Miracle-dz/UniFAR-FTUs huggingface dataset:
4D-QSAR investigation and pharmacophore identification of pyrrolo[2,1-c][1,4]benzodiazepines using electron conformational–genetic algorithm method

Abstract In this paper, we present the results of pharmacophore identification and bioactivity prediction for pyrrolo[2,1-c][1,4]benzodiazepine derivatives using the electron conformational–genetic algorithm (EC–GA) method as 4D-QSAR analysis. Using the data obtained from quantum chemical calculations at PM3/HF level, the electron conformational matrices of congruity (ECMC) were constructed by EMRE software. The ECMC of the lowest energy conformer of the compound with the highest activity was chosen as the template and compared with the ECMCs of the lowest energy conformer of the other compounds within given tolerances to reveal the electron conformational submatrix of activity (ECSA, i.e. pharmacophore) by ECSP software. A descriptor pool was generated taking into account the obtained pharmacophore. To predict the theoretical activity and select the best subset of variables affecting bioactivities, the nonlinear least square regression method and genetic algorithm were performed. For four types of activity including the GI50, TGI, LC50 and IC50 of the pyrrolo[2,1-c][1,4] benzodiazepine series, the r2train, r2test and q2 values were 0.858, 0.810, 0.771; 0.853, 0.848, 0.787; 0.703, 0.787, 0.600; and 0.776, 0.722, 0.687, respectively.
Antithrombotic drugs in coronary artery disease: risk benefit ratio and bleeding

Summary. The antithrombotic treatment of coronary artery disease is becoming increasingly complex. Aspirin is often combined with more potent antiplatelet agents such as thienopyridines and glycoprotein IIb/IIIa inhibitors. The classic anticoagulant unfractionated heparin is giving way to low‐molecular‐weight heparin, the pentasaccharide fondaparinux and the direct thrombin inhibitor bivalirudin. Warfarin (or another vitamin K antagonist) and antiplatelet agents are often required in combination for several months. Patients and physicians who have experienced major bleeding complications sometimes question the benefit of these treatment strategies. It is therefore crucial to try and weigh the impact on efficacy against safety. In this review the net benefit is discussed both numerically, comparing absolute reductions vs. increases in risks, and also by addressing the qualitative importance of each component in reaching the net benefit. Except for primary prophylaxis in patients at low‐moderate risk for coronary events, there is a net benefit of antithrombotic therapy. With increasing severity of the coronary condition the net benefit generally prevails even with an increasing number of antithrombotic drugs combined. However, as the patient slowly stabilizes after appropriate interventions, it is necessary to de‐escalate the treatment in accordance with decreasing net benefit of prolonged combination therapy.
Novel HDAC8 inhibitors: A multi-computational approach

Abstract Abnormal HDAC function triggers irregular gene transcription that hampers the essential cellular activities leading to tumour activation and progression. HDAC inhibition has, therefore, been reported as a potential target for cancer treatment. In the present study, a sequential computational framework was carried out to discover newer lead compounds, namely HDAC8 inhibitors for cancer therapy. Pharmacophoric hypotheses were generated based on hydroxamic acid derivatives reported earlier for HDAC inhibition. The model AAADR.122, demonstrated statistical significance (r2 = 0.93, Q2 = 0.81) and proved robust on validation with a cross-validated correlation coefficient of 0.89. It was utilized to arrive at novel hits through a virtual screening workflow. The specificity of the process was enhanced further by analysing the crucial interactions of the ligands with key catalytic residues, achieved by induced fit docking (PDB ID: 1T64). On assessment, the filtered leads displayed optimal drug like features. Investigations using density functional theory (DFT) also facilitated the recognition of molecular spots in the leads beneficial for HDAC8 interaction. Overall, two leads were proposed for HDAC8 inhibition with potential anti-cancer activity.
Burkitt Lymphoma in Elderly Patients

SUMMARY Burkitt lymphoma (BL) is a disease of predominantly young population, while in the elderly it occurs as a rare neoplasm. Elderly patients (age >60 years) represent a significant problem because of the inability to apply effective aggressive chemiotherapy in these cases. The risk of induction death is very high and unacceptible. Mainly, palliative treatments are applied, whose goal is not curing but maintaining the quality of life. We present the case of a person 75 years old with a diagnosis of sporadic, typical BL treated with CHOP+R in the induction therapy with excellent response but rapid progression after the abolition of rituximab. In discussion, the authors are looking for relevant data on the therapeutic approach in BL in the elderly. Sažetak Burkitt-ov limfom (BL) je bolest pretežno mlade populacije, dok je kod starijih retka neoplazma. Stariji bolesnici (>60 god) predstavljaju svojevrstan problem zbog nemogućnosti primene efektivne agresivne hemioterapije. Rizik od indukcione smrti je jako visok, neprihvatljiv. Uglavnom se pribegava palijativnim tretmanima, čiji cilj nije izlečenje nego održanje kvaliteta života. Prikazan je slučaj osobe stare 75 godina sa dijagnozom sporadičnog, tipičnog BL, koja je tretirana CHOP+R terapijom u indukciji sa odličnim odgovorom, ali brzom progresijom nakon ukidanja Rituximaba. Autori u diskusiji tragaju za relevantnim podacima o terapijskom pristupu kod BL starijih osoba.
An Autopsied Case of Primary Pulmonary Hypertension

A twenty four-year-old female patient had suffered progressive dyspnea for 6 years until death. She denied any symptoms suggestive of connective tissue disease, or deep vein thrombosis. She suffered an episode of pontine infarct in 1995. Four years after diagnosis of primary pulmonary hypertension, she died of sudden death during hospitalization. Gross features of pulmonary arteries at autopsy were as follows: left main pulmonary artery showed dilation of the lumen and thickening of the wall, and right main pulmonary artery was markedly dilated and contained fresh thrombus. Hematoxylin and eosin-stained sections of lung tissue showed plexiform lesions of pulmonary arteries, complete luminal obliteration of pulmonary arterioles and dilated lesion of pulmonary arterioles, and capillaries. This patient represents a typical case with a primary pulmonary arteriopathy with plexiform lesions with thrombotic lesion, demonstrating the importance of thrombosis in situ in the pathogenesis of primary pulmonary hypertension. To our knowledge, this is the first autopsy report on the primary pulmonary hypertension in Korea. (Korean Circulation J 1998;28(8):1414-1419)
Multiple significance tests: the Bonferroni correction

Researchers assessed the effects of hormone replacement therapy, consisting of combined oestrogen and progestogen, on health related quality of life. A randomised placebo controlled, double blind trial study design was used. Women were recruited if they were postmenopausal, had a uterus, and were aged 50-69 at randomisation. Outcome measures included health related quality of life and psychological wellbeing. The study period was one year.1 The researchers investigated the effects of combined hormone replacement therapy compared with placebo at one year, using a 0.05 (5%) critical level of significance and adjusting this with the Bonferroni correction. The researchers concluded that combined hormone replacement therapy started many years after the menopause can improve health related quality of life. For which of the following does the Bonferroni correction reduce the probability of occurring? The Bonferroni correction reduces the …
Setting safety standards by designing a low-budget and compatible patient identification system based on passive RFID technology

This paper outlines a large-scale audit for the enhancement of quality of care and staff and patient safety using passive RFID (Radio Frequency ID) wrist bands, which link to a patient's database, in order to reduce errors in patient care. It has been developed with a collaboration between the University Hospital, Birmingham, UK and Napier University, UK. The key feature of the work is the usage of passive RFID tags as an integral part of a low budget out-of-the box strategic patient information system which should be compatible with most hospital IT systems.
Pharmacology of the EndothelinA Receptor Antagonist: LU 135252

Endothelin (ET) was described for the first time in 1988 as a “novel potent vasoconstrictor peptide produced by vascular endothelial cells” (84). Since then many studies with ET were published (for review see ref. 78). ET-1 (one of the three isoforms of ET) is important in mammals as an autocrine and a paracrine hormone. The effects of ET-1 are mediated by two different receptors, ETA and ET,. The ETA receptors are located predominantly on vascular smooth muscle cells. They are coupled to G proteins and promote vasoconstriction as well as hypertrophy and hyperplasia. The ET, receptors are found in the cardiovascular system, primarily on endothelial cells; they are linked to the formation of vasodilator substances such as nitric oxide (NO) and prostacyclin and may be important in conditions such as congestive heart failure (CHF), pulmonary hypertension, elevated systemic blood pressure, arteriosclerosis, and renal failure. The antagonism of the effects of ET by ET antibodies has been proven beneficial in animal models of hypertension (68), myocardial infarction (83), and renal ischemia (49). These observations, taken together with the characterization of ET receptors, provided the rationale for the development of ET-receptor antagonists. Several pharmaceutical companies decided to focus on the development of selective antagonists of ETA receptors, since for the cardiovascular indications antagonism of the ET,-mediated responses could be detrimental. This review will focus on the pharmacology of (+)-(S)-2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-methoxy3,3-diphenyl-propionic acid (LU 135252, Fig. l), a propionic acid derivative (76) with a molecular weight of 410.4.
LUMBAR SYMPATHECTOMY: A SINGLE NEEDLE TECHNIQUE

A single-needle lumbar sympathectomy technique is described which uses the tip of the 12th rib as a marker to determine the appropriate position for the insertion of the needle. Radiological screening is used to control final placement at the body of L3 and to visualize spread of radioopaque phenol in the correct prevertebral plane. Following sympathectomy, fore-foot temperatures increased by a mean of 3 °C and lower leg blood flow doubled, these being accompanied by significant increases in ankle pressure index and venous oxygen tensions in the affected foot. These physiological improvements brought about resolution of ischaemic foot pain in 70% of patients at follow up 1 month later. As these results were not significantly different from those obtained in patients having two-needle sympathectomy, blockade with a single needle under x-ray control is considered to be an effective technique for the performance of neurolytic sympathectomy.
The Effect of Rest Interval Length on Repetition Consistency and Perceived Exertion During Near Maximal Loaded Bench Press Sets

Abstract Scudese E, Willardson JM, Simão R, Senna G, de Salles BF, and Miranda H. The effect of rest interval length on repetition consistency and perceived exertion during near maximal loaded bench press sets. J Strength Cond Res 29(11): 3079–3083, 2015—The purpose of this study was to compare different rest intervals between sets on repetition consistency and ratings of perceived exertion (RPE) during consecutive bench press sets with an absolute 3RM (3 repetition maximum) load. Sixteen trained men (23.75 ± 4.21 years; 74.63 ± 5.36 kg; 175 ± 4.64 cm; bench press relative strength: 1.44 ± 0.19 kg/kg of body mass) attended 4 randomly ordered sessions during which 5 consecutive sets of the bench press were performed with an absolute 3RM load and 1, 2, 3, or 5 minutes of rest interval between sets. The results indicated that significantly greater bench press repetitions were completed with 2, 3, and 5 minutes vs. 1-minute rest between sets (p ⩽ 0.05); no significant differences were noted between the 2, 3, and 5 minutes rest conditions. For the 1-minute rest condition, performance reductions (relative to the first set) were observed commencing with the second set; whereas for the other conditions (2, 3, and 5 minutes rest), performance reductions were not evident until the third and fourth sets. The RPE values before each of the successive sets were significantly greater, commencing with the second set for the 1-minute vs. the 3 and 5 minutes rest conditions. Significant increases were also evident in RPE immediately after each set between the 1 and 5 minutes rest conditions from the second through fifth sets. These findings indicate that when utilizing an absolute 3RM load for the bench press, practitioners may prescribe a time-efficient minimum of 2 minutes rest between sets without significant impairments in repetition performance. However, lower perceived exertion levels may necessitate prescription of a minimum of 3 minutes rest between sets.
Activation mechanisms of ASK 1 in response to various stresses and its signi fi cance in intracellular signaling

Apoptosis signal-regulating kinase 1 (ASK1) is a member of the mitogen-activated protein kinase kinase kinase family. ASK1 activates c-jun N-terminal kinase (JNK) and p38 in response to various stimuli such as oxidative stress, endoplasmic reticulum stress, infection and calcium influx. Under these stress conditions, ASK1 plays important roles in intracellular signaling pathways and biological functions. Diverse proteins are known to interact with ASK1 and regulate the activity of ASK1. However, activation mechanisms of ASK1 and ASK1-binding proteins which regulate the activity of ASK1 have not been completely understood. In this review, we focus on the recent findings on ASK1 and update the regulatory mechanisms of ASK1 activity. 2012 Published by Elsevier Ltd.
Image‐based cytometry reveals three distinct subsets of activated granulocytes based on phagocytosis and oxidative burst

Granulocytes play a key role in innate immunity and the most common functional assays are phagocytosis and oxidative burst. The purpose of this technical note is to use image‐based flow cytometry to divide activated granulocytes into unique subsets based on their degree of phagocytosis and oxidative burst in response to different experimental incubations. Prior to the experiments, all reagents were titered to determine the lowest dose that resulted in an acceptable signal to noise ratio. Heparinized, whole blood (100 µl) was mixed with one of two bioparticles (E. coli and S. aureus) and DHE (10 µg/ml) and incubated for 5, 10, 20, 40, 60, 80, 100, 120, and 140 min in a 37°C water bath. An additional tube kept on ice was used as a negative control. All subsequent processing steps were completed on ice in the dark to minimize additional activation of cells. After the 37°C incubation, N‐ethylmaleimide (15 mM) was added to halt phagocytosis, preventing the uptake of additional microparticles. Suspensions were labeled with CD66b‐APC and CD45‐APCeFluor780 for 60 min and a fix/lyse solution was added. Prior to acquisition, 7AAD was added to stain nuclear DNA. A minimum of 5,000 granulocyte (CD66b+) events were acquired using a Millipore‐Amnis FlowSight equipped with blue (488 nm, 60 mW), red (642 nm, 100 mW), and side scatter (785 nm, 12 mW) lasers. Samples were compensated and analyzed using Amnis IDEAS software (v.5.0.983.0). Image‐based analysis allowed us to divide activated granulocytes into three distinct subsets, whose relative abundance changed as a function of both bioparticle type and incubation length. The method described in this technical note represents a potential novel adaptation to common methods of assessing granulocyte function. More research is needed to test and validate our image‐based method in clinical conditions that impair granulocyte function. © 2013 International Society for Advancement of Cytometry
A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study)

Summary. Background: Prevention of arthropathy is a major goal of hemophilia treatment. While studies in adults have demonstrated an impact of prophylaxis on the incidence of joint bleeds and patients’ well‐being in terms of improved quality of life (QoL), it is unclear whether or not prophylaxis influences the outcome and perception of well‐ of children with hemophilia. Objective: This randomized controlled study compared the efficacy of prophylaxis with episodic therapy in preventing hemarthroses and image‐proven joint damage in children with severe hemophilia A (factor VIII <1%) over a 10‐year time period. Methods: Forty‐five children with severe hemophilia A, aged 1–7 years (median 4), with negative clinical‐radiologic joint score at entry and at least one bleed during the previous 6 months, were consecutively randomized to prophylaxis with recombinant factor VIII (25 IU kg−1 3 × week) or episodic therapy with ≥25 IU kg−1 every 12–24 h until complete clinical bleeding resolution. Safety, feasibility, direct costs and QoL were also evaluated. Results: Twenty‐one children were assigned to prophylaxis, 19 to episodic treatment. Children on prophylaxis had fewer hemarthroses than children on episodic therapy: 0.20 vs. 0.52 events per patient per month (P < 0.02). Plain‐film radiology showed signs of arthropathy in six patients on prophylaxis (29%) vs. 14 on episodic treatment (74%) (P < 0.05). Prophylaxis was more effective when started early (≤36 months), with patients having fewer joint bleeds (0.12 joint bleeds per patient per month) and no radiologic signs of arthropathy. Conclusion: This randomized trial confirms the efficacy of prophylaxis in preventing bleeds and arthropathy in children with hemophilia, particularly when it is initiated early in life.
A Review of Police Pursuit Fatalities in the United States From 1982–2004

Background. High-speed police pursuits are common in the United States (US). Most states do not gather statistics on police pursuits, pursuit crashes, injuries or fatalities for annual review. Objective. The objective of this study is to determine the number of pursuit fatalities to officers, those in the chased vehicle, andthose uninvolved in pursuits from 1982–2004. Methods. A review of police pursuit fatalities reported to the National Highway Traffic Safety Administration (NHTSA) Fatality Analysis Reporting System (FARS) database from 1982–2004. The data was reviewed for fatalities, demographic data, alcohol involvement, road surface type (rural versus urban) andmechanism of collision leading to a pursuit fatality. Results. From 1982–2004, 881,733 fatal crashes were reported to NHTSA, leading to 987,523 fatalities. Of fatal crashes, 6,336 (0.7%) were secondary to pursuits, leading to 7,430 (0.8%) fatalities, a mean of 323 per year. Among these fatalities, chased vehicle occupants accounted for 5,355 (72%); police for 81 (1%); those uninvolved for 1994 (27%). Of fatalities, 6074 (82%) were male, 2,092 (28%) were children andadolescents. Mean age of death was 24 years. African–Americans 1,154 (24%) andNative Americans 101 (2%) died at a higher proportion than their percentage of the US population. Collisions with solid objects accounted for 3,175 (59%) of fatalities in the chased vehicles. Collisions with other moving vehicles accounted for 1,434 (80%) of fatalities of vehicular occupants uninvolved in pursuits. Most fatal crashes, 3,130 (62%), occurred on urban roadways. Alcohol was involved in 4,628 (62%) fatalities. Of police fatalities, 20 (25%) were intoxicated. Conclusions. Police pursuits results in a small yet significant number of fatal motor vehicular crashes andfatalities. All states should record the total number of police pursuits, pursuit crashes, injuries andfatalities for annual review. The findings in this study have important operational implications for EMS care.
Basophil activation after nonsteroidal anti‐inflammatory drugs stimulation in patients with immediate hypersensitivity reactions to these drugs

Nonsteroidal anti‐inflammatory drugs (NSAIDs) are the drugs most frequently involved in allergic reactions of which two main types exist: IgE‐mediated and crossintolerance. The diagnosis of crossintolerance reactions is often based on the drug provocation test. The potential value of the basophil activation test (BAT) was evaluated using different basophil markers in the diagnosis of patients with crossintolerance to NSAIDs and cutaneous symptoms. We studied 46 patients with crossintolerance to NSAIDs and 45 tolerant controls. BAT was performed with acetyl salicylic acid, paracetamol, diclofenac, dipyrone, naproxen, and ibuprofen at four different concentrations using CD193 and CD203c as basophil markers and CD63 as activation marker. We compared BAT results using CD193+ or CD193+CD203c+ for basophil selection and found a significant increase in the stimulation index when using CD193+CD203c+ in both patients and controls (P = 0.004 and P = 0.017, respectively). Selection of living cells only produced an increase in basophil stimulation in patients for both CD193+ and CD193+CD203c+ (P < 0.001 for both), whereas in controls there was no change with CD193+ and a decrease with CD193+CD203c+ (P = 0.001). We found that CD193+CD203c+ increased the percentage of positive cases in patients and controls when compared with CD193+. When excluding dead cells, there was an increase of 21.7% in patients and 10% in controls. These results indicate that using CD193+CD203+, excluding dead cells, is the best approach for BAT although this test is not recommended for the diagnosis of patients with crossintolerance to NSAIDs owing to its low sensitivity and specificity. © 2014 International Society for Advancement of Cytometry
Economic impact of an electronic alert system to prevent venous thromboembolism in hospitalised patients

Summary. Objectives: The prevention of venous thromboembolism (VTE) is a priority for improved safety in hospitalised patients. Worldwide, there is growing concern over the undersuse of appropriate thromboprophylaxis. Computerised decision support improves the implementation of thromboprophylaxis and reduces inpatient VTE. However, an economic assessment of this approach has not yet been performed. Objectives: To evaluate the economic impact of an electronic alert (e‐alert) system to prevent VTE in hospitalised patients over a 4 year period. Patients/methods: All hospitalised patients at a single institution during the first semesters of 2005–2009 (n = 32 280) were included. All cases of VTE developed during hospitalisation were followed and direct costs of diagnosis and management collected. Results: E‐alerts achieved a sustained reduction of the incidence of in‐hospital VTE, OR 0.50 (95% CI, 0.29–0.84), the impact being especially significant in medical patients, OR 0.44 (95% CI, 0.22–0.86). No increase in prophylaxis‐related bleeding was observed. In our setting, the mean direct cost (during hospitalisation and after discharge) of an in‐hospital VTE episode is €7058. Direct costs per single hospitalised patient were reduced after e‐alerts from €21.6 to €11.8, while the increased use of thromboprophylaxis and the development of e‐alerts meant €3 and €0.35 per patient, respectively. Thus, the implementation of e‐alerts led to a net cost saving of €6.5 per hospitalised patient. Should all hospitalised patients in Spain be considered, total yearly savings would approach €30 million. Conclusions: E‐alerts are useful and cost‐effective tools for thromboprophylaxis strategy in hospitalised patients. Fewer thromboembolic complications and lower costs are achieved by its implementation.