<Emphasis Type="Italic">In vitro</Emphasis> Enhancement of Lactate Esters on the Percutaneous Penetration of Drugs with Different Lipophilicity

Lactate esters are widely used as food additives, perfume materials, medicine additives, and personal care products. The objective of this work was to investigate the effect of a series of lactate esters as penetration enhancers on the in vitro skin permeation of four drugs with different physicochemical properties, including ibuprofen, salicylic acid, dexamethasone and 5-fluorouracil. The saturated donor solutions of the evaluated drugs in propylene glycol were used in order to keep a constant driving force with maximum thermodynamic activity. The permeability coefficient (K _p), skin concentration of drugs (SC), and lag time (T), as well as the enhancement ratios for K _p and SC were recorded. All results indicated that lactate esters can exert a significant influence on the transdermal delivery of the model drugs and there is a structure-activity relationship between the tested lactate esters and their enhancement effects. The results also suggested that the lactate esters with the chain length of fatty alcohol moieties of 10–12 are more effective enhancers. Furthermore, the enhancement effect of lactate esters increases with a decrease of the drug lipophilicity, which suggests that they may be more efficient at enhancing the penetration of hydrophilic drugs than lipophilic drugs. The influence of the concentration of lactate esters was evaluated and the optimal concentration is in the range of 5∼10 wt.%. In sum, lactate esters as a penetration enhancer for some drugs are of interest for transdermal administration when the safety of penetration enhancers is a prime consideration.     

Proton Pump Inhibitors and the Risk of Adverse Cardiac Events

Background

Recent evidence suggests that proton pump inhibitors (PPIs) might be linked with adverse cardiac events, but a causal relationship is unproven.

Methods

We applied the self-matched case series method to two studies using population-based health care data from Ontario, Canada between 1996 and 2008. The first included subjects aged 66 years or older hospitalized for acute myocardial infarction within 12 weeks following initiation of PPI, while the second included subjects hospitalized for heart failure. In both studies we designated the primary risk interval as the initial 4 weeks of therapy and the control interval as the final 4 weeks. To test the specificity of our findings we examined use of histamine H2 receptor antagonists and benzodiazepines, drugs with no plausible causal link to adverse cardiac events.

Results

During the 13-year study period, we identified 5550 hospital admissions for acute myocardial infarction and 6003 admissions for heart failure within 12 weeks of commencing PPI therapy. In the main analyses, we found that initiation of a PPI was associated with a higher risk of acute myocardial infarction (odds ratio 1.8; 95% confidence interval 1.7 to 1.9) and heart failure (odds ratio 1.8; 95% confidence interval 1.7 to 1.9). However, secondary analyses revealed similar risk estimates histamine H2 receptor antagonists and benzodiazepines, drugs with no known or suspected association with adverse cardiac events.

Conclusion

PPIs are associated with a short-term risk of adverse cardiac events, but similar associations are seen with other drugs exhibiting no known cardiac toxicity. Collectively these observations suggest that the association between PPIs and adverse cardiac events does not represent reflect cause-and-effect.     

Cardiovascular disease after Escherichia coli O157:H7 gastroenteritis

Background:

Escherichia coli O157:H7 is one cause of acute bacterial gastroenteritis, which can be devastating in outbreak situations. We studied the risk of cardiovascular disease following such an outbreak in Walkerton, Ontario, in May 2000.

Methods:

In this community-based cohort study, we linked data from the Walkerton Health Study (2002–2008) to Ontario’s large healthcare databases. We included 4 groups of adults: 3 groups of Walkerton participants (153 with severe gastroenteritis, 414 with mild gastroenteritis, 331 with no gastroenteritis) and a group of 11 263 residents from the surrounding communities that were unaffected by the outbreak. The primary outcome was a composite of death or first major cardiovascular event (admission to hospital for acute myocardial infarction, stroke or congestive heart failure, or evidence of associated procedures). The secondary outcome was first major cardiovascular event censored for death. Adults were followed for an average of 7.4 years.

Results:

During the study period, 1174 adults (9.7%) died or experienced a major cardiovascular event. Compared with residents of the surrounding communities, the risk of death or cardiovascular event was not elevated among Walkerton participants with severe or mild gastroenteritis (hazard ratio [HR] for severe gastroenteritis 0.74, 95% confidence interval [CI] 0.38–1.43, mild gastroenteritis HR 0.64, 95% CI 0.42–0.98). Compared with Walkerton participants who had no gastroenteritis, risk of death or cardiovascular event was not elevated among participants with severe or mild gastroenteritis.

Interpretation:

There was no increase in the risk of cardiovascular disease in the decade following acute infection during a major E. coli O157:H7 outbreak.Escherichia coli O157:H7 is one cause of acute bacterial gastroenteritis, causing 63 000 infections each year and 12 major outbreaks since 2006 in the United States alone.^1,2 This strain was most recently implicated in the outbreak involving beef from XL Foods (September 2012), with 17 confirmed cases across Canada.³ A similar enterohemorrhagic strain E. coli O104:H4 was responsible for an outbreak in Germany in May 2011, causing 3792 cases of gastroenteritis and 43 deaths.^4,5Most patients fully recover from acute gastroenteritis caused by E. coli. However, such an illness may predispose patients to long-term disease. Shiga toxin is produced by E. coli O157:H7; this toxin damages the microvasculature of the kidneys leading to hypertension^6–13 and directly damages the systemic vasculature.^14–16 Infected people may progress from a state of acute inflammation of the vasculature to subclinical chronic inflammation, which could promote atherosclerosis.^17–20In Walkerton, Ontario, in May 2000, heavy rains transported bovine fecal matter into the town’s well, contaminating the inadequately chlorinated municipal water supply with E. coli O157:H7.²¹ Over 2300 people developed acute gastroenteritis, and 7 people died.²² The unique circumstances of this outbreak provided a rare opportunity to study the natural history following exposure to this pathogen in a single cohort.²³ Other outbreaks have been geographically dispersed, making it difficult to track cases.^24,25In Walkerton, affected individuals were followed annually in a clinic to assess their long-term outcomes (Walkerton Health Study, 2002–2008). We previously reported that adults who experienced acute gastroenteritis during the outbreak had a higher than expected incidence of hypertension, chronic kidney disease and self-reported cardiovascular disease in follow-up.²³ However, 46% of participants were lost to follow-up by the end of the study, and there were limitations associated with the assessment of cardiovascular disease by participant recall. Thus, we conducted an expanded and extended follow-up study, linking the Walkerton study data to Ontario’s health care databases. Our objective was to more accurately determine the 10-year risk of major cardiovascular events after exposure to E. coli O157:H7.     

Synthesis and evaluation of aminobenzothiazoles as blockers of N- and T-type calcium channels

Both N- and T-type calcium ion channels have been implicated in pain transmission and the N-type channel is a well-validated target for the treatment of neuropathic pain. An SAR investigation of a series of substituted aminobenzothiazoles identified a subset of five compounds with comparable activity to the positive control Z160 in a FLIPR-based intracellular calcium response assay measuring potency at both Ca_V2.2 and Ca_V3.2 channels. These compounds may form the basis for the development of drug leads and tool compounds for assessing in vivo effects of variable modulation of Ca_V2.2 and Ca_V3.2 channels.     

2001-2019年台风干扰下我国东南沿海地区植被抵抗力和恢复力评估

台风是影响我国陆地生态系统结构和功能的主要自然灾害之一,尤其对东南沿海地区植被具有明显的干扰效应。为深入了解台风对我国沿海地区植被的影响及其响应,基于MODIS增强型植被指数(Enhanced Vegetation Index, EVI)和叶面积指数(Leaf Area Index, LAI),分析了2001-2019年间不同等级的台风对植被EVI和LAI的影响,评估台风登陆时植被的抵抗力及台风过后植被的恢复力。结果表明:(1)2001-2019年间,共有70个台风登陆我国东南沿海地区,其中,台风(TY)、强台风(STY)与超强台风(SuperTY)的数量分别为35、26和9个。我国台湾省的台风登陆次数最多,为26个,其次为广东省(20个);(2)在整个研究区范围内,台风(TY)、强台风(STY)与超强台风(SuperTY) 登陆后的EVI净变化率分别为4.88%、-7.48%、-1.85%,LAI净变化率分别为22.28%、-65.70%、-17.60%;(3)在经历台风干扰后,沿海地区大部分植被可在3个月之内得到恢复,其中浙江省与广东省植被的恢复时间较长,海南省与台湾省植被的恢复时间较短。研究结果对我国沿海地区森林经营管理和生态环境保护具有重要意义。     

生境不完全重叠的两种鲤科鱼类耐低氧及运动能力比较

以乌江流域亲缘关系近,但分布并不完全重叠的马口鱼(Opsariichthys bidens)和宽鳍鱲(Zacco platypus)作为实验对象,分别考察这两种实验鱼的低氧耐受及游泳运动能力。将野外采回的实验鱼置于(25±1)℃条件下,分别测定两种鱼的临界氧分压(Pcrit)、水面呼吸(ASR)、失去平衡点(LOE)以及在不同溶氧水平(8.0、4.0和2.0 mg/L)下的临界游泳速度(Ucrit)和活跃耗氧率(MO2active)。研究发现:马口鱼的Pcrit(2.44±0.20)mg/L显著高于宽鳍鱲(1.86±0.10)mg/L(P=0.031)。但马口鱼的50%ASR(1.23±0.16)mg/L显著低于宽鳍鱲(1.97±0.11)mg/L(P=0.023);马口鱼的50%LOE(0.84±0.01)mg/L同样显著低于宽鳍鱲(0.97±0.02)mg/L(P=0.004)。宽鳍鱲在8.0和4.0 mg/L下的游泳能力显著高于马口鱼,然而马口鱼和宽鳍鱲的Ucrit均随测定溶氧水平的下降而显著降低(P0.01);宽鳍鱲和马口鱼的运动耗氧率均随水流速度的增加而呈现指数增加,但随测定溶氧水平的降低运动耗氧曲线变得相对平缓,尤其是在溶氧为4.0 mg/L时马口鱼的运动耗氧曲线与宽鳍鱲相比越发平缓;两种实验鱼的MO2active随溶氧水平下降的变化趋势与Ucrit相似(P0.001)。结果表明:两种野外生存的实验鱼不仅在低氧耐受能力方面存在显著差异,而且两者的游泳运动能力也有不同表现,这很有可能与其遗传特征、生存环境及生态习性相关。     

Postpartum mental illness during the COVID-19 pandemic: a population-based,repeated cross-sectional study

BACKGROUND:It is unclear whether the clinical burden of postpartum mental illness has increased during the COVID-19 pandemic. We sought to compare physician visit rates for postpartum mental illness in Ontario, Canada, during the pandemic with rates expected based on prepandemic patterns.METHODS:In this population-based, repeated cross-sectional study using linked health administrative databases in Ontario, Canada, we used negative binomial regression to model expected visit rates per 1000 postpartum people for March–November 2020 based on prepandemic data (January 2016–February 2020). We compared observed visit rates to expected visit rates for each month of the pandemic period, generating absolute rate differences, incidence rate ratios (IRRs) and their 95% confidence intervals (CIs). The primary outcome was a visit to a primary care physician or a psychiatrist for any mental disorder. We stratified analyses by maternal sociodemographic characteristics.RESULTS:In March 2020, the visit rate was 43.5/1000, with a rate difference of 3.11/1000 (95% CI 1.25–4.89) and an IRR of 1.08 (95% CI 1.03–1.13) compared with the expected rate. In April, the rate difference (10.9/1000, 95% CI 9.14–12.6) and IRR (1.30, 95% CI 1.24–1.36) were higher; this level was generally sustained through November 2020. From April–November, we observed elevated visit rates across provider types and for diagnoses of anxiety, depressive and alcohol or substance use disorders. Observed increases from expected visit rates were greater for people 0–90 days postpartum compared with 91–365 days postpartum; increases were small among people living in low-income neighbourhoods. Public health units in the northern areas of the province did not see sustained elevations in visit rates after July; southern health units had elevated rates through to November.INTERPRETATION:Increased visits for mental health conditions among postpartum people during the first 9 months of the COVID-19 pandemic suggest an increased need for effective and accessible mental health care for this population as the pandemic progresses.

Postpartum mental illness affects as many as 1 in 5 mothers,¹ and can result in maternal suffering and diminished functioning.² Related impaired mother–infant interactions are linked to poor social, cognitive and behavioural outcomes in children across their lifespan.³ When mental illness becomes chronic and recurrent, its effects can extend to the entire family and across generations.⁴ With emergence of the novel coronavirus (SARS-CoV-2), the World Health Organization declared a global COVID-19 pandemic on Mar. 11, 2020. Globally, efforts to contain the virus have led to widespread travel restrictions, physical distancing and work limitations, causing broad social and financial disruption that has been associated with substantial mental health effects.^5,6During the COVID-19 pandemic, people have been reporting concerns about postpartum infection,⁷ and difficulty accessing the extended postpartum social support networks and key community programs that protect against mental illness, such as home visits from public health nurses, breastfeeding clinics and support groups, owing to public health measures.⁸ In Canadian surveys, about 50% of pregnant people reported psychological distress in spring 2020,⁹ and alcohol use increased among women, particularly among those with young children.¹⁰ Whether this represents an increased clinical burden of mental illness or need for care is unknown.Using routinely collected health care data from Ontario, Canada, (population of about 14.6 million), we aimed to examine whether rates of maternal visits to physicians for postpartum mental illness from March to November 2020 differed from expected visit rates based on pre-COVID-19 patterns, and to identify variation by provider type, clinical diagnosis, postpartum timing, parity, income, ethnicity and region of residence.     

基于废物资源化的美极梅奇酵母产油研究现状及应用潜力分析

清洁可再生能源生物柴油的开发利用是对当今能源短缺环境下化石燃料替代物的有益探索。微生物油脂作为一种可能实现生物柴油廉价、高效生产的原料引起了广泛的关注,但由于封闭式培养模式操作复杂、成本高制约了其大规模应用。美极梅奇酵母Metschnikowia pulcherrmia是一种新型产油酵母,具有适应性强、底物利用范围广、可在开放体系培养等特点,很有潜力代替传统产油微生物,实现基于生物柴油的废水及固废能源化工程应用。文中对美极梅奇酵母相关研究开展了全面调研,在分析其产油研究及应用现状的基础上,总结了美极梅奇酵母在油脂生产方面所具有的独特优势和关键影响因素,突出强调了其在开放体系培养及利用有机废弃物生产微生物油脂的可行性。此外,文中还指出了美极梅奇酵母在油脂产量、产油机理等方面存在的问题与不足,为实现生物柴油高效生产提供了新的方向和思路,有利于进一步促进其工业化应用。