Nearly 70 years after the proposal of semiconservative replication of generic material by Watson and Crick, we now understand many of the proteins involved in the replication of host chromosomes and how they operate. The initiator and replicator, proposed in the replicon hypothesis, are now well defined in both prokaryotes and eukaryotes. On the other hand, studies in prokaryotes and Archaea indicate alternative modes of initiation, which may not depend on an initiator. Here I summarize recent progress in the field of DNA replication and discuss the evolution of replication systems.

Replicon hypothesis revisited.

Biochemical and Biophysical Research Communications

Traumatic brain injury is one of the leading causes of morbidity and mortality worldwide and is one of the major public healthcare burdens in the US, with millions of patients suffering from the traumatic brain injury itself (approximately 1.6 million/year) or its repercussions (2-6 million patients with disabilities). The severity of traumatic brain injury can range from mild transient neurological dysfunction or impairment to severe profound disability that leaves patients completely non-functional. Indications for treatment differ based on the injury's severity, but one of the goals of early treatment is to prevent secondary brain injury. Hemodynamic stability, monitoring and treatment of intracranial pressure, maintenance of cerebral perfusion pressure, support of adequate oxygenation and ventilation, administration of hyperosmolar agents and/or sedatives, nutritional support, and seizure prophylaxis are the mainstays of medical treatment for severe traumatic brain injury. Surgical management options include decompressive craniectomy or cerebrospinal fluid drainage via the insertion of an external ventricular drain. Several emerging treatment modalities are being investigated, such as anti-excitotoxic agents, anti-ischemic and cerebral dysregulation agents, S100B protein, erythropoietin, endogenous neuroprotectors, anti-inflammatory agents, and stem cell and neuronal restoration agents, among others.

Clinical Management in Traumatic Brain Injury.

Biomedicines

The role of aldosterone has yet to be well appreciated in chronic kidney disease (CKD). Two variables define CKD: an estimated glomerular filtration rate of &lt;60&#x2009;ml/min/1.73 m2 and a spot urine albumin-creatinine ratio of &gt;30&#x2009;mg/g. Both are needed for an accurate diagnosis. The presence of CKD at this level is associated with an elevated risk of cardiovascular death and a greater risk of CKD progression to kidney failure and subsequent dialysis. This paper presents an overview of aldosterone's importance in CKD and its contribution to the inflammatory processes involved in CKD development. Data on outcomes, both surrogate and hard, related to outcomes on CKD progression will also be discussed in the context of mineralocorticoid blockade. Based on recent epidemiological data as well as data examining markers of diabetic kidney disease progression, it is clear that use of both renin-angiotensin system inhibitors and aldosterone receptor antagonists have a significant role in altering the natural history of kidney disease progression itself, as well as reducing the risk of cardiovascular events that generally accompany long-standing kidney disease. This paper will discuss these issues and the management of consequent hyperkalaemia when both steroidal and non-steroidal mineralocorticoid receptor antagonists are used in detail.

Mineralocorticoid receptor antagonists and reno-protection: What's the evidence & where do they fit? A guide for non-specialists.

Diabetes, Obesity & Metabolism

Heart failure with reduced ejection fraction (HFrEF) is a clinical syndrome characterized by volume overload, impaired exercise capacity, and recurrent hospital admissions. A major contributor to the pathophysiology and clinical presentation of heart failure is the activation of the renin-angiotensin-aldosterone system (RAAS). Normally, RAAS is responsible for the homeostatic regulation of blood pressure, extracellular fluid volume, and serum sodium concentration. In HFrEF, RAAS gets chronically activated in response to decreased cardiac output, further aggravating the congestion and cardiotoxic effects. Hence, inhibition of RAAS is a major approach in the pharmacologic treatment of those patients. The most recently introduced RAAS antagonizing medication class is angiotensin receptor blocker/ neprilysin inhibitor (ARNI). In this paper, we discuss ARNIs' superiority over traditional RAAS antagonizing agents in reducing heart failure hospitalization and mortality. We also tease out the evidence that shows ARNIs' renoprotective functions in heart failure patients including those with chronic or end stage kidney disease. We also discuss the evidence showing the added benefit resulting from combining ARNIs with a sodium-glucose cotransporter-2 (SGLT-2) inhibitor. Moreover, how ARNIs decrease the risk of arrhythmias and reverse cardiac remodeling, ultimately lowering the risk of cardiovascular death, is also discussed. We then present the positive outcome of ARNIs' use in patients with diabetes mellitus and those recovering from acute decompensated heart failure. ARNIs' side effects are also appreciated and discussed. Taken together, the provided insight and critical appraisal of the evidence justifies and supports the implementation of ARNIs in the guidelines for the treatment of HFrEF.

Angiotensin Receptor Blocker-Neprilysin Inhibitor for Heart Failure with Reduced Ejection Fraction.

Pharmacological Research : the Official Journal of the Italian Pharmacological Society

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterised by the presence of diastolic dysfunction and elevated left ventricular filling pressure, in the setting of a left ventricular ejection fraction of at least 50%. Despite the epidemiological prevalence of HFpEF, a prompt diagnosis is challenging and many uncertainties exist. HFpEF is characterised by different phenotypes driven by various cardiac and non-cardiac comorbidities. This is probably the reason why several HFpEF clinical trials in the past did not reach strong outcomes to recommend a single therapy for this syndrome; however, this paradigm has recently changed, and the unmet clinical need for HFpEF treatment found a proper response as a result of a new class of drug, the sodium-glucose cotransporter 2 inhibitors, which beneficially act through the whole spectrum of left ventricular ejection fraction. The aim of this review was to focus on the therapeutic target of HFpEF, the role of new drugs and the potential role of new devices to manage the syndrome.

The Therapy and Management of Heart Failure with Preserved Ejection Fraction: New Insights on Treatment.

Cardiac Failure Review

Since its description by Guillain, Barr&#xe9;, and Strohl in 1916, Guillain-Barr&#xe9; syndrome (GBS) has attracted a large literature. The author reviews the history of research into its pathogenesis and treatment to highlight promising avenues for future research.

Since the early 1900s, the clinical picture of GBS has been illustrated in multiple series culminating in the ongoing International Guillain-Barr&#xe9; Syndrome study of 2000 patients. In the 1950s and 1960s, the inflammatory nature of the commonest form, acute inflammatory demyelinating polyradiculoneuropathy (AIDP), was described. In the 1990s, two axonal forms, acute motor-sensory axonal neuropathy and acute motor axonal neuropathy, were recognized. In the 1990s and early 2000s, these forms were shown to be due to antibodies against Campylobacter jejuni glycans cross-reacting with glycolipids on axonal membranes. The pathogenesis of AIDP remains unknown, but T-cell responses to the compact myelin proteins, P2 and P0, which cause experimental autoimmune neuritis, suggest that T cells are important. Randomized controlled trials in the 1970s and 1980s showed no benefit from corticosteroids. Trials in the 1980s showed benefit from plasma exchange and in the 1990s from intravenous immunoglobulin.

Future research should seek biomarkers to identify subgroups with different treatment responses, define the true natural history of the disease with population-based epidemiological studies, study the pathology in autopsies early in the disease, seek causative antibodies and confirm autoimmune T-cell responses in AIDP, and expand treatment trials to include anti-T-cell agents.

Guillain-Barré syndrome: History, pathogenesis, treatment, and future directions.

European Journal of Neurology

Respiratory symptoms are ubiquitous and impair health-related quality of life in people with respiratory disease. This European Respiratory Society (ERS) task force aimed to provide recommendations for symptomatic treatment in people with serious respiratory illness.The ERS task force comprised 16 members, including representatives of people with serious respiratory illness and informal caregivers. Seven questions were formulated, six in the "Population, Intervention, Comparison, Outcome" (PICO) format, which were addressed with full systematic reviews and evidence assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE). One question was addressed narratively. An "evidence-to-decision" framework was used to formulate recommendations.To treat symptoms in people with serious respiratory illness, the task force suggests the use of graded exercise therapy (conditional recommendation, low certainty of evidence); and suggests the use of a multicomponent services, handheld fan and breathing techniques (conditional recommendations, very low certainty of evidence). The task force suggests not to use opioids (conditional recommendation, very low certainty of evidence); and suggests either administering or not administering supplemental oxygen therapy (conditional recommendation, low certainty of evidence). The task force suggests that needs assessment tools may be used as part of a comprehensive needs assessment, but do not replace patient centred care and shared decision making (conditional recommendation, low certainty of evidence). The low certainty of evidence, modest impact of interventions on patient-centred outcomes, and absence of effective strategies to ameliorate cough highlight the need for new approaches to reduce symptoms and enhance wellbeing for individuals who live with serious respiratory illness.

Replicon hypothesis revisited.

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