Betel Nut Chewing Was Associated with Obstructive Lung Disease in a Large Taiwanese Population Study

The prevalence of betel nut chewing in Taiwan is high at approximately 7%, however, few studies have evaluated the relationship between betel nut chewing and lung disease. Therefore, the aim of this study was to investigate associations between betel nut chewing and lung function in 80,877 participants in the Taiwan Biobank (TWB). We further investigated correlations between betel nut chewing characteristics such as years of use, frequency, daily amount, and accumulative dose, with obstructive lung disease. We used data from the TWB. Lung function was assessed using spirometry measurements of forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1). The participants were classified into normal lung function and obstructive lung function (FEV1/FVC < 70%) groups. The participants were asked questions about betel nut chewing, including years of use, frequency, and daily amount. After multivariable analysis, betel nut chewing (odds ratio [OR] = 1.159; p < 0.001) was significantly associated with FEV1/FVC < 70% in all participants (n = 80,877). Further, in the participants who chewed betel nut (n = 5135), a long duration of betel nut chewing (per 1 year; OR = 1.008; p = 0.012), betel nut use every day (vs. 1–3 days/month; OR = 1.793; p = 0.036), 10–20 quids a day (vs. <10 quids; OR = 1.404; p = 0.019), 21–30 quids a day (vs. <10 quids; OR = 1.662; p = 0.010), ≥31 quids a day (vs. <10 quids; OR = 1.717; p = 0.003), and high cumulative dose (per 1 year × frequency × daily score; OR = 1.001; p = 0.002) were significantly associated with FEV1/FVC < 70%. In this large population-based cohort study, chewing betel nut was associated with obstructive lung disease. Furthermore, a long duration of betel nut chewing, more frequent use, higher daily amount, and high cumulative dose were associated with obstructive lung disease. This suggests that preventing betel nut chewing should be considered to reduce obstructive lung disease in Taiwan.

Premedication with pioglitazone prevents doxorubicin-induced left ventricular dysfunction in mice

Background Doxorubicin (DOX) is widely used as an effective chemotherapeutic agent for cancers; however, DOX induces cardiac toxicity, called DOX-induced cardiomyopathy. Although DOX-induced cardiomyopathy is known to be associated with a high cumulative dose of DOX, the mechanisms of its long-term effects have not been completely elucidated. Pioglitazone (Pio) is presently contraindicated in patients with symptomatic heart failure owing to the side effects. The concept of drug repositioning led us to hypothesize the potential effects of Pio as a premedication before DOX treatment, and to analyze this hypothesis in mice. Methods First, for the hyperacute (day 1) and acute (day 7) DOX-induced dysfunction models, mice were fed a standard diet with or without 0.02% (wt/wt) Pio for 5 days before DOX treatment (15 mg/kg body weight [BW] via intraperitoneal [i.p.] administration). The following 3 treatment groups were analyzed: standard diet + vehicle (Vehicle), standard diet + DOX (DOX), and Pio + DOX. Next, for the chronic model (day 35), the mice were administrated DOX once a week for 5 weeks (5 mg/kg BW/week, i.p.). Results In the acute phase after DOX treatment, the percent fractional shortening of the left ventricle (LV) was significantly decreased in DOX mice. This cardiac malfunction was improved in Pio + DOX mice. In the chronic phase, we observed that LV function was preserved in Pio + DOX mice. Conclusions Our findings may provide a new pathophysiological explanation by which Pio plays a role in the treatment of DOX-induced cardiomyopathy, but the molecular links between Pio and DOX-induced LV dysfunction remain largely elusive.

A comparative study of the effects of Aducanumab and scanning ultrasound on amyloid plaques and behavior in the APP23 mouse model of Alzheimer disease

Background Aducanumab is an anti-amyloid-β (Aβ) antibody that achieved reduced amyloid pathology in Alzheimer’s disease (AD) trials; however, it is controversial whether it also improved cognition, which has been suggested would require a sufficiently high cumulative dose of the antibody in the brain. Therapeutic ultrasound, in contrast, has only begun to be investigated in human AD clinical trials. We have previously shown that scanning ultrasound in combination with intravenously injected microbubbles (SUS), which temporarily and safely opens the blood-brain barrier (BBB), removes amyloid and restores cognition in APP23 mice. However, there has been no direct testing of how the effects of SUS compare to immunotherapy or whether a combination therapy is more effective. Methods In a study comprising four treatment arms, we tested the efficacy of an Aducanumab analog, Adu, both in comparison to SUS, and as a combination therapy, in APP23 mice (aged 13–22 months), using sham as a control. The active place avoidance (APA) test was used to test spatial memory, and histology and ELISA were used to measure amyloid. Brain antibody levels were also determined. Results We found that both Adu and SUS reduced the total plaque area in the hippocampus with no additive effect observed with the combination treatment (SUS + Adu). Whereas in the cortex where there was a trend towards reducing the total plaque area from either Adu or SUS, only the combination treatment yielded a statistically significant decrease in total plaque area compared to sham. Only the SUS and SUS + Adu groups included animals that had their plaque load reduced to below 1% from above 10%. There was a robust improvement in spatial memory for the SUS + Adu group only, and in this group the level of Adu, when measured 3 days post-treatment, was 5-fold higher compared to those mice that received Adu on its own. Together, these findings suggest that SUS should be considered as a treatment option for AD. Alternatively, a combination trial using Aducanumab together with ultrasound to increase brain levels of the antibody may be warranted.

Coronary microcirculation damage in anthracycline cardiotoxicity

Aims The aim of this study was to study changes in coronary microcirculation status during and after several cycles of anthracycline treatment. Methods and Results Large-White male pigs (n = 40) were included in different experimental protocols (ExPr.) according to anthracycline cumulative exposure (0.45 mg/kg intracoronary (IC) doxorubicin per injection) and follow-up: Control (no doxorubicin); Single injection and sacrifice either at 48 hours (ExPr. 1) or 2 weeks (ExPr. 2); Three injections two weeks apart (low cumulative dose) and sacrifice either 2 weeks (ExPr. 3) or 12 weeks (ExPr. 4) after third injection; Five injections two weeks apart (high cumulative dose) and sacrifice 8 weeks after fifth injection (ExPr. 5). All groups were assessed by serial cardiac magnetic resonance (CMR) to quantify perfusion and invasive measurement of coronary flow reserve (CFR). At the end of each protocol, animals were sacrificed for ex vivo analyses. Vascular function was further evaluated by myography in explanted coronary arteries of pigs undergoing ExPr. 3 and controls. A single doxorubicin injection had no impact on microcirculation status, excluding a direct chemical toxicity. A series of five fortnightly doxorubicin injections (high cumulative dose) triggered a progressive decline in microcirculation status, evidenced by reduced CMR-based myocardial perfusion and CFR-measured impaired functional microcirculation. In the high cumulative dose regime (ExPr. 5), microcirculation changes appeared long before any contractile defect became apparent. Low cumulative doxorubicin dose (3 biweekly injections) was not associated with any contractile defect across long-term follow-up, but provoked persistent microcirculation damage, evident soon after third dose injection. Histological and myograph evaluations confirmed structural damage to arteries of all calibers even in animals undergoing low cumulative dose regimes. Conversely, arteriole damage and capillary bed alteration occurred only after high cumulative dose regime. Conclusion Serial in vivo evaluations of microcirculation status using state-of-the-art CMR and invasive CFR show that anthracyclines treatment is associated with progressive and irreversible damage to the microcirculation. This long-persisting damage is present even in low cumulative dose regimes, which are not associated with cardiac contractile deficits. Microcirculation damage might explain some of the increased incidence of cardiovascular events in cancer survivors who received anthracyclines without showing cardiac contractile defects.

A comparative study of the effects of Aducanumab and scanning ultrasound on amyloid plaques and behavior in the APP23 mouse model of Alzheimer disease

BackgroundAducanumab is an anti-amyloid-β (Aβ) antibody that achieved reduced amyloid pathology in Alzheimer’s disease (AD) trials, but it is controversial whether it also improved cognition. It has been claimed that this would require a sufficiently high cumulative dose of the antibody in the brain. Therapeutic ultrasound, in contrast, has only begun to be investigated in human AD clinical trials. We have previously shown that scanning ultrasound in combination with intravenously injected microbubbles (SUS), that temporarily and safely opens the blood-brain barrier (BBB), removes amyloid and restores cognition in APP23 mice. It has not been directly tested how the effects of SUS compare to immunotherapy or whether a combination therapy is more effective.MethodsIn a study comprising four treatment arms, we tested the efficacy of an Aducanumab analogue, Adu, in comparison to SUS, as well as a combination therapy in APP23 mice, using sham as a control (aged 13-22 months). The active place avoidance (APA) test was used to test spatial memory, and histology and ELISA were used to measure amyloid. Brain antibody levels were also determined.ResultsWe found that both Adu and SUS reduced the total plaque area in the hippocampus to a similar degree, with no additive effect in the combination treatment (SUS+Adu). Whereas there was only a trend towards a reduction for both Adu and SUS in the cortex, the combination trial yielded a statistically significant reduction compared to sham. Only the SUS and SUS+Adu groups included animals that had their plaque load reduced to below 1% from above 10%. There was a robust improvement in spatial memory for SUS+Adu only. In this group, when measured three days post-treatment, Adu levels were still 5-fold increased in the combination therapy compared to delivery of Adu on its own.Together, these findings suggest that SUS should be seriously considered as a treatment option for AD. Alternatively, a combination trial using Aducanumab together with ultrasound to increase brain levels of Aducanumab may be warranted, as the two approaches may engage different (albeit shared) clearance mechanisms.

Association between Use of Hydrochlorothiazide and Nonmelanoma Skin Cancer: Common Data Model Cohort Study in Asian Population

Although hydrochlorothiazide (HCTZ) has been suggested to increase skin cancer risk in white Westerners, there is scant evidence for the same in Asians. We analyzed the association between the use of hydrochlorothiazide and non-melanoma in the Asian population using the common data model. Methods: A retrospective multicenter observational study was conducted using a distributed research network to analyze the effect of HCTZ on skin cancer from 2004 to 2018. We performed Cox regression to evaluate the effects by comparing the use of HCTZ with other antihypertensive drugs. All analyses were re-evaluated using matched data using the propensity score matching (PSM). Then, the overall effects were evaluated by combining results with the meta-analysis. Results: Positive associations were observed in the use of HCTZ with high cumulative dose for non-melanoma skin cancer (NMSC) in univariate analysis prior to the use of PSM. Some negative associations were observed in the use of low and medium cumulative doses. Conclusion: Although many findings in our study were inconclusive, there was a non-significant association of a dose-response pattern with estimates increasing in cumulative dose of HCTZ. In particular, a trend with a non-significant positive association was observed with the high cumulative dose of HCTZ.

An association of intrapartum synthetic oxytocin dosing and the odds of developing autism

A case-control study was performed to determine whether an association exists between exposure to synthetic oxytocin and a subsequent autism spectrum disorder diagnosis; 171 children under age 18 meeting Diagnostic and Statistical Manual of Mental Disorders (5th ed.) autism spectrum disorder criteria were compared to 171 children without autism spectrum disorder diagnosis matched by gender, birth year, gestational age, and maternal age at birth. A conditional logistic regression model was used to examine the association of clinical variables and autism spectrum disorder. Significantly elevated odds ratios for autism spectrum disorder were associated with first-time Cesarean section (odds ratio = 2.56), but not a repeat Cesarean section. Odds ratios were also significantly elevated for subjects whose mother’s body mass index was 35 or higher at birth (odds ratio = 2.34) and subjects in which the reason for delivery was categorized as “fetal indication” (odds ratio = 2.00). When controlling for these and other variables, the odds of developing autism spectrum disorder were significantly elevated in males with long duration of exposure (odds ratio = 3.48) and high cumulative dose of synthetic oxytocin (odds ratio = 2.79). No significant associations of synthetic oxytocin dosing and autism spectrum disorder were noted in female subjects. The association of elevated autism spectrum disorder odds found with high duration and high cumulative dose synthetic oxytocin in male subjects suggests the need for further investigation to fully elucidate any cause and effect relationship. Lay abstract Oxytocin is a hormone naturally produced in the human body that can make the womb (uterus) contract during labor. Manufactured oxytocin is frequently given to mothers in labor to strengthen the contractions or in some cases to start labor. This study compared children with a diagnosis of autism and children without autism to see whether children with autism received more oxytocin during labor. The odds of a child having an autism diagnosis were significantly higher if the delivery was a first-time Cesarean section, if the mother had a body mass index of 35 or higher, or if the reason for delivery were a range of fetal problems that made delivery necessary. It was found that boys who were exposed to oxytocin for longer periods of time during labor and received higher total doses of oxytocin had significantly higher odds of developing autism. There were no significant associations of oxytocin dosing and autism noted in female children. As this is the first study to look at any relationship between the dose of oxytocin received during labor and the odds of developing autism, further study needs to be done to determine whether there is any cause and effect relationship. Thus, at this time, there is no recommended change in clinical practice.

Prevalence of Major Cardiac Events of Anthracycline-Induced Cardiotoxicity in Southwestern Iran: Different Response Patterns to Cumulative Dose

Background: Anthracyclines are widely used chemotherapeutic agents in several cancers. Since its use, survival improved significantly among cancer patients and has been reported to be up to 80%. However, anthracyclines possess several cardiac, renal and hematological toxicities which limit their use in practice. Cardiotoxicity is still the most important and dose-limiting side effect of anthracycline treatment. Here we aimed to investigate the frequency of anthracyclineinduced cardiomyopathy in pediatric malignancies in Khuzestan Province, Iran. Methods: A total of 112 patients were enrolled in the present study. Patients were allocated to the case or control group based on receiving anthracycline. Echocardiographic examinations were performed by a cardiologist. Electrocardiograms were also recorded. Results: We showed that cancer patients who underwent anthracycline treatment showed cardiomyopathy as defined by lower LVEF (Left Ventricular Ejection Fraction) among patients (p = 0.041). Abnormal LVEF was reported with a frequency of about 9.5% in patients (p = 0.026). However, LVFS (Left Ventricular Fraction Shortening), QRS voltage and QT interval did not differ significantly between treatment and control groups. Our data analysis revealed that this difference is mainly related to high cumulative dose since high cumulative dose of anthracycline (>300 mg/m2) leads to lower LVEF and LVFS and higher QRS voltage in comparison with lower cumulative dose (<300 mg/m2) and control group; but there was no significant difference between low dose and control group. Different age groups and type of malignancy including hematological and solid tumors did not show any significant differences for echocardiographic and electrocardiograms parameters. Conclusion: In our study, lower LVEF among patients who received anthracyclines were mainly related to a high cumulative dose of anthracyclines, which emphasizes the effect of cumulative dose for cardiotoxic effects. Larger studies are needed to investigate possible other risk factors for cardiotoxicity.