Explore the vast range of titles available.

RNA antisense oligonucleotide therapy to restore normal splicing of a ciliopathy gene shows promising safety and efficacy results in a clinical trial to treat a form of childhood blindness.

Dysregulation of the mineralocorticoid hormone aldosterone is an increasingly prevalent cause of hypertension. Aldosterone synthase (CYP11B2) shares 93% homology to 11β‐hydroxylase (CYP11B1), which produces cortisol. Lorundrostat, a highly selective inhibitor of CYP11B2, is a potential safe and effective treatment for aldosterone‐dependent, uncontrolled hypertension, including treatment‐resistant hypertension. Lorundrostat showed highly selective inhibition of CYP11B2 in vitro, with 374‐fold selectivity for CYP11B2 vs. CYP11B1. A first‐in‐human study of single ascending doses ranging from 5 to 800 mg and multiple ascending doses ranging from 40 to 360 mg once daily was conducted in healthy participants. After single‐ and multiple‐dose administration, lorundrostat plasma levels peaked 1–3 h after administration with a t1/2 of 10–12 h. Plasma aldosterone decreased up to 40% with single 100‐mg to 200‐mg doses and up to 70% with single 400 to 800‐mg doses. Plasma aldosterone returned to baseline within 16 h after single 100‐mg doses and multiple once‐daily 120‐mg doses. Lorundrostat demonstrated a favorable safety profile in healthy participants. Dose‐ and exposure‐dependent inhibition of renal tubular sodium reabsorption was observed across a clinically relevant dose range with no suppression of basal or cosyntropin‐stimulated cortisol production and only a modest increase in mean serum potassium.

The State of Israel faced one of its most difficult challenges during the 1973 Yom Kippur War. Though the Israel Defense Forces (IDF) eventually emerged as the clear victor in the war, it suffered serious reverses at the outset of hostilities, as well as substantial losses in men and equipment. This book revisits the Yom Kippur War by exploring a number of issues that have not previously received the attention they deserve or that would benefit from a fresh evaluation. Among the issues examined are: the American-Israeli and Jordanian-Israeli relationships during the war; the roles of Israeli nuclear weapons and airpower; the IDF's practice of combined arms warfare; the reasons why the IDF turned the tide of the war more quickly on the Golan front than on the Sinai front; the impact of American arms transfers; and the lessons derived from the war by the United States Army and the IDF. This book, which relies heavily on government documents and other primary sources of information, fills important descriptive and analytical gaps in the academic literature about the Yom Kippur War. No other book compares to it in respect of content and interpretation. It is, in short, essential reading for all scholars interested in the diplomatic and military dimensions of the war.

The Israel Air Force (IAF) has accumulated as much battle experience as any air force in the world during the post-Second World War era, and it has recorded many outstanding accomplishments throughout a seemingly endless string of interstate wars, asymmetrical wars, counterinsurgency campaigns, and special operations. This book examines the IAF's experience in the ArabIsraeli conflict from the establishment of Israel in 1948 to the present day. It analyses this experience through the prisms of manoeuvre warfare, attrition warfare, counterinsurgency warfare, special operations, and humanitarian operations. The book reviews the IAF's performance in such wars as the 1967 Six-Day War, the 196970 War of Attrition, the 1973 Yom Kippur War, the 2006 Second Lebanon War, and the 20089 Gaza War. The book also scrutinizes the IAF's participation in major counterinsurgency campaigns and special operations, traces the air force's experience with unmanned aerial vehicles (UAVs), which have occupied a very prominent place in air operations since the 1982 Lebanon War, and chronicles its experience with anti-aircraft defences and satellites. Up-to-date information on the IAF's bases, squadrons, and other infrastructure is provided as well. The book is based on personal visits to the IAF over the past few years, during which the author had the opportunity to tour bases, listen to lectures and briefings, and speak with numerous retired, reserve, and active duty officers.

Although the median survival for patients with cystic fibrosis (CF) is 32.9 years, a small group of patients live much longer. We analyzed the genotype and phenotype of CF patients 40 years and older seen between 1992 and 2004 at the National Jewish Medical and Research Center (n = 55). These patients were divided into two groups according to age at diagnosis: an early diagnosis (ED) group, median age at diagnosis 2.0 years (range 0.1-15 years, n = 28), and a late diagnosis (LD) group, median age of diagnosis 48.8 years (range 24-72.8 years, n = 27). Consistent with the hypothesis that the CFTR genotype affects the age at diagnosis, CFTR DeltaF508 homozygous individuals were more common in the ED group. Although patients in the ED group were predominantly male, the majority of LD patients were female. Patients with CF diagnosed late had a significantly lower prevalence of pancreatic insufficiency and CF-related diabetes, and better lung function. Fewer patients in the LD groups were infected with Pseudomonas aeruginosa, whereas a greater percentage had cultures positive for nontuberculous mycobacteria. This is the largest cohort of older patients with CF described to date, and our findings indicate that patients diagnosed as adults differ distinctly from survivors of long-term CF diagnosed as children.

The massive Israeli–Egyptian tank battle in the Sinai on 14 October 1973 constituted a turning point on the southern front during the Yom Kippur War. The crushing Israeli victory set the stage for another turning point on this front, the Israeli counter-crossing of the Suez Canal. Yet, the battle of 14 October has received rather scant attention from military historians. This article, therefore, attempts to fill a gap in the literature about the Yom Kippur War by describing and analysing the battle itself, as well as by highlighting its broader impact on the course of hostilities in the Sinai.

The Israel Air Force (IAF) has accumulated as much battle experience as any air force in the world during the post-Second World War era, and it has recorded many outstanding accomplishments throughout a seemingly endless string of interstate wars, asymmetrical wars, counterinsurgency campaigns, and special operations. This book examines the IAF's experience in the Arab-Israeli conflict from the establishment of Israel in 1948 to the present day. It analyzes this experience through the prisms of maneuver warfare, attrition warfare, counterinsurgency warfare, special operations, and humanitarian operations. The book reviews the IAF's performance in such wars as the 1967 Six-Day War, the 1969-70 War of Attrition, the 1973 Yom Kippur War, the 2006 Second Lebanon War, and the 2008-9 Gaza War. The book also scrutinizes the IAF's participation in major counterinsurgency campaigns and special operations, traces the air force's experience with unmanned aerial vehicles (UAVs), which have occupied a very prominent place in air operations since the 1982 Lebanon War, and chronicles its experience with anti-aircraft defenses and satellites. Up-to-date information on the IAF's bases, squadrons, and other infrastructure is provided as well. The book is based on personal visits to the IAF over the past few years, during which the author had the opportunity to tour bases, listen to lectures and briefings, and speak with numerous retired, reserve, and active duty officers.

Abstract The pulmonary endothelin (ET) system has been implicated in the pathogenesis of chronic lung diseases such as pulmonary hypertension, asthma, chronic obstructive lung disease, idiopathic pulmonary fibrosis, and bronchiolitis obliterans. However, the etiologic role of ET-1 in these diseases has not yet been established. We recently demonstrated that ET-1 transgenic mice, generated using the human prepro–ET-1 expression cassette including the cis-acting transcriptional regulatory elements, had predominant transgene expression in lung, brain, and kidney. We used these mice in the present study to analyze the pathophysiologic consequences of long-term pulmonary overexpression of ET-1. We found that ET-1 overexpression in the lungs did not result in significant pulmonary hypertension, but did result in development of a progressive pulmonary fibrosis and recruitment of inflammatory cells (predominantly CD4-positive cells). Our study provides evidence that a long-term activated pulmonary ET system, without any other stimuli, produces chronic lymphocytic inflammation and lung fibrosis. This suggests that overexpression of ET-1 may be a central event in the pathogenesis of lung diseases associated with fibrosis and chronic inflammation, such as pulmonary fibrosis and bronchiolitis.

Rationale Patients with asthma demonstrate depletion of the endogenous bronchodilator GSNO and upregulation of GSNOR. Objectives An exploratory proof of concept clinical study of N6022 in mild asthma to determine the potential bronchoprotective effects of GSNOR inhibition. Mechanistic studies aimed to provide translational evidence of effect. Methods Fourteen mild asthma patients were treated with intravenous N6022 (5 mg) or placebo and observed for 7 days, with repeated assessments of the provocative dose of methacholine causing a 20% fall in FEV1 (methacholine PC20 FEV1), followed by a washout period and crossover treatment and observation. In vitro studies in isolated eosinophils investigated the effect of GSNO and N6022 on apoptosis. Measurements and Main Results This was a negative trial as it failed to reach its primary endpoint, which was change from baseline in methacholine PC20 FEV1 at 24 h. However, our exploratory analysis demonstrated significantly more two dose‐doubling increases in PC20 FEV1 for N6022 compared with placebo (21% vs 6%, P < 0.05) over the 7‐day observation period. Furthermore, a significant treatment effect was observed in the change in PC20FEV1 from baseline averaged over the 7‐day observation period (mean change: +0.82 mg/ml [N6022] from 1.34 mg/ml [baseline] vs −0.18 mg/ml [placebo] from 1.16 mg/ml [baseline], P = 0.023). N6022 was well tolerated in mild asthmatics. In vitro studies demonstrated enhanced eosinophilic apoptosis with N6022. Conclusions In this early phase exploratory proof of concept trial in asthma, N6022 did not significantly alter methacholine PC20 FEV1 at 24 h, but did have a treatment effect at 7 days compared to baseline. Further investigation of the efficacy of S‐nitrosoglutathione reductase inhibition in a patient population with eosinophilic asthma is warranted. This is an early stage proof of concept cross‐over trial for an S‐nitrosoglutathione reductase inhibitor, N6022, in 14 patients with mild non‐corticosteroid treated asthma. Although the study did not reach its primary endpoint of a reduction in methacholine PC 20 FEV1 at 24 h, a reduced methacholine PC 20 FEV1 at 7 days compared with baseline was achieved.