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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.earscirev.2006.03.005 Byline: D. Soudry (a), C.R. Glenn (b), Y. Nathan (a), I. Segal (a), D. VonderHaar (b) Keywords: phosphogenesis; south Tethys margins; Cretaceous-Eocene; I[micro].sub.Nd(T); [delta].sup.44/42Ca; P accumulation rates; paleoceanography; TCC; deep water formation Abstract: The evolution of Tethyan phosphogenesis during the Cretaceous-Eocene is examined to try to explain fluctuations of phosphogenesis through time, and whether or not they reflect long-term changes in ocean circulation or in continental weathering. Twenty-seven time-stratigraphic phosphate levels in various Tethyan sites, covering a time span of about 90 Myr from the Hauterivian to the Eocene, were analyzed for.sup.44Ca/.sup.42Ca and.sup.143Nd/.sup.144Nd in their carbonate fluorapatite (CFA) fraction. P and Ca accumulation rates and bulk sedimentation rates were quantified throughout the Cretaceous-Eocene Negev sequence to examine how changes in.sup.44Ca/.sup.42Ca and.sup.143Nd/.sup.144Nd are reflected in the intensity of phosphogenesis. A clear-cut change occurs in I[micro].sub.Nd(T) and [delta].sup.44Ca and in the rates of P and Ca accumulation and bulk sedimentation through the time analyzed. I[micro].sub.Nd(T) is much lower in the Hauterivian-Lower Cenomanian (-12.8 to -10.9) than in the Upper Cenomanian-Eocene (-7.8 to -5.9). Much lower [delta].sup.44Ca values occur in the Hauterivian-Turonian (-0.22 to +0.02) than in the Coniacian-Eocene (+0.23 to +0.40). P accumulation rates in the Negev steeply increase from The culmination of P accumulation rates in the Negev during the Campanian, occurring with a high in I[micro].sub.Nd(T) and [delta].sup.44Ca and a low in sedimentation rates, indicates that paleoceanographic and paleogeographical factors mostly governed phosphorite accumulation in this area. The abrupt I[micro].sub.Nd(T) rise after the Cenomanian is attributed to increased incursion of Pacific (radiogenic) water masses into the Tethys, driven by the Late Cretaceous global sea-level rise, the connection between North and South Atlantic, the global post-Santonian cooling, and the progressive widening of the Caribbean threshold, all acting in combination to significantly intensify the Tethyan circumglobal current (TCC). It also reflects a weakening of the continental Nd signal due to a reduction of exposed landmasses caused by increased flooding of continental shelves. High [delta].sup.44Ca values at those times also point to a decrease in weathering Ca.sup.+2 fluxes and expansion of carbonate sedimentation in shelves, both enriching seawater with isotopically heavy Ca.sup.+2. Deep ocean circulation intensified by the post-Santonian cooling of high latitudes increased P inventory in the Tethys basin, whereas the strengthened TCC and the folded shelf likely resulted in coastal and topographically-induced upwelling, supplying P-rich intermediate waters to southeastern Tethys shelves. Only in the Paleocene-Eocene, following major changes in global circulation produced by narrowing of Tethys and widening of the Atlantic, did phosphogenesis shifts its locus of high intensity to the western (Atlantic) Tethys and West African Atlantic coasts. This change in paleocirculation is expressed by distinctly differing I[micro].sub.Nd(T) in the Middle East and the North and West African phosphorites, suggesting different oceanic P sources and current systems for these two major groups of phosphorites. Our Nd isotope results further suggest a weaker TCC during the Mid-Cretaceous, becoming more intense in Late Cretaceous times. They also point to the North Pacific Ocean as major source of deep water formation for the intermediate-deep waters in the Tethys Basin during the Late Cretaceous. Author Affiliation: (a) Geological Survey Israel, 30 Malkhe Israel St., Jerusalem 95501, Israel (b) Department of Geology and Geophysics, University of Hawaii, Honolulu, Hawaii 96822, USA Article History: Received 19 September 2005; Accepted 27 March 2006

Abstract Background L-arginine is the common substrate for the two isoforms of arginase. Arginase I, highly expressed in the liver and arginase II mainly expressed in the kidney. Arginase I-producing myeloid derived suppressor cells have been shown to inhibit T-cell function by the depletion of L-arginine. On the other hand, arginase II has been detected in patients with cancer and is thought to metabolize L-arginine to L-ornithine needed to sustain rapid tumor growth; however its role in L-arginine depletion is unclear. Thus, in tumor biology, L-arginine metabolism may play a dual role in tumor growth and in the induction of T cell dysfunction. Therefore, we studied in murine renal cell carcinoma (RCC) cell lines, the effect of arginase II on tumor cell proliferation and L-arginine depletion. The effect of arginase inhibitors on cell proliferation was also tested. Methods Three murine renal cell carcinoma (mRCC) cell lines were tested for the presence of arginase. nor-NOHA, an arginase inhibitor was used to substantiate the effect of arginase on cell growth and L-arginine depletion. Amino acid levels were tested by HPLC. Results Our results show that mRCC cell lines express only arginase II and were able to deplete L-arginine from the medium. Cell growth was independent of the amount of arginase activity expressed by the cells. nor-NOHA significantly (P = 0.01) reduced arginase II activity and suppressed cell growth in cells exhibiting high arginase activity. The depletion of L-arginine by mRCC induced the decrease expression of CD3ζ a key element for T-cell function. Conclusion The results of this study show for the first time that arginase II produced by RCC cell lines depletes L-arginine resulting in decreased expression of CD3ζ. These results indicate that RCC cell lines expressing arginase II can modulate the L-arginine metabolic pathway to regulate both cell growth and T-cell function. Blocking arginase may lead to a decrease in RCC cell growth and aid in restoring immune function by increasing L-arginine availability for T-cell use. Understanding the interplay between arginase II and its interaction with the immune system may provide future therapeutic benefits to treat patients with RCC.

BACKGROUND Whether video laryngoscopy as compared with direct laryngoscopy increases the likelihood of successful tracheal intubation on the first attempt among critically ill adults is uncertain. METHODS In a multicenter, randomized trial conducted at 17 emergency departments and intensive care units (ICUs), we randomly assigned critically ill adults undergoing tracheal intubation to the video-laryngoscope group or the direct-laryngoscope group. The primary outcome was successful intubation on the first attempt. The secondary outcome was the occurrence of severe complications during intubation; severe complications were defined as severe hypoxemia, severe hypotension, new or increased vasopressor use, cardiac arrest, or death. RESULTS The trial was stopped for efficacy at the time of the single preplanned interim analysis. Among 1417 patients who were included in the final analysis (91.5% of whom underwent intubation that was performed by an emergency medicine resident or a critical care fellow), successful intubation on the first attempt occurred in 600 of the 705 patients (85.1%) in the video-laryngoscope group and in 504 of the 712 patients (70.8%) in the direct-laryngoscope group (absolute risk difference, 14.3 percentage points; 95% confidence interval [CI], 9.9 to 18.7; PcO.OOl). A total of 151 patients (21.4%) in the video-laryngoscope group and 149 patients (20.9%) in the direct-laryngoscope group had a severe complication during intubation (absolute risk difference, 0.5 percentage points; 95% CI, -3.9 to 4.9). Safety outcomes, including esophageal intubation, injury to the teeth, and aspiration, were similar in the two groups. CONCLUSIONS Among critically ill adults undergoing tracheal intubation in an emergency department or ICU, the use of a video laryngoscope resulted in a higher incidence of successful intubation on the first attempt than the use of a direct laryngoscope. (Funded by the U.S. Department of Defense; DEVICE ClinicalTrials.gov number, NCT05239195). [ABSTRACT FROM AUTHOR]

Introduction: Diuretics are commonly discontinued in patients with cirrhosis with acute kidney injury (AKI) because they are presumed to trigger hepatorenal syndrome type 1 (HRS-1). We hypothesized that if HRS-1 is adequately treated with a vasoconstrictor (mean arterial pressure [MAP] effectively increased), diuretics are safe and effective., Methods: Records of hospitalized patients with cirrhosis who received i.v. furosemide while receiving i.v. norepinephrine as a vasoconstrictor to treat HRS-1 were examined. We assessed change in urine output (UOP), trajectory of serum creatinine (sCr), and impact of portopulmonary hypertension (PoPHTN) on the therapeutic response., Results: Twenty-six patients with HRS-1 received i.v. furosemide (median: 2 days, 160 mg boluses every 6-24 hours) added to i.v. norepinephrine. Median age was 51 years; 91% were of White race, 36% were women, and median model for end-stage liver disease score was 32. The median initial sCr was 4.0 mg/dl. Before treatment, median UOP was 358 ml/d. Norepinephrine alone led to a median increase in UOP to 850 ml/d. Addition of furosemide to norepinephrine induced a subsequent increase in median UOP to 2072 ml/d ( P  < 0.0001), which was not observed in a control group ( n  = 22) who did not receive furosemide. Nineteen patients (73%) treated with norepinephrine plus furosemide (median MAP increase, 16 mm Hg) either maintained or improved their sCr trajectory. The magnitude of norepinephrine-induced increase in MAP correlated with the norepinephrine plus furosemide-induced UOP ( r  = 0.67, P  = 0.0002), and the correlation coefficient was numerically stronger among those with PoPHTN., Conclusion: In patients with HRS-1 who are adequately treated with norepinephrine and achieved an optimal MAP increment, addition of i.v. furosemide enhances diuresis without negatively affecting renal recovery., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Importance: Preclinical models suggest dysregulation of the renin-angiotensin system (RAS) caused by SARS-CoV-2 infection may increase the relative activity of angiotensin II compared with angiotensin (1-7) and may be an important contributor to COVID-19 pathophysiology., Objective: To evaluate the efficacy and safety of RAS modulation using 2 investigational RAS agents, TXA-127 (synthetic angiotensin [1-7]) and TRV-027 (an angiotensin II type 1 receptor-biased ligand), that are hypothesized to potentiate the action of angiotensin (1-7) and mitigate the action of the angiotensin II., Design, Setting, and Participants: Two randomized clinical trials including adults hospitalized with acute COVID-19 and new-onset hypoxemia were conducted at 35 sites in the US between July 22, 2021, and April 20, 2022; last follow-up visit: July 26, 2022., Interventions: A 0.5-mg/kg intravenous infusion of TXA-127 once daily for 5 days or placebo. A 12-mg/h continuous intravenous infusion of TRV-027 for 5 days or placebo., Main Outcomes and Measures: The primary outcome was oxygen-free days, an ordinal outcome that classifies a patient's status at day 28 based on mortality and duration of supplemental oxygen use; an adjusted odds ratio (OR) greater than 1.0 indicated superiority of the RAS agent vs placebo. A key secondary outcome was 28-day all-cause mortality. Safety outcomes included allergic reaction, new kidney replacement therapy, and hypotension., Results: Both trials met prespecified early stopping criteria for a low probability of efficacy. Of 343 patients in the TXA-127 trial (226 [65.9%] aged 31-64 years, 200 [58.3%] men, 225 [65.6%] White, and 274 [79.9%] not Hispanic), 170 received TXA-127 and 173 received placebo. Of 290 patients in the TRV-027 trial (199 [68.6%] aged 31-64 years, 168 [57.9%] men, 195 [67.2%] White, and 225 [77.6%] not Hispanic), 145 received TRV-027 and 145 received placebo. Compared with placebo, both TXA-127 (unadjusted mean difference, -2.3 [95% CrI, -4.8 to 0.2]; adjusted OR, 0.88 [95% CrI, 0.59 to 1.30]) and TRV-027 (unadjusted mean difference, -2.4 [95% CrI, -5.1 to 0.3]; adjusted OR, 0.74 [95% CrI, 0.48 to 1.13]) resulted in no difference in oxygen-free days. In the TXA-127 trial, 28-day all-cause mortality occurred in 22 of 163 patients (13.5%) in the TXA-127 group vs 22 of 166 patients (13.3%) in the placebo group (adjusted OR, 0.83 [95% CrI, 0.41 to 1.66]). In the TRV-027 trial, 28-day all-cause mortality occurred in 29 of 141 patients (20.6%) in the TRV-027 group vs 18 of 140 patients (12.9%) in the placebo group (adjusted OR, 1.52 [95% CrI, 0.75 to 3.08]). The frequency of the safety outcomes was similar with either TXA-127 or TRV-027 vs placebo., Conclusions and Relevance: In adults with severe COVID-19, RAS modulation (TXA-127 or TRV-027) did not improve oxygen-free days vs placebo. These results do not support the hypotheses that pharmacological interventions that selectively block the angiotensin II type 1 receptor or increase angiotensin (1-7) improve outcomes for patients with severe COVID-19., Trial Registration: ClinicalTrials.gov Identifier: NCT04924660.

Tracheal intubation (TI) is a common procedure in critical care, often performed with a Macintosh curved blade used for direct laryngoscopy (DL). Minimal evidence informs the choice between Macintosh blade sizes during TI. We hypothesized that Macintosh 4 blade would have higher first-attempt success than Macintosh 3 blade during DL., Design: Retrospective analysis using a propensity score and inverse probability weighting of data from six prior multicenter randomized trials., Setting and Participants: Adult patients who underwent nonelective TI at participating emergency departments and ICUs. We compared the first-pass success of TI with DL in subjects intubated with a size 4 Macintosh blade on the first TI attempt to subjects with a size 3 Macintosh blade on the first TI attempt., Main Results: Among 979 subjects, 592 (60.5%) had TI using DL with a Macintosh blade, of whom 362 (37%) were intubated with a size 4 blade and 222 (22.7%) with a size 3 blade. We used inverse probability weighting with a propensity score for analyzing data. We found that patients intubated with a size 4 blade had a worse (higher) Cormack-Lehane grade of glottic view than patients intubated with a size 3 blade (adjusted odds ratio [aOR], 1.458; 95% CI, 1.064-2.003; p = 0.02). Patients intubated with a size 4 blade had a lower first pass success than those with a size 3 blade (71.1% vs 81.2%; aOR, 0.566; 95% CI, 0.372-0.850; p = 0.01)., Conclusions and Relevance: In critically ill adults undergoing TI using DL with a Macintosh blade, patients intubated using a size 4 blade on first attempt had a worse glottic view and a lower first pass success than patients intubated with a size 3 Macintosh blade. Further prospective studies are needed to examine the optimal approach to selecting laryngoscope blade size during TI of critically ill adults., Competing Interests: Dr. Khan has received research funding from Eli Lilly, AstraZeneca, Regeneron pharmaceuticals, United Therapeutics, Johnson & Johnson, Dompe Pharmaceuticals, and 4D Medical, as site Principal Investigator for research enrollment, and consulting fees from Dompe Pharmaceuticals for clinical trial design. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)