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Background: Allopurinol, a xanthine inhibitor that lowers uric acid concentration, has been proven to reduce inflammation and oxidative stress in patients with cardiovascular disease. However, it is unknown whether these beneficial effects translate into favorable plaque modification in acute coronary syndromes (ACS). This study aimed to investigate whether allopurinol could improve coronary plaque stabilization using coronary computed tomography angiography (CCTA)., Methods: This was a prospective, single-center, randomized, double-blind clinical trial began in March 2019. A total of 162 ACS patients aged 18-80 years with a blood level of high-sensitivity C-reactive protein (hsCRP) ​> ​2 ​mg/L were included. The subjects were randomly assigned in a 1:1 ratio to receive either allopurinol sustained-release capsules (at a dose of 0.25 ​g once daily) or placebo for 12 months. The plaque analysis was performed at CCTA. The primary efficacy endpoint was the change in low-attenuation plaque volume (LAPV) from baseline to the 12-month follow-up., Results: Among 162 patients, 54 in allopurinol group and 51 in placebo group completed the study. The median follow-up duration was 14 months in both groups. Compared with placebo, allopurinol therapy did not significantly alter LAPV (-13.4 ​± ​3.7 ​% vs. -17.8 ​± ​3.6 ​%, p ​= ​0.390), intermediate attenuation plaque volume (-16.1 ​± ​3.0 ​% vs. -16.2 ​± ​2.9 ​%, p ​= ​0.992), dense calcified plaque volume (12.2 ​± ​13.7 ​% vs. 9.7 ​± ​13.0 ​%, p ​= ​0.894), total atheroma volume (-15.2 ​± ​3.2 ​% vs. -16.4 ​± ​3.1 ​%, p ​= ​0.785), remodeling index (2.0 ​± ​3.9 ​% vs. 5.4 ​± ​3.8 ​%, p ​= ​0.536) or hsCRP levels (-73.6 [-91.6-17.9] % vs. -81.2 [-95.4-47.7] %, p ​= ​0.286)., Conclusions: Our findings suggest that allopurinol does not improve atherosclerotic plaque stability or inflammation in ACS., (Copyright © 2024 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

An in vitro drug release test was developed to establish a level A in vitro-in vivo correlation (IVIVC) for predicting the in vivo performance of potassium chloride extended-release (ER) matrix tablets. Three ER formulations of potassium chloride with different in vitro release rates were designed using the USP dissolution test, and their urinary pharmacokinetic profiles were evaluated in healthy subjects. Due to the lack of IVIVC with the USP method, experiments were designed to investigate the effects of in vitro test conditions on drug release in order to match in vitro drug release with in vivo behaviors of different formulations. The evaluated in vitro variables included the type of USP apparatus, surfactant, and ionic strength of the dissolution medium. Based on the study findings and data analysis, a discriminatory drug release method was successfully developed that enabled the establishment and validation of a level A IVIVC model of the potassium chloride ER tablet using urinary pharmacokinetic data. This method uses USP apparatus I at 50 rpm in 900 mL of 150 mM NaCl solution containing 40 mM sodium dodecyl sulfate at 37 °C. The current study highlights the value of investigating test conditions in developing a predictive in vitro test method for establishing IVIVC.

An ongoing debate regarding the evolution of morality is whether other species show precursory moral behavior. The veil of ignorance (VOI) paradigm is often used to elicit human moral judgment but has never been tested in other primates. We study the division of resources behind the VOI in Formosan macaques. Monkeys choose the equal division more often when a conspecific is present than when it is absent, suggesting a degree of impartiality. To better understand this impartiality, we measure a monkey's reactions to two directions of inequity: one regarding inequity to its advantage and the other to its disadvantage. We find that disadvantageous inequity aversion correlates with the degree of impartiality behind the VOI. Therefore, seemingly impartial behavior could result from a primitive negative reaction to being disadvantaged. This suggests a mechanism to explain a tendency toward impartiality., (© The Author(s) 2022. Published by Oxford University Press on behalf of National Academy of Sciences.)

Establishing quantitative structure-property relationships for the rational design of small molecule drugs at the early discovery stage is highly desirable. Using natural language processing (NLP), we proposed a machine learning model to process the line notation of small organic molecules, allowing the prediction of their melting points. The model prediction accuracy benefits from training upon different canonicalized SMILES forms of the same molecules and does not decrease with increasing size, complexity, and structural flexibility. When a combination of two different canonicalized SMILES forms is used to train the model, the prediction accuracy improves. Largely distinguished from the previous fragment-based or descriptor-based models, the prediction accuracy of this NLP-based model does not decrease with increasing size, complexity, and structural flexibility of molecules. By representing the chemical structure as a natural language, this NLP-based model offers a potential tool for quantitative structure-property prediction for drug discovery and development.

BACKGROUND This study aimed to evaluate the factors associated with a survival benefit for patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib, with and without cytoreductive nephrectomy (CN). MATERIAL AND METHODS This retrospective clinical study included 118 patients with mRCC who were treated with CN and sunitinib (CN-sunitinib) (N=70) and with sunitinib-alone (N=48). Categorical clinicopathological variables were compared with hypothesis tests using contingency tables and a chi-squared test. Independent indicators for progression-free survival (PFS) and overall survival (OS) were analyzed with univariate and multivariate Cox regression models. The Kaplan-Meier method and log-rank test were used to evaluate patient survival. RESULTS The median PFS and OS for the 118 patients were 8.38 and 15.48 months, respectively. There were no significant differences between the CN-sunitinib group and the sunitinib-alone group for either PFS (7.2 months vs. 11.6 months; P=0.525) or OS (16.7 months vs. 15.2 months; P=0.839). Stratification of patients based on clinicopathological characteristics showed that CN was significantly associated with reduced PFS and OS for patients with lymph node metastasis (PFS, P<0.001; OS, P<0.001) and high International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk scores (PFS, P=0.003; OS, P=0.011). However, CN was associated with a significant survival benefit for patients with low levels of serum C-reactive protein (CRP<10 mg/L) (PFS, P=0.026; OS, P=0.007). CONCLUSIONS Sunitinib-alone without CN improved the survival of patients with mRCC who had high IMDC risk scores or lymph node metastasis. CN and sunitinib resulted in significantly improved survival in patients with low serum CRP.

Purpose: Management of anorectal abscess is traditionally by incision and drainage with packing. This study assessed the use of mushroom catheters compared with packing of anorectal abscess after incision and drainage in adults. Placement of a mushroom catheter to allow ongoing drainage of the cavity may have advantages by eliminating the need for painful dressing changes., Methods: This was a retrospective observational study. Following ethical approval, a chart review of 167 patients treated for anorectal abscess with either packing or mushroom catheter at Cork University Hospital from 2010 to 2015 was performed. Treatment decision was based on individual surgeon preference. Outcome measures included recurrence and fistula development. Telephone follow-up was also performed to assess patient satisfaction and quality of life (EQ-5D-3L)., Results: One hundred and twenty-nine patients were treated with incision and drainage with packing, and 38 patients were treated with mushroom catheter. There was no statistically significant difference in recurrence (p = 0.691) or fistula development (p = 0.299) between the groups. Twenty-three patients had Crohn's disease, 17 patients had diabetes and 66 patients were smokers. There was no statistically significant difference in recurrence or fistula development between the treatment groups in Crohn's (p = 0.493), diabetics (p = 0.949) and smokers (p = 0.275). On average, patients treated with mushroom catheter reported a statistically significant higher satisfaction score (9.2 ± 1.0) than patients treated with packing (7.6 ± 1.8, p = 0.013)., Conclusion: Mushroom catheter drainage of anorectal abscesses is a safe alternative to traditional packing and results in higher patient satisfaction. This study provides a rationale for a future randomised controlled trial.

Isothermal microcalorimetry was utilized to monitor the crystallization process of amorphous ritonavir (RTV) and its hydroxypropylmethylcellulose acetate succinate-based amorphous solid dispersion under various stressed conditions. An empirical model was developed: ln(τ)=ln(A)+EaRT-b⋅wc, where τ is the crystallization induction period, A is a pre-exponential factor, Ea is the apparent activation energy, b is the moisture sensitivity parameter, and wc is water content. To minimize the propagation of errors associated with the estimates, a nonlinear approach was used to calculate mean estimates and confidence intervals. The physical stability of neat amorphous RTV and RTV in hydroxypropylmethylcellulose acetate succinate solid dispersions was found to be mainly governed by the nucleation kinetic process. The impact of polymers and moisture on the crystallization process can be quantitatively described by Ea and b in this Arrhenius-type model. The good agreement between the measured values under some less stressful test conditions and those predicted, reflected by the slope and R(2) of the correlation plot of these 2 sets of data on a natural logarithm scale, indicates its predictability of long-term physical stability of amorphous RTV in solid dispersions. To further improve the model, more understanding of the impact of temperature and moisture on the amorphous physical stability and fundamentals regarding nucleation and crystallization is needed., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Objective: This study aims to present the graft pathology at the time of harvest and its impact on long-term survival., Methods: The remnants of the bypass grafts from 66 consecutive patients with coronary artery disease receiving a coronary artery bypass grafting were investigated pathologically, and pertinent predictive risk factors and survival were analyzed., Results: Medial degenerative changes with or without intimal proliferation were present in 36.8%, 37.8% and 35.6% of left internal mammary artery (IMA), radial artery and saphenous vein grafts. There were 2 (3.0%) hospital deaths and 9 (14.1%) late deaths. Multinomial logistic regression revealed left IMA pathological changes, dyslipidemia, history of percutaneous transluminal coronary angioplasty/stent deployment and Y-graft were significant predictive risk factors negatively influencing the patients' long-term survival. Kaplan-Meier survival analysis revealed that the long-term survival of patients with left IMA pathological changes were significantly reduced compared with those without (74.1% vs. 91.4%, P=0.002); whereas no differences were noted in long-term survivals between patients with and without pathological changes of the radial arterial or saphenous vein grafts., Conclusion: Pathological changes may be seen in the bypass graft at the time of harvest. The subtle ultrastructural modifications and the expressions of vascular tone regulators might be responsible for late graft patency. The pathological changes of the left IMA at the time of harvest rather than those of the radial artery or saphenous vein graft affect significantly longterm survival. Non-traumatic maneuver of left IMA harvest, well-controlled dyslipidemia and avoidance of using composite grafts can be helpful in maintaining the architecture of the grafts.

Despite the fact that oxidation is the second most frequent degradation pathway for pharmaceuticals, means of evaluating the oxidative stability of pharmaceutical solids, especially effective stress testing, are still lacking. This paper describes a novel experimental method for peroxide-mediated oxidative stress testing on pharmaceutical solids. The method utilizes urea-hydrogen peroxide, a molecular complex that undergoes solid-state decomposition and releases hydrogen peroxide vapor at elevated temperatures (e.g., 30°C), as a source of peroxide. The experimental setting for this method is simple, convenient, and can be operated routinely in most laboratories. The fundamental parameter of the system, that is, hydrogen peroxide vapor pressure, was determined using a modified spectrophotometric method. The feasibility and utility of the proposed method in solid form selection have been demonstrated using various solid forms of ephedrine. No degradation was detected for ephedrine hydrochloride after exposure to the hydrogen peroxide vapor for 2 weeks, whereas both anhydrate and hemihydrate free base forms degraded rapidly under the test conditions. In addition, both the anhydrate and the hemihydrate free base degraded faster when exposed to hydrogen peroxide vapor at 30°C under dry condition than at 30°C/75% relative humidity (RH). A new degradation product was also observed under the drier condition. The proposed method provides more relevant screening conditions for solid dosage forms, and is useful in selecting optimal solid form(s), determining potential degradation products, and formulation screening during development., (Copyright © 2011 Wiley-Liss, Inc.)

Aim: To explore effects of FOXP3 on the progression of atherosclerosis plaque in hypercholesterolemic apoliprotein(apo)E-/- mice., Methods: At 8 weeks of age, 32 male ApoE-/- mice were randomly divided into four groups of eight. Labeled: negative control group, positive control group, small interfering RNA (siRNA) group, and regulatory T cells transfer (Tregs) group. Lentivirus-mediated (siRNA) identified its function by Western blot was used to knock down FOXP3 and Foxp3(high+);CD4(+); CD25(+); Tregs acquired through magnetic activated cell sorting adoptive transfer assays in high fat diet ApoE-/- mice were done. The resulting atherosclerotic lesions were assessed by determining the number and function of CD4(+);CD25(+); Tregs, FOXP3 transcript levels and investigating the expression of Foxp3 protein in different tissues. Inflammatory cytokines were determined by ELISA., Results: Animals treated with siRNA of FOXP3 showed a significant increase in atherosclerotic lesion formation and a reduction in the number and function of Foxp3(+);CD4(+);CD25(+); Tregs compared with other groups. Transfer of Foxp3(high+);CD4(+);CD25(+); Tregs significantly decreased atherosclerotic plaque formation and increased the number and function of Foxp3(+); CD4(+); CD25(+); Tregs. Foxp3 protein levels and FOXP3 transcript levels were lowest in the siRNA group, and were highest in tissues from the Tregs transfer group., Conclusion: FOXP3 plays an important role in regulating the inflammatory response within the atherosclerotic lesion. It can inhibit significant the progression of the atherosclerosis plaque in ApoE-/- mice.

A hypothesis of " blood-stasis and toxin causing catastrophe engender acute cardiovascular event (ACE)" was put forward according to TCM cognition on blood-stasis and toxin, in combining with the up to date concept of atherosclerosis and coronary heart disease, and together with our clinical practical experiences. The etiology, pathogenesis, evolving law, initial characteristics, clinical manifestation, therapeutic methods, prescriptions and their compatibility, as well as the well-suited time for applying TCM intervention were discussed. The authors stressed that it is of great significance for further reducing the morbidity of ACE and improving the effect of integrative medicine for preventing and treating cardiovascular thrombotic disease.

Objective: To investigate the influence of endothelial dysfunction induced by inoculated dendritic cells (DCs) loaded heat shock protein 60 (HSP60) in apolipoprotein (Apo) E-null mice, and the effect of Puerarin on it., Methods: HSP60 DC (DChsp) acquired after prepared bone marrow-derived DCs of ApoE-null mice and treated with HSP60. In vitro, the function of DCs and the effect of Puerarin were detected. While in vivo, ApoE-null mice fed with high-cholesterol forage were divided into two groups and intravenous inoculated with DCh-sp or normal saline via vein twice respectively. The mice in the two groups were subdivided into the Puerarin group and non-treated group, and they were injected intraperitoneally with Puerarin and normal saline at the beginning of inoculation and the following 3 weeks, respectively. In addition, C57BL/6 mice without inoculation were taken as the normal control group. Two weeks after the last time inoculated, the response of T lymphocytes to HSP60 and endothelial-dependent diastolic function of aortic ring were detected., Results: HSP60 could promote DCs expressed CD86 and stimulate T lymphocytes proliferation in vitro, while Puerarin had significantly inhibitory effect. After inoculated, DChsp activated inflammatory response in vivo and aggravated endothelium-dependent dilation in mice. Puerarin could significantly inhibit inflammatory reaction caused by DChsp and improve endothelium dilation., Conclusion: Hsp60 could activate DCs in vitro and in vivo, Puerarin could significantly inhibit specific immunity induced by HSP60 and improve vascular endothelium-dependent dilation.

Objective: To investigate the function of dendritic cells (DC) in patients with unstable angina pectoris (UAP) and the effects of atorvastatin on it., Methods: 27 patients with UAP were divided into two groups treated respectively with regular pharmacotherapy and regular pharmacotherapy plus atorvastatin. PBMC from the UAP patients (before and 2 weeks after the treatment) and 11 healthy subjects were incubated and induced to mature DC in a completed medium containing GM-CSF and IL-4. Flow cytometric analysis was used to detect the expression of co-stimulating factor CD86 (B7-2) on DC. The stimulating capacity of DC was determined in allogenic mixed lymphocyte reaction (MLR). ELISA was used to analyze the level of cytokines (IL-1beta, IL-6, IL-10 and TNF-alpha) in the medium of MLR. Relationship of expression of CD86 to risk factors and blood CRP level was also analyzed., Results: When compared with normal group, CD86 on DC was much more expressed in UAP patients; the stimulating capacity of DC in MLR was higher; T lymphocytes in MLR secreted higher levels of pro-inflammation cytokines (IL-1beta, IL-6 and TNF-alpha) and lower level of anti-inflammation cytokine (IL-10). Blood LDL-C before treatment was positively related to the expression of CD86. Atorvastatin inhibited the function of DC and lowered blood level of CRP and CD86, the levels of which were significantly positively correlated., Conclusions: DC in UAP are activated, which may play an important role in initiating immune reaction in the plaque. LDL-C may be one of the activators of DC; inhibitory effect of atorvastatin on inflammation in UAP may be due to its inhibition on DC.

Objectives: To study applying auditory brainstem reaction (ABR) to monitor the general anesthesia depth and awaken degree in children as an objective guide., Methods: Forty-five infant or children patients, American Society of Anesthesiologists(ASA) graded I-II, with normal audition, were selected and divided into 3 groups (15 cases per group) to receive propofal venous anesthesia, fentanyl venous anesthesia, or isoflurane anesthesia, respectively. During anesthesia, peak latencies (PL) of I, III, V wave, and interpeak latencies (IPL) of I-III, III-V, I-V were monitored and recorded after short sound stimulation of 90 db which accumulated 1,000 times with Madsen. The changing of PL and IPL with time passing and anesthesia dosage was studied to discuss the feature of ABR in each anesthesia procedure as above., Results: There is a significant positive correlation between PL and IPL of ABR waves as above and the dosage of propofol or the concentration of isoflurane. The dosage or the concentration increased, and PL and IPL prolonged. It is important of PL of wave I to reflect anesthesia degree. It is wave V with the best stability and correlation to monitor anesthesia degree. After anesthesia period or patients almost awaken, PL and IPL of some ABR waves were still more than normal values, which is detention reaction. For the fentanyl anesthesia, ABR is not sensible enough, i.e. has little correlation., Conclusion: The changing of PL and IPL of ABR waves could conclude anesthesia degree in children and be treated as reference of whether awaken or not in some certain, but have possibility of detention reaction.