Background The pericoronary fat attenuation index (pFAI) has emerged as a marker of coronary inflammation, which is measurable from standard coronary computed tomography angiography (CCTA). It ...compares well with gold-standard methods for the assessment of coronary inflammation and can predict future cardiovascular events. pFAI could prove invaluable to differentiate an inflammatory from a noninflammatory coronary artery status, helping unravel the mechanisms subtending an event classified as myocardial infarction with nonobstructive coronary arteries (MINOCA) or Tako-Tsubo syndrome (TTS). Methods and Results Patients admitted with MINOCA and TTS between 2011 and 2018, who had both CCTA and cardiac magnetic resonance during or shortly after the acute phase, were selected and pFAI measured in their CCTA; pFAI was also measured in control subjects who had CCTA for atypical chest pain workup, no obstructive coronary artery disease found in their CCTA, and no cardiac events at 2-year follow-up. In the n=106 MINOCA/TTS patients, mean pFAI was -68.37±8.29 versus -78.03±6.20 in the n=106 controls (P<0.0001), and the difference was confirmed also when comparing mean pFAI in each coronary artery between MINOCA/TTS and controls (P<0.0001). Nonobstructive coronary plaques at CCTA, high-risk plaques in particular, were more frequently found (P<0.01) in the MINOCA/TTS group compared with controls. Conclusions In MINOCA and TTS patients, CCTA is not only able to detect angiographically invisible atherosclerotic plaques, but its diagnostic yield can be expanded using the simple measurement of pFAI to characterize pericoronary fat tissue; in MINOCA/TTS mean pFAI demonstrates higher values compared with controls, a finding that has been associated with coronary artery inflammation.
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•The 4-azasteroid from diosgenin was prepared in three steps under MW irradiation.•The β-lactam in ring B was achieved from Beckmann rearrangement of the oxime in C-7.•The ...cytotoxicity test of the azasteroidal compounds showed lower toxicity in LPBH.•Lactam-type enamide derivative shows activity in cancer cell line MDA-MB-231.
In this work, we report the synthesis of two new azasteroids through the modification of the A and B rings of diosgenin 1. The 4-azasteroid derivative 12 was prepared in three steps using the α,β-insaturated-3-keto compound 11 as a precursor, which was first oxidized with KMnO4/KIO4 followed by an oxidative cleavage of ring A, and subsequently cyclized with an ammonium salt, under focused microwave irradiation for a short time of 3 min. A second azasteroid was synthesized, for which the key step was the Beckmann rearrangement of ring B of the oxime 16, affording the lactam-type enamide 17 in good yield. The methodologies developed for the synthesis of the precursors derivatives 10 and 11 contribute to improved yields, compared to those reported in the literature. The biological activity of the azasteroidal compounds 12 and 17 and their precursors has been evaluated in cervical cancer cells (HeLa), colon (HCT-15), and triple negative breast cancer (MDA-MB-231) lines.
Background: Despite several investigations, second malignancy risks (SMR) following radiotherapy alone (RT), chemotherapy alone (CT) and combined chemoradiotherapy (CRT) for Hodgkin's lymphoma (HL) ...remain controversial. Patients and Methods: We sought individual patient data from randomised trials comparing RT versus CRT, CT versus CRT, RT versus CT or involved-field (IF) versus extended-field (EF) RT for untreated HL. Overall SMR (including effects of salvage treatment) were compared using Peto's method. Results: Data for between 53% and 69% of patients were obtained for the four comparisons. (i) RT versus CRT (15 trials, 3343 patients): SMR were lower with CRT than with RT as initial treatment (odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.62–0.98 and P = 0.03). (ii) CT versus CRT (16 trials, 2861 patients): SMR were marginally higher with CRT than with CT as initial treatment (OR = 1.38, CI 1.00–1.89 and P = 0.05). (iii) IF-RT versus EF-RT (19 trials, 3221 patients): no significant difference in SMR (P = 0.28) although more breast cancers occurred with EF-RT (P = 0.04 and OR = 3.25). Conclusions: Administration of CT in addition to RT as initial therapy for HL decreases overall SMR by reducing relapse and need for salvage therapy. Administration of RT additional to CT marginally increases overall SMR in advanced stages. Breast cancer risk (but not SMR in general) was substantially higher after EF-RT. Caution is needed in applying these findings to current therapies.
Children and adults with frequent and severe episodes of epilepsy that do not respond to standard treatments (such as carbamazepine, phenytoin and valproate) have long been prescribed cannabidiol ...(CBD) as an anticonvulsant drug. However, the safety of its chronic use in relation to reproduction has not been fully examined. This study aimed to assess the effects of chronic CBD exposure on the male reproductive system. CBD was orally administered to 21‐day‐old male Swiss mice at doses of 15 and 30 mg kg−1 daily (CBD 15 and 30 groups, respectively), with a control group receiving sunflower oil, for 34 consecutive days. After a 35 day recovery period, the following parameters were evaluated: weight of reproductive organs, testosterone concentration, spermatogenesis, histomorphometry, daily sperm production and its morphology. The CBD 30 group had a 76% decrease in total circulating testosterone, but it remained within the physiological normal range (240–1100 ng dl−1). CBD treatment induced a significant increase in the frequency of stages I–IV and V–VI of spermatogenesis, and a decrease in the frequency of stages VII–VIII and XII. A significant decrease in the number of Sertoli cells was observed only in the CBD 30 group. In both CBD groups the number of spermatozoa in the epididymis tail was reduced by 38%, sperm had head abnormalities, and cytoplasmic droplets were observed in the medial region of flagellum. These results indicated that chronic CBD exposure was associated with changes in the male reproductive system, suggesting its reproductive toxicity.
This study aimed to assess the effects of chronic cannabidiol (CBD) exposure on the male reproductive system. CBD was orally administered to 21‐day‐old male Swiss mice at doses of 15 and 30 mg kg−1 for 34 consecutive days. Control group receiving sunflower oil. After a 35 day recovery period, reproductive organ weights, testosterone concentration, spermatogenesis, histomorphometry, daily sperm production and its morphology were evaluated. The results indicated that chronic CBD exposure was associated with changes in the male reproductive system, suggesting its reproductive toxicity.
The effect of solar radiation on the inactivation of multidrug resistant Escherichia coli (MDR) strains selected from an urban wastewater treatment plant (UWWTP) effluent and the change of their ...resistance to a mixture of three antibiotics (evaluated in terms of minimum inhibit concentration (MIC)) in wastewater polluted stream were investigated. The solar photodegradation of the mixture of the three target antibiotics (amoxicillin (AMX), ciprofloxacin (CPX), and sulfamethoxazole (SMZ)) was also evaluated. Additionally, since UWWTP effluents are possible sources of antibiotics and antibiotic resistant bacteria, the disinfection by conventional chlorination process of the UWWTP effluent inoculated with MDR strains was investigated too. Solar radiation poorly affected the inactivation of the two selected antibiotic resistant E. coli strains (40 and 60% after 180min irradiation). Moreover, solar radiation did not affect strain resistance to AMX (MIC>256μg/mL) and SMZ (MIC>1024μg/mL), but affected resistance of the lower resistance strain to CPX (MIC decreased by 33% but only after 180min of irradiation). Chlorination of wastewater sample strongly decreased the number of the two selected antibiotic resistant E. coli strains (99.667 and 99.999%), after 60min of contact time at 2.0mg/L initial chlorine concentration, but the resistance of survived colonies to antibiotics was unchanged. Finally, the solar photodegradation rate of the antibiotic mixture (1mg/L initial concentration respectively) resulted in the following order (half-life time): CPX (t1/2=24min)<AMX (t1/2=99min)<SMZ (t1/2=577min). Accordingly, the risk of the development of resistance to SMZ in surface water is significantly higher compared to CPX and AMX.
► Solar radiation did not affect E. coli strain resistance to AMX and SMZ. ► Solar radiation affected the resistance of one E. coli strain to CPX. ► MIC for CPX decreased by 33% after 180min of solar irradiation. ► Chlorination did not affect E. coli strain resistance to antibiotics. ► Antibiotics t1/2 under solar radiation: 24min CPX, 99min AMX, and 577min SMZ.
A lack of glycemic control and diabetes are risk factors for complications related to COVID-19, and social isolation can hinder adherence to physical activity. Thus, this study sought to assess the ...impacts of social distancing on the practice of physical activity of individuals with type 1 diabetes mellitus (T1DM). This was a transversal study carried out using an online form to collect sociodemographic, practice of physical activity, and social distancing data. Of the 472 participants, 85.6% reported that they were respecting the steps of social distancing. Social distancing affected the practice of physical activity in adherence to the habit of practicing in frequency, duration, and perception of change in intensity. An association was found between noticing a lot of stress in the home environment and stopping physical activity; lower levels of tolerance to social distancing were associated with less physical activity, and maintaining the habit of practicing physical activity was associated with decreasing the intensity of the practice. Hence, social distancing harmed the practice of physical activity as part of the treatment of individuals with T1DM, both in the habit of practicing and in the characteristics of these practices of physical activity, such as frequency, duration, and intensity.
This systematic review aimed to identify nutritional interventions and supplements that improve the performance for wheelchair athletes. Intervention trials involving high-performance wheelchair ...athletes were analyzed, including those that comprised a nutritional intervention, defined as any intervention related to food, beverages, and supplementation aiming at evaluating the performance of wheelchair athletes. Of the included studies, four evaluated caffeine supplementation, of which one also evaluated sodium citrate supplementation; two studies evaluated vitamin D supplementation; one study assessed creatine monohydrate supplementation; and one assessed carbohydrate supplementation. Most studies were conducted on athletes with spinal cord injury. Athletes who consumed caffeine exhibited an improvement in performance, but this finding is not strong enough to become a recommendation.
Sibutramine is a non‐selective serotonin‐norepinephrine reuptake inhibitor orally administered for weight loss. In a previous study, we showed pharmacological mechanisms involved in the reduction of ...sperm quality and fertility of rats exposed for 30 days to this anorexigen in the light phase of the light‐dark (l/d) cycle. It is already known that rodents are nightlife animals, with higher metabolic activity during the dark phase than in the light phase of the light‐dark (l/d) cycle. Thus, the present study aimed to investigate whether the deleterious effects on reproductive parameters after sibutramine administration would be enhanced after a shorter period of exposure during the dark phase of the l/d cycle. For this, adult male Wistar rats were treated with sibutramine (10 mg/kg/d) or vehicle for 15 days during the dark phase of the l/d cycle. Sibutramine treatment decreased final body and reproductive organ weights, as well as serum testosterone levels. Sperm transit time through the epididymis was accelerated, and sperm concentration and motility were diminished in the sibutramine‐exposed rats. The decrease in sperm concentration was also verified in the epididymal histological sections. In conclusion, the deleterious effects of sibutramine on reproductive parameters of male rats were enhanced when the exposure occurred in the dark phase of the l/d cycle, even after a short exposure duration. Our results reinforce the impact of timing on drug therapeutic action.
Kisspeptin is the most potent stimulator of LH release. There are two kisspeptin neuronal populations in the rodent brain: in the anteroventral periventricular nucleus (AVPV) and in the arcuate ...nucleus. The arcuate neurons coexpress kisspeptin, neurokinin B, and dynorphin and are called KNDy neurons. Because estradiol increases kisspeptin expression in the AVPV whereas it inhibits KNDy neurons, AVPV and KNDy neurons have been postulated to mediate the positive and negative feedback effects of estradiol on LH secretion, respectively. Yet the role of KNDy neurons during the positive feedback is not clear. In this study, ovariectomized rats were microinjected bilaterally into the arcuate nucleus with a saporin-conjugated neurokinin B receptor agonist for targeted ablation of approximately 70% of KNDy neurons. In oil-treated animals, ablation of KNDy neurons impaired the rise in LH after ovariectomy and kisspeptin content in both populations. In estradiol-treated animals, KNDy ablation did not influence the negative feedback of steroids during the morning. Surprisingly, KNDy ablation increased the steroid-induced LH surges, accompanied by an increase of kisspeptin content in the AVPV. This increase seems to be due to lack of dynorphin input from KNDy neurons to the AVPV as the following: 1) microinjections of a dynorphin antagonist into the AVPV significantly increased the LH surge in estradiol-treated rats, similar to KNDy ablation, and 2) intra-AVPV microinjections of dynorphin in KNDy-ablated rats restored LH surge levels. Our results suggest that KNDy neurons provide inhibition to AVPV kisspeptin neurons through dynorphin and thus regulate the amplitude of the steroid-induced LH surges.
Prolactin (PRL) secretion is inhibited by hypothalamic dopamine. Kisspeptin controls luteinising hormone (LH) secretion and is also involved in PRL regulation. We further investigated the effect of ...kisspeptin‐10 (Kp‐10) on the activity of tuberoinfundibular dopaminergic (TIDA) neurones and the role of oestradiol (E2) in this mechanism. Female and male rats were injected with i.c.v. Kp‐10 and evaluated for PRL release and the activity of dopamine terminals in the median eminence (ME) and neurointermediate lobe of the pituitary (NIL). Kp‐10 at the doses of 0.6 and 3 nmol increased plasma PRL and decreased 4‐dihydroxyphenylacetic acid (DOPAC) levels in the ME and NIL of ovariectomised (OVX), E2‐treated rats but had no effect in OVX. In gonad‐intact males, 3 nmol Kp‐10 increased PRL secretion and decreased DOPAC levels in the ME but not in the NIL. Castrated males treated with either testosterone or E2 also displayed increased PRL secretion and reduced ME DOPAC in response to Kp‐10, whereas castrated rats receiving oil or dihydrotestosterone were unresponsive. By contrast, the LH response to Kp‐10 was not E2‐dependent in either females or males. Additionally, immunohistochemical double‐labelling demonstrated that TIDA neurones of male rats contain oestrogen receptor (ER)‐α, with a higher proportion of neurones expressing ERα than in dioestrous females. The dopaminergic neurones of periventricular hypothalamic nucleus displayed much lower ERα expression. Thus, TIDA neurones express ERα in male and female rats, and kisspeptin increases PRL secretion through inhibition of TIDA neurones in an E2‐dependent manner in both sexes. These findings provide new evidence about the role of kisspeptin in the regulation of dopamine and PRL.
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