Nucleoside triphosphates inhibit ADP,collagen, and epinephrine-induced platelet aggregation: Role of P2Y1 and P2Y12 receptors

Background

Platelets express two ADP receptors namely P2Y₁ and P2Y₁₂ that regulate ADP and other agonists-induced platelet aggregation. P2Y₁ receptor activation causes platelet shape change while P2Y₁₂ receptor activation induces platelet aggregation. Previously, anti-aggregatory effects of ATP on ADP-induced and pro-aggregatory effects on epinephrine-induced platelet aggregation have been reported. However, the effects of other nucleoside triphosphates on platelet aggregation have never been described. The aim of the present study was to characterise the effects of nucleoside triphosphates (ATP, UTP, GTP, and CTP) on agonist-induced platelet aggregation.

Methods

The experiments were performed on platelet rich plasma freshly isolated from blood donated by healthy human volunteers.

Results

All the nucleoside triphosphates tested inhibited ADP- and collagen-induced platelet aggregation in a concentration-dependent manner with a rank order of potency, 2MeSATP > ATP ≥ α,β,methyleneATP > UTP  >> CTP ≥ GTP. The IC₅₀ values against ADP (10 μM)-induced platelet aggregation were 0.039 ± 0.013, 18 ± 7, 25 ± 6, 32 ± 9, 360 ± 130, and 400 ± 160 μM, respectively. Low concentrations of ATP induced platelet shape change which was due to contaminating ADP. However, higher concentrations antagonised ADP and MRS2365-induced platelet shape change. The ATP analogue α,β,methyleneATP and CTP but not UTP and GTP also antagonised ADP-induced platelet shape change. Similarly, low ATP concentrations potentiated epinephrine-induced platelet aggregation that was abolished by P2Y₁ antagonist MRS2500 suggesting P2Y₁ receptor activation due to contaminating ADP. Higher ATP concentrations, α,β,methyleneATP, UTP, CTP, and GTP antagonised epinephrine-induced platelet aggregation.

Conclusion

Thus, the data demonstrate nucleoside triphosphates in general act as P2Y₁₂ receptor antagonists and antagonise ADP-, collagen-, and epinephrine-induced platelet aggregation.     

Can South Asian Countries Cope with the Mental Health Crisis Associated with COVID-19?

International Journal of Mental Health and Addiction -     

Readmission Following Gastric Cancer Resection: Risk Factors and Survival

Background

This study utilized a multi-institutional database to evaluate risk factors for readmission in patients undergoing curative gastrectomy for gastric adenocarcinoma with the intent of describing both perioperative risk factors and the relationship of readmission to survival.

Methods

Patients who underwent curative resection of gastric adenocarcinoma from 2000 to 2012 from seven academic institutions of the US Gastric Cancer Collaborative were analyzed. In-hospital deaths and palliative surgeries were excluded, and readmission was defined as within 30 days of discharge. Univariate and multivariable logistic regression analyses were employed and survival analysis conducted.

Results

Of the 855 patients, 121 patients (14.2 %) were readmitted. Univariate analysis identified advanced age (p?<?0.0128), American Society of Anesthesiology status ≥3 (p?=?0.0045), preexisting cardiac disease (p?<?0.0001), hypertension (p?=?0.0142), history of smoking (p?=?0.0254), increased preoperative blood urea nitrogen (BUN; p?=?0.0426), concomitant pancreatectomy (p?=?0.0056), increased operation time (p?=?0.0384), estimated blood loss (p?=?0.0196), 25th percentile length of stay (<7 days, p?=?0.0166), 75th percentile length of stay (>12 days, p?=?0.0256), postoperative complication (p?<?0.0001), and total gastrectomy (p?=?0.0167) as risk factors for readmission. Multivariable analysis identified cardiac disease (odds ratio (OR) 2.4, 95 % confidence interval (CI) 1.6–3.3, p?<?0.0001), postoperative complication (OR 2.3, 95 % CI 1.6–5.4, p?<?0.0001), and pancreatectomy (OR 2.2, 95 % CI 1.1–4.1, p?=?0.0202) as independent risk factors for readmission. There was an association of decreased overall median survival in readmitted patients (39 months for readmitted vs. 103 months for non-readmitted). This was due to decreased survival in readmitted stage 1 (p?=?0.0039), while there was no difference in survival for other stages. Stage I readmitted patients had a higher incidence of cardiac disease than stage I non-readmitted patients (58 vs. 24 %, respectively, p?=?0.0002).

Conclusions

Within this multi-institutional study investigating readmission in patients undergoing curative resection for gastric cancer, cardiac disease, postoperative complication, and concomitant pancreatectomy were identified as significant risk factors for readmission. Readmission was associated with decreased overall median survival, but on further analysis, this was driven by differences in survival for stage I disease only.

     

Derivation of the tumor position from external respiratory surrogates with periodical updating of the internal/external correlation

In this work we develop techniques that can derive the tumor position from external respiratory surrogates (abdominal surface motion) through periodically updated internal/external correlation. A simple linear function is used to express the correlation between the tumor and surrogate motion. The function parameters are established during a patient setup session with the tumor and surrogate positions simultaneously measured at a 30 Hz rate. During treatment, the surrogate position, constantly acquired at 30 Hz, is used to derive the tumor position. Occasionally, a pair of radiographic images is acquired to enable the updating of the linear correlation function. Four update methods, two aggressive and two conservative, are investigated: (A1) shift line through the update point; (A2) re-fit line through the update point; (C1) re-fit line with extra weight to the update point; (C2) minimize the distances to the update point and previous line fit point. In the present study of eight lung cancer patients, tumor and external surrogate motion demonstrate a high degree of linear correlation which changes dynamically over time. It was found that occasionally updating the correlation function leads to more accurate predictions than using external surrogates alone. In the case of high imaging rates during treatment (greater than 2 Hz) the aggressive update methods (A1 and A2) are more accurate than the conservative ones (C1 and C2). The opposite is observed in the case of low imaging rates.     

Combination of tigecycline and N-acetylcysteine reduces biofilm-embedded bacteria on vascular catheters

To assess the efficacy of an antibiofilm/antimicrobial agent combination, we incubated catheter segments colonized with one of six studied bacterial organisms in N-acetylcysteine, tigecycline, N-acetylcysteine-tigecycline, or saline. Segments were washed, sonicated, and cultured. N-acetylcysteine-tigecycline significantly decreased all viable biofilm-associated bacteria and was synergistic for methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis.     

Synthesis of novel pyrazolobenzothiazine 5,5-dioxide derivatives as potent anti-HIV-1 agents

A new series of pyrazolobenzothiazine-based carbohydrazides was prepared in a facile way, starting with commercially available sodium saccharine. The final products were sufficiently characterized by spectroscopic techniques. In addition, compound 5k was confirmed with X-ray crystallography as well. All the compounds were screened for anti-HIV-1 and cytotoxicity activities. Overall, out of 15 compounds, seven exhibited good activity with EC₅₀ values <20 μM. Compounds 5c, 5d, 5g, 5j and 5k appeared as the potent anti-HIV-1 agents with EC₅₀ values <5.0 μM. The structure–activity relationship would facilitate the discovery of new molecules with better profile of HIV inhibition activity.