patients treated with preoperative CRT followed by postoperative 5-Fluorouracil and oxaliplatin (OxF) chemotherapy for locally advanced rectal cancer. The pelvic bone marrow (PBM) was divided into ilium (IBM), lower pelvis (LPBM), and lumbosacrum (LSBM). Dose volume histograms (DVH) measured the mean doses and percentage of BM volume receiving between 5-40 Gy (i.e.: PBM-V5, LPBM-V5). The Wilcoxon signed rank tests evaluated the differences in absolute hematologic nadirs during neoadjuvant vs. adjuvant treatment. Logistic regressions evaluated the association between dosimetric parameters and ≥ grade 3 hematologic toxicity (HT3) and hematologic event (HE) defined as ≥ grade 2 HT and a dose reduction in OxF. Receiver Operator Characteristic (ROC) curves were constructed to determine optimal threshold values leading to HT3. RESULTS During OxF chemotherapy, 40.0% (n=14) and 48% (n=17) of rectal cancer patients experienced HT3 and HE, respectively. On multivariable logistic regression, increasing pelvic mean dose (PMD) and lower pelvis mean dose (LPMD) along with increasing PBM-V (25-40), LPBM-V25, and LPBM-V40 were significantly associated with HT3 and/or HE during postoperative chemotherapy. Exceeding ≥36.6 Gy to the PMD and ≥32.6 Gy to the LPMD strongly correlated with causing HT3 during postoperative chemotherapy. CONCLUSIONS Neoadjuvant RT for rectal cancer has lasting effects on the pelvic BM, which are demonstrable during adjuvant OxF. Sparing of the BM during preoperative CRT can aid in reducing significant hematologic adverse events and aid in tolerance of postoperative chemotherapy.

Open-Label Study of Craving in Smokers With Schizophrenia Using Nicotine Nasal Spray Compared to Nicotine Patch

ABSTRACT Rationale: Nicotine nasal spray (NNS) may be better for relieving acute cigarette cravings than other nicotine replacement and it may help smokers with schizophrenia because of its rapid onset of action. Objectives: We tested whether NNS was more effective than a nicotine patch (NP; 21 mg) in reducing cue-induced craving during a 3-day abstinence. Methods: Twenty-five smokers with schizophrenia or schizoaffective disorder (SA) were randomized to open-label NNS or NP treatment after baseline measures of craving were assessed. NNS users were instructed to dose at a minimum of 1/hour and up to a maximum of 40/day. Averages from a 4-item visual analogue scale (need, urge, want to smoke, crave a cigarette) measured craving. Results: Five subjects who smoked (4 NP, 1 NNS) were excluded, leaving 21 (11 NP, 10 NNS) for analyses. No differences were detected between groups on baseline craving. On day 3, NNS users reported significantly less craving in response to smoking cues compared to NP users (mean craving scores: NNS, 7.0; NP, 20.3; p = .014). A repeated measure ANCOVA demonstrated significantly reduced craving in the NNS group compared to the NP group from baseline to day 3 (F = 5.09; p = .037). NNS users took an average of 20 doses/day, and NNS was rated as being as easy to use as NP. Conclusions: The potential utility of NNS in smokers with schizophrenia supports the need for placebo-controlled studies.

In vitro comparative studies of resveratrol and triacetylresveratrol on cell proliferation, apoptosis, and STAT3 and NFκB signaling in pancreatic cancer cells.

Resveratrol (RES) has been studied extensively as an anticancer agent. However, the anticancer effects of triacetylresveratrol (TRES, an acetylated analog of RES) which has higher bioavailability have not been well established. We comparatively evaluated their effects on cell proliferation, apoptosis and the molecular changes in STAT3, NFκB and apoptotic signaling pathways in pancreatic cancer cells. Apoptosis was determined by flow cytometry. The nuclear translocation and interaction of STAT3 and NFκB were detected by Western blotting and immunoprecipitation, respectively. Both TRES and RES inhibited cell viability, and induced apoptosis of pancreatic cancer cells in a concentration and incubation time-dependent manner. TRES, similarly to RES, inhibited the phosphorylation of STAT3 and NFκB, down-regulated Mcl-1, and up-regulated Bim and Puma in pancreatic cancer cells. Remarkably, we, for the first time, observed that both TRES and RES suppressed the nuclear translocation, and interrupted the interaction of STAT3 and NFκB in PANC-1 cells. Comparative anticancer effects of TRES and RES on pancreatic cancer suggested that TRES with higher bioavailability may be a potential agent for pancreatic cancer prevention and treatment. Further in vivo experiments and functional studies are warranted to investigate whether TRES exhibits better beneficial effects than RES in mice and humans.

Resilience During War: Better Unit Cohesion and Reductions in Avoidant Coping Are Associated With Better Mental Health Function After Combat Deployment.

Objective: The majority of individuals who endure traumatic events are resilient; however, we do not yet understand why some individuals are more resilient than others. We used data from a prospective longitudinal study Army National Guard and Reserve personnel to examine how unit cohesion (military-specific social support) and avoidant coping relate to resilience over the first year after return from deployment. Method: Soldiers (N = 767) were assessed at 4 phases: predeployment (P1), immediately postdeployment (P2), 3 months’ postdeployment (P3), and 1-year postdeployment (P4). Results: After controlling for predeployment avoidant coping and overall social support, higher unit cohesion was associated with a reduction in avoidant coping (from P1 to P3). This reduction in avoidant coping (from P1 to P3) mediated the relationship between unit cohesion (P2) and improvement in mental health function (from P1 to P3). Conclusions: The results are consistent with the hypothesis that higher unit cohesion may mitigate increases in avoidant coping in military personnel after a combat deployment and in turn may improve mental health function.