Miracle-dz/UniFAR-FTUs huggingface dataset:
The Significance of Endothelial Heterogeneity in Thrombosis and Hemostasis

The endothelium is recognized today as a functional and dynamic component of the body that plays an important part in health and disease. This article brieﬂy reviews the role of endothelium in thrombosis and hemostasis. There is a paradigm shift from one that regards the endothelium as one single entity to the concept that the endothelium is heterogeneous. Thrombotic complications in many disorders show a predilection to speciﬁc locations, despite the fact that a hypercoagulable state affects the entire body. Likewise, bleeding is more commonly encountered in certain anatomical locations than in others. Recent observations of the heterogeneous distribution of coagulation and ﬁbrino-lytic factors in the endothelium and the adaptation of the endothelium to various stimuli may provide an explanation for the diverse phenotypes. Recognition of this changing paradigm is helpful to for the diagnosis and management of bleeding and thrombotic complications. It also helps in the understanding of the pathogenesis of many bleeding and thrombotic disorders, and in the development of new drug designs for site-speciﬁc therapy.
Different Accuracies of Rapid Enzyme-Linked Immunosorbent, Turbidimetric, and Agglutination D-Dimer Assays for Thrombosis Exclusion: Impact on Diagnostic Work-Ups of Outpatients with Suspected Deep Vein Thrombosis and Pulmonary Embolism

The requirement for a safe diagnostic strategy should be based on an overall posttest incidence of venous thromboembolism (VTE) of less than 1%, with a negative predictive value of more than 99 to 100% during 3-month follow-up. Compression ultrasonography (CUS) and spiral computed tomography (CT) currently are the methods of choice to conﬁrm or rule out deep venous thrombosis (DVT) and pulmonary embolism (PE), respectively. CUS has a negative predictive value (NPV) of 97 to 98%, indicating the need to improve the diagnostic work-up of patients with suspected DVT by clinical score assessment and D-dimer testing. Spiral CT as a stand-alone method detects all clinically relevant PEs and a large number of alternative diagnoses. It rules out PE with a NPV of 98 to 99%. Spiral CT is expensive, emphasizing the need to improve the diagnostic work-up of patients with suspected PE by the use of clinical score assessment and D-dimer testing. Clinical score assessment for DVT and PE has not safely ruled out VTE in multicenter studies and in routine daily practices. Modiﬁcation of the Wells clinical score assessment for DVT by elimination of
Inhibition of Angiogenesis by Small-Molecule Antagonists of Protease-Activated Receptor-1

Angiogenesis, the growth of new blood vessels from preexisting ones, is a necessary component of embryogenesis, wound healing, and the proliferative phase of the female reproductive cycle. Angiogenesis also plays a critical role in important pathologic processes such as cancer and cardiovascular complications. In addition, clinical, laboratory, and pharmacologic evidence has shown a link between angiogenesis, coagulation, hemostasis, and thrombosis in the settings of these pathologies. Recent studies in our laboratory revealed that thrombin has a signiﬁcant stimulatory effect on angiogenesis. This effect of thrombin is independent of ﬁbrin formation and can be attributed mainly to the activation of protease-activated receptor-1 (PAR-1). PAR-1 is widely expressed in vascular cells and is involved in cardiovascular complications such as atherosclerosis, restenosis, and neointimal formation. It is also expressed in many cancer cells contributing to induction of tumor growth and metastasis. In this review, we will summarize our present-day understanding of the role of thrombin and PAR-1 in angiogenesis and the potential therapeutic utility of targeting PAR-1 in angiogenesis-related disease, such as atherosclerosis, restenosis, and cancer.
Cell Signaling in Oxidative Stress-Induced Liver Injury

Oxidative stress is a common mechanism of liver injury. Recent investigations have demonstrated that oxidant-induced liver injury is mediated by the direct effects of reactive oxygen species on signal transduction pathways. Although the function of cell signaling in this form of injury is complex and likely variable depending on the type and duration of oxidative stress, common regulatory pathways of hepatocyte oxidant injury have been identiﬁed that include the mitogen-activated protein kinases extracellular signal-regulated kinase 1/2 (ERK1/2) c-Jun N-terminal kinase (JNK), and the nuclear factor k B (NF-k B) pathway. Studies in cultured hepatocyte and rodent models of oxidative stress have demonstrated that ERK1/2 typically induces resistance to oxidant stress, whereas JNK promotes cell death. The effects of NF-k B activation are more complex and cell-type speciﬁc. A further understanding of the signaling pathways that regulate oxidant-induced liver injury may suggest new therapies for hepatic diseases resulting from oxidative stress.
Management Options for Thrombophilias

Thrombophilias may be inherited or acquired, continuing or transient, and may contribute strongly or weakly to thrombosis. They may predispose to venous thromboembolism alone or also to artery occlusion. Advice on management must recognize these variations. The presence of an inherited thrombophilia should not alter the intensity of anticoagulant therapy, given that antithrombin, protein C, or protein S deﬁciency, factor V Leiden, and the prothrombin G20210A mutation are not unusually anticoagulant resistant. However, they can increase the optimal treatment duration after a ﬁrst thromboembolic event. Optimal duration depends on the balance between thrombosis risk off treatment and bleeding risk during extended anticoagulant therapy, and needs to be separately estimated for each individual with thrombosis and thrombophilia. The higher the thrombosis risk and the lower the bleeding risk, the longer the optimal treatment duration. This balance favors continued (but perhaps not indeﬁnite) therapy in antithrombin, protein C, and protein S deﬁciency, and perhaps also in patients with the factor V Leiden or prothrombin mutations if their bleeding risk is low. Thrombosis that complicates active malignancy, the antiphospholipid syndrome, or heparin-induced thrombocytopenia needs special consideration: recent clinical trials suggest that low molecular weight heparins are more effective than warfarin in thrombosis with cancer, and that a more intense warfarin effect is not needed for patients with antiphospholipid syndrome and thrombosis. Debate continues about the place of screening for presymptomatic but affected relatives of patients with thrombosis and an inherited predisposition. It is essential that any family testing be done only with the informed consent of all concerned. Given consent, there is general support for family testing in antithrombin, protein C, or protein S de-ﬁciency and where the factor V Leiden or prothrombin mutation is strongly penetrant and expressed. There is, however, a strong argument that any testing in families in which clotting factor polymorphisms are weakly expressed should be restricted to young women when they consider hormonal contraception or pregnancy, given that these acquired factors multiply the risk.
Alcohol and Substance Abuse

Alcoholic liver disease is an important cause of cirrhosis, liver-associated death, and need for liver transplant. Up to 50% of recipients use some alcohol, and perhaps 10% drink addictively. Careful evaluation by an addiction medicine specialist is the best predictive instrument before transplant surgery, whereas the 6-month rule lacks sensitivity and speciﬁcity. Addictive drinking, but not minor slips, is associated with increased mortality. There is no standard therapy for alcoholism in alcoholics waiting for a transplant or for those who have undergone a transplant. Stably abstinent, methadone-maintained opiate-dependent patients should continue methadone; are generally good candidates for liver transplant; and show low relapse rates. Pre-and post-transplant smoking rates are high and cause signiﬁcant morbidity and mortality. Transplant teams should encourage smoking cessation treatments. Marijuana use in liver transplant recipients is common, although risks associated with this practice are unknown.
Measurement of Androgens in Women

Much of our knowledge about the physiologic role of androgens in women is based on measurements, primarily in serum, using radioimmunoassay (RIA) methodology that involves puriﬁcation of the analyte by organic solvent extraction and column chromatography. Although the extraction/chromatographic RIA is highly reliable when properly validated, it is time consuming and costly. For this reason, direct RIA methods were developed. Subsequently, the radioactive marker was replaced by other labels that have been used in direct chemiluminescent, ﬂuorescent, and enzyme immunoassays on autoanalyzers. Although direct immunoassays are simple and rapid, they are seldom thoroughly validated, and generally lack the sensitivity and speciﬁcity for reliable measurements of testosterone levels found in postmenopausal serum. In recent years there has been increased use of mass spectrometry assay methods to quantify steroid hormones. These methods are touted to become the gold standard for all steroid hormone measurements. Because urine contains predominantly glucuronidated androgens, multistep procedures are required for the measurement, which is not practical for diagnostic testing. Androgens also can be measured in saliva, but major methodologic problems are associated with the measurements. In addition, there is a misconception that salivary testosterone levels reﬂect free testosterone levels in serum.
Alcohol Dosing and the Heart: Updating Clinical Evidence

The consequences of heavy or irregular alcohol drinking have long been known. Recently, consistent information has been provided in support of an association between light/moderate alcohol consumption and protection from vascular and all-cause mortality, ischemic stroke, peripheral arterial disease, congestive heart failure, and recurrence of ischemic events. After reviewing the information with respect to major aspects of cardiovascular pathophysiology, to potential confounders and to underlying mechanisms, several concepts emerge. First, the recommended amounts of ‘‘safe alcohol drinking’’ in healthy individuals are up to two standard drinks ( (cid:2) 20 g/d) for a man and up to one drink (10 g/d) for a nonpregnant woman. The overall balance for young premenopausal women, but not for older women, would be unfavorable for drinking. The risk of cancer would not outweigh potential beneﬁts of alcohol on heart disease. Second, within the frame of a balanced pattern of dietary energy intake, patients with cardiovascular disease who drink alcohol should not exceed one or two standard drinks per day for women or up to two or three drinks per day for men. Third, the low rates of coronary heart disease among the Mediterranean people may be related to their pattern of drinking wine every day during meals. Regular drinking is associated with better outcomes than occasional (binge)/weekly drinking. Fourth, wine (ethanol with antioxidants) exhibits signiﬁcantly higher anti-inﬂammatory effects than gin (ethanol without polyphenols), and thus in general wine should be preferred to liquor or beer.
Diagnosis of Deep Vein Thrombosis

Deep vein thrombosis (DVT) requires a prompt and accurate diagnosis to avoid the potentially fatal consequences of a delay in adequate treatment. The diagnostic strategy of suspected venous thromboembolism is an example of the application of Bayes' theorem. As a result, the available diagnostic tools, both noninvasive (such as ultrasonography, D-dimer, and computed tomography) and invasive (such as venography), are usually integrated in diagnostic strategies that require the evaluation of the a priori clinical probability of disease (pretest probability). These strategies also vary according to the patient characteristics that allow the definition of five different categories: symptomatic outpatients, symptomatic inpatients, high-risk asymptomatic subjects, patients with suspected recurrence, and pregnant women. Some areas are still a matter of debate, such as the clinical relevance of isolated distal DVT and the diagnosis of suspected ipsilateral recurrence.
An Overview of the Heparin-Induced Thrombocytopenia Syndrome

Heparin-induced thrombocytopenia (HIT) is caused by heparin-dependent, platelet-activating IgG antibodies that increase thrombin generation in vivo, producing a prothrombotic phenotype. In addition to platelet activation, there is in vitro evidence that activation of endothelium and monocytes occurs, perhaps directly by HIT antibodies, but more likely through activated platelet (or microparticle)–endothelial–leukocyte interactions. Patients with cardiac disease receiving heparin present important diagnostic and therapeutic issues when unexpected thrombocytopenia arises. Concomitant vascular disease burden and intravascular catheter use further increase risk of HIT-associated arterial thrombosis in this patient population. Whether arterial thrombosis simply reﬂects the ‘‘hypercoagulability state’’ of HIT interacting with diseased or injured arteries, or whether arterial ‘‘white clots’’ reﬂect additional prothrombotic effects of HIT via endothelial and monocyte activation, remains uncertain. Patients with HIT can also develop deep-vein thrombosis, which can progress to limb loss if coumarin (warfarin) leads to severe protein C depletion (coumarin-induced venous limb gangrene). Therapy for patients strongly suspected to have HIT should focus on inhibiting thrombin (or its generation) pharmacologically. Two direct thrombin inhibitors (lepirudin, argatroban) are approved for treating HIT. When using these agents, coumarin anticoagulation should be delayed pending substantial resolution of thrombocytopenia, before cautiously introducing over-lapping coumarin therapy.
Obstructive Sleep Apnea Syndromes

Complete or partial collapse of the upper airway during sleep has different effects on the human body ranging from noisy breathing (snoring) to signiﬁcant cardiovascular sequelae as seen in obstructive sleep apnea (OSA). Snoring is very common in the adult population and has been associated with morbidity in epidemiological studies. A variety of treatments may be used for primary snoring (snoring without symptoms) but none are universally successful. The upper airway resistance syndrome is thought to occur when incomplete obstruction of the upper airway results in frequent disruptions in sleep. Whether it is a true ‘‘syndrome’’ or just one end of the continuum of OSA is unclear. Obstructive sleep apnea causes not only sleep disruption but oxygen desaturation. It has been associated with numerous cardiovascular sequelae, including hypertension (systemic and pulmonary), arrhythmias, and stroke. Nasal continuous positive airway pressure (CPAP) is the current treatment of choice, with lesser alternatives including oral appliances, surgery, and weight loss. Further study on outcomes is required to determine how aggressively to treat these syndromes.
In Search of Meaning: Reading and Writing in Alzheimer's Disease

Decline in semantic memory is a key feature of Alzheimer’s disease, and reading and writing performance reﬂects this loss. The article presents an overview of theoretical reading and spelling models, including deﬁnitions of key terminology and controversies surrounding the interaction of semantics and the orthographic lexicon. We review literature supporting a direct lexical nonsemantic route in reading and writing. The reading and writing deﬁcits of Alzheimer’s disease are contrasted with those of semantic dementia. Methods of assessing semantic memory in reading and writing are outlined, including administering published tests, word lists, homophones, written confrontation naming, verbal ﬂuency, and written narrative analysis.
A Black Golfer’s Career Comes Full Circle: The Resiliency of Lee Elder

ABSTRACT:On April 8, 2021, legendary golfer Lee Elder stepped onto the first tee as an honorary starter at the historic Augusta National Golf Club—a club where 45 years prior he became the first Black golfer to integrate the Masters Tournament. As a participant at the 1975 Masters, Elder was the recipient of death threats and was forced to keep security close by for precautionary measures. In 2021, after a storied career, Elder returned to Augusta and was received in a more welcoming fashion. This article explores the career of Elder, including the golfer’s challenging upbringing, transition to the PGA, and participation in the 1975 Masters. Emphasis will be given to Augusta’s rationale to anoint Elder as an honorary starter. The article will also integrate the concept of resiliency to suggest that Elder’s success and ability to play golf through the most trying of racial circumstances is a testament to the golfer’s resiliency.
Noncritical behavior in Pb(In1/2Nb1/2)O3-Pb(Mg1/3Nb2/3)O3-PbTiO3 relaxor ferroelectric crystals detected by acoustic emission method

Abstract [011]-oriented unpoled relaxor ferroelectric Pb(In1/2Nb1/2)O3-Pb(Mg1/3Nb2/3)O3-PbTiO3 crystals are studied by means of acoustic emission and dielectric methods in dependence on both temperature and dc bias electric field. The rhombohedral-cubic ferroelectric phase transition and the dielectric maximum as well as the intermediate temperature are successfully detected. Both rhombohedral-cubic ferroelectric phase transition and the dielectric maximum are studied in dependence on dc bias electric field, too. No the critical end point, but the tricritical one is detected. Existence of the supercritical behavior is discussed in these crystals.
Recombinant Platelet Factor 4: A Therapeutic, Anti-Neoplastic Chimera?

Angiogenesis plays a pivotal role in many serious and life-threatening disorders (e.g., cancer, atherosclerosis, diabetes, arthritis, psoriasis, nephropathy, and retinopathy) and is regulated by a delicate equilibrium between a variety of pro-and anti-angiogenic factors. Although recombinant platelet factor 4 (PF4) was originally developed and evaluated as a clinical alternative to protamine for heparin neutralization, the current scientiﬁc evidence supports a role for this protein and derivative peptides in inhibiting tumor growth and spread, by suppression of tumor-induced neovascularization in many different types of solid tumors. As a heparin-binding tetramer, recombinant PF4 interferes with several steps of endothelial cell proliferation, migration, and angiogenesis, regulates apoptotic death through activation of distinct signal transduction pathways, inhibits growth factor receptor binding, ampliﬁes the inﬂammatory response of natural killer cells through regulation of cytokines production, and induces and maintains a nonspeciﬁc immune response to cancer cells. These biological evidences paved the way for the development and marketing of novel PF4-based angiostatic agents characterized by reduced toxicity and improved bioavailability, thus raising the possibility of an alternative approach for preventing and treating growth and metastasis of tumors. Some PF4-derived molecules such as carboxyl-terminal fragments of recombinant human PF4 and modiﬁed and chimeric peptides have already been developed that exhibit stronger anti-angiogenic properties than the parent molecule and may serve as leads for further therapeutic developments. Newer means of delivering of this anti-angiogenic agent are also being attempted, including PF4-bearing polymeric micro-spheres, vector-mediated PF4 transduction, transgene transfection into oncolytic viruses, and molecular targeting therapy against PF4 and rHuPF4 conjugates. These delivery systems aim to produce high concentrations of the therapeutic agent in a local area for a sustained period, thereby avoiding the typical problems encountered with long-term administration of recombinant proteins.
Platelet Function in Pre-Eclampsia

Pronounced hemostatic changes occur during pregnancy, and the balance shifts markedly in favor of hypercoagulability. Although primarily a result of a marked rise in the levels of several procoagulants and a fall in some natural anticoagulants, platelet activation also contributes to this prothrombotic tendency. Several studies have conﬁrmed the accentuation of platelet activation in pre-eclampsia (P-EC), which remains an important obstetric complication affecting (cid:1) 2 to 4% of pregnancies. Although there is still a long way to go, signiﬁcant inroads have been made in the understanding of this enigmatic condition. Whereas the pathogenesis of P-EC is protean and involves a complex interplay of placental and maternal tissues, platelet activation is likely to contribute to several clinical features. Several techniques have been used to assess platelet activation in P-EC. Detection of aberrations of platelet function and activation appear to have predictive value for its diagnosis. The ﬁndings also lend support to the use of antiplatelet agents as prophylaxis in those women with a high risk of developing the condition.
Measurement units as quantities of objects or values of quantities: a discussion

Measurement units have historically been defined as quantities (i.e. specific properties) of objects, such as the mass of a particular piece of metal or the length of a particular rod. While the current International System of Units (SI) Brochure endorses this position, the draft 9th SI Brochure proposes to change it, and instead define measurement units as values of quantities. The reason for this proposed change is not provided, but it does not seem plausible that it is related to the redefinition of the SI units in terms of fundamental constants of nature: the very concept of what a unit is does not depend on the concrete way any given unit is defined. This paper is intended to open a discussion of whether measurement units should be defined as quantities or as quantity values, and provides our rationale for maintaining the definition of units as quantities.
PET/CT in Musculoskeletal Infection

Early diagnosis of musculoskeletal infections is the key to successful therapy and prevention of complications. Fluorine-18 (F-18) ﬂuorodeoxyglucose-positron emission tomography (FDG-PET) is a promising modality for imaging musculoskeletal infection and might play an important role in the evaluation of chronic osteomyelitis and spinal infection. FDG-PET has shown promising results for diagnosing both acute and chronic infection of the axial and appendicular skeletons. PET imaging will have increased importance in patients with metallic implants because FDG uptake, in contrast to magnetic resonance imaging (MRI) and computed tomography (CT), is not hampered by metallic artifacts. In patients with suspected prosthetic joint infection, results of PET are controversial, and combined indium-111-labeled leukocyte and technetium-99m-sulfur colloid marrow scintigraphy still remains the gold standard. PET/CT with the combination of PET and a low-dose or full-dose diagnostic CT provides exact anatomical correlation of bone and joint lesions and increases the accuracy of the test compared with PET alone. The question of in which situations PET/CT becomes the preferred imaging method in suspected musculoskeletal infection depends on several factors, including cost and availability. This article reviews the currently available literature and addresses the use of FDG-PET/CT in the diagnosis of musculoskeletal infections.