Antithrombin is a plasma protein of the serpin superfamily that may occur as several conformational variants. The native form of antithrombin is a major regulator of blood clotting. In the present study, we have identified the mechanism underlying the antiangiogenic action of a heat-denatured form, denoted latent antithrombin. Fibroblast growth factor (FGF)-induced angiogenesis in the chick embryo and angiogenesis in mouse fibrosarcoma tumors were inhibited by treatment with latent antithrombin at 1 mg/kg/day. Thermolysin-cleaved and native antithrombin were less efficient in these respects. Treatment with latent antithrombin induced apoptosis of cultured endothelial cells and inhibited cell migration toward FGF-2. Under these conditions, FGF-2-stimulated FGF receptor kinase activity was unaffected. However, actin reorganization, activation of focal adhesion kinase, and focal adhesion formation were disturbed by latent antithrombin treatment of FGF-2-stimulated endothelial cells. These data indicate that latent antithrombin induces apoptosis of endothelial cells by disrupting cell-matrix interactions through uncoupling of focal adhesion kinase.

Antiangiogenic effects of latent antithrombin through perturbed cell-matrix interactions and apoptosis of endothelial cells.

Cancer Research

Patients with bacteremia caused by gram positive bacteria are at risk for infective endocarditis (IE). Since IE needs long antibiotic treatment and sometimes heart valve surgery, it is very important to identify patients with IE.

In this narrative review we present and discuss how to determine which investigations to detect IE that are needed in individual patients with gram positive bacteremia.

Published original studies and previous reviews in English, within the relevant field are used.

First, the different qualities of the bacteremia in relation to IE-risk are discussed. The risk for IE in bacteremia is related to the species of the bacterium but also to monomicrobial bacteremia and the number of positive cultures. Secondly, patient-related factors for IE risk in bacteremia are presented. Next, the risk stratification systems to determine the risk for IE in gram positive bacteremia caused by Staphylococcus aureus, viridans streptococci and Enterococcus faecalis are presented and their use is discussed. In the last part of the review, an account for the different modalities of IE-investigations is given. The main focus is on echocardiography which is the cornerstone of IE-investigations. Furthermore, 18 F-FDG PET/CT and cardiac CT are presented and their use is also discussed. A brief account for investigations used to identify embolic phenomena in IE is also given. Finally, we present a flow-chart suggesting which investigations to perform in relation to IE in patients with gram positive bacteremia.

For the individual patient as well as the healthcare system, it is important both to diagnose IE and to decide when to stop looking for IE. This review might be helpful in finding that balance.

Bacteremia with gram positive bacteria - when and how do I need to look for endocarditis?

Clinical Microbiology and Infection

Abdominal wall closure.

British Journal of Surgery

Antireflux treatment is recommended to reduce esophageal adenocarcinoma in patients with Barrett's esophagus. Antireflux surgery (fundoplication) counteracts gastroesophageal reflux of all types of carcinogenic gastric content, and reduces esophageal acid exposure to a greater extent than antireflux medication (proton pump inhibitors). We examined the hypothesis that antireflux surgery prevents esophageal adenocarcinoma to a larger degree than antireflux medication in patients with Barrett's esophagus.

This multi-national and population-based cohort study included all patients with a diagnosis of Barrett's esophagus in any of the national patient registries in Denmark (2012-2020), Finland (1987-1996 and 2010-2020), Norway (2008-2020), or Sweden (2006-2020). Patients who underwent antireflux surgery were compared with non-operated patients using antireflux medication. The risk of esophageal adenocarcinoma was calculated using multivariable Cox regression, providing hazard ratios (HR) with 95% confidence intervals (CI) adjusted for age, sex, country, calendar year, and comorbidity.

The cohort consisted of 33,939 patients with Barrett's esophagus. Of these, 542 (1.6%) had undergone antireflux surgery. During up to 32 years of follow-up, the overall HR was not decreased in patients having undergone antireflux surgery compared to non-operated patients using antireflux medication but rather increased (adjusted HR 1.9, 95% CI 1.1-3.5). Additionally, HRs did not decrease with longer follow-up, but instead increased for each follow-up category, from 1.8 (95% CI 0.6-5.0) within 1-4 years of follow-up to 4.4 (95% CI 1.4-13.5) after 10-32 years of follow-up.

Patients with Barrett's esophagus who undergo antireflux surgery do not seem to have a lower risk of esophageal adenocarcinoma than those using antireflux medication.

Antireflux surgery versus antireflux medication and risk of esophageal adenocarcinoma in patients with Barrett's esophagus.

Gastroenterology

This Consensus Statement from an international, multidisciplinary workshop sponsored by the Pituitary Society offers evidence-based graded consensus recommendations and key summary points for clinical practice on the diagnosis and management of prolactinomas. Epidemiology and pathogenesis, clinical presentation of disordered pituitary hormone secretion, assessment of hyperprolactinaemia and biochemical evaluation, optimal use of imaging strategies and disease-related complications are addressed. In-depth discussions present the latest evidence on treatment of prolactinoma, including efficacy, adverse effects and options for withdrawal of dopamine agonist therapy, as well as indications for surgery, preoperative medical therapy and radiation therapy. Management of prolactinoma in special situations is discussed, including cystic lesions, mixed growth hormone-secreting and prolactin-secreting adenomas and giant and&#xa0;aggressive prolactinomas. Furthermore, considerations for pregnancy and fertility are outlined, as well as management of prolactinomas in children and adolescents, patients with an underlying psychiatric disorder, postmenopausal women, transgender individuals and patients with chronic kidney disease. The workshop concluded that, although treatment resistance is rare, there is a need for additional therapeutic options to address clinical challenges in treating these patients and a need to facilitate international registries to enable risk stratification and optimization of therapeutic strategies.

Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international Consensus Statement.

Nature Reviews. Endocrinology

To investigate brain MRI abnormalities in a cohort of patients with rapidly progressive dementia (RPD) with and without a diagnosis of Creutzfeldt-Jakob disease (CJD).

One hundred and seven patients with diagnosis of prion disease (60 with definite sCJD, 33 with probable sCJD and 14 with genetic prion disease) and 40 non-prion related RPD patients (npRPD) underwent brain MRI including DWI and FLAIR. MRIs were evaluated with a semiquantitative rating score, which separately considered abnormal signal extent and intensity in 22 brain regions. Clinical findings at onset, disease duration, cerebrospinal-fluid 14-3-3 and t-tau protein levels, and EEG data were recorded.

Among patients with definite/probable diagnosis of CJD or genetic prion disease, 2/107 had normal DWI-MRI: in one patient a 2-months follow-up DWI-MRI showed CJD-related changes while the other had autopsy-proven CJD despite no DWI abnormalities 282&#xa0;days after clinical onset. CJD-related cortical changes were detected in all lobes and involvement of thalamus was common. In the npRPD groups, 6/40 patients showed DWI alterations that clustered in three different patterns: (1) minimal/doubtful signal alterations (limbic encephalitis, dementia with Lewy bodies); (2) clearly suggestive of alternative diagnoses (status epilepticus, Wernicke or metabolic encephalopathy); (3) highly suggestive of CJD (mitochondrial disease), though cortical swelling let exclude CJD.

In the diagnostic work-up of RPD, negative/doubtful DWI makes CJD diagnosis rather unlikely, while specific DWI patterns help differentiating CJD from alternative diagnoses. The pulvinar sign is not exclusive of the variant form.

MRI abnormalities in Creutzfeldt-Jakob disease and other rapidly progressive dementia.

Journal of Neurology

Hyperkalemia (HK) is a life-threatening condition that often occurs in patients with chronic kidney disease (CKD). High serum potassium (sKsK) is responsible for a higher risk of end-stage renal disease, arrhythmias and mortality. This risk increases in patients that discontinue cardio-nephroprotective renin-angiotensin-aldosterone system inhibitor (RAASi) therapy after developing HK. Hence, the management of HK deserves the attention of the clinician in order to optimize the therapeutic strategies of chronic treatment of HK in the CKD patient. The adoption in clinical practice of the new hypokalaemic agents patiromer and sodium zirconium cyclosilicate (SZC) for the prevention and chronic treatment of HK could allow patients, suffering from heart failure and chronic renal failure, to continue to benefit from RAASi therapy. We have updated a narrative review of the clear variables, correct definition, epidemiology, pathogenesis, etiology and classifications for HK among non-dialysis CKD (ND CKD) patients. Furthermore, by describing the prognostic impact on mortality and on the progression of renal damage, we want to outline the strategies currently available for the control of potassium (K+) plasma levels.

Hyperkalemia in CKD: an overview of available therapeutic strategies.

Frontiers in Medicine

Glucocorticoids are widespread anti-inflammatory medications used in medical practice. The immunosuppressive effects of systemic glucocorticoids and increased susceptibility to infections are widely appreciated. However, the dose-dependent model frequently used may not accurately predict the risk of infection in all patients treated with long-term glucocorticoids. In this review, we examine the risks of opportunistic infections (OIs) in patients requiring glucocorticoid therapy by evaluating the influence of the glucocorticoid dose, duration, and potency, combined with biological and host clinical factors and concomitant immunosuppressive therapy. We propose strategies to prevent OIs, which involve screening, antimicrobial prophylaxis, and immunizations. While this review focuses on patients with autoimmune, inflammatory, or neoplastic diseases, the potential risks and preventative strategies are likely applicable to other populations. Clinicians should actively assess the benefit-harm ratios of systemic glucocorticoids and implement preventive efforts to decrease their associated infections complications.

Unintended Consequences: Risk of Opportunistic Infections Associated With Long-term Glucocorticoid Therapies in Adults.

Clinical Infectious Diseases

Heart failure (HF) and chronic kidney disease (CKD) are two pathological conditions with a high prevalence in the general population. When they coexist in the same patient, a strict interplay between them is observed, such that patients affected require a clinical multidisciplinary and personalized management. The diagnosis of HF and CKD relies on signs and symptoms of the patient but several additional tools, such as blood-based biomarkers and imaging techniques, are needed to clarify and discriminate the main characteristics of these diseases. Improved survival due to new recommended drugs in HF has increasingly challenged physicians to manage patients with multiple diseases, especially in case of CKD. However, the safe administration of these drugs in patients with HF and CKD is often challenging. Knowing up to which values &#x200b;&#x200b;of creatinine or renal clearance each drug can be administered is fundamental. With this review we sought to give an insight on this sizable and complex topic, in order to get clearer ideas and a more precise reference about the diagnostic assessment and therapeutic management of HF and CKD.

Antiangiogenic effects of latent antithrombin through perturbed cell-matrix interactions and apoptosis of endothelial cells.

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