The transsulfuration pathway converts homocysteine to cysteine and represents the metabolic link between antioxidant and methylation metabolism. The first and committing step in this pathway is catalyzed by cystathionine ␤-synthase (CBS), which is subject to complex regulation, including allosteric activation by the methyl donor, S-adenosylmethionine (AdoMet). In this study, we demonstrate that methionine restriction leads to a >10-fold decrease in CBS protein levels, and pulse proteolysis studies reveal that binding of AdoMet stabilizes the protein against degradation by Ϸ12 kcal͞mol. These observations predict that under pathological conditions where AdoMet levels are diminished, CBS, and therefore glutathione levels, will be reduced. Indeed, we demonstrate this to be the case in a mouse model for spontaneous steatohepatitis in which the gene for the MAT1A isoenzyme encoding AdoMet synthetase has been disrupted, and in human hepatocellular carcinoma, where MAT1A is silenced. Furthermore, diminished CBS levels are associated with reduced cell viability in hepatoma cells challenged with tert-butyl hydroperoxide. This study uncovers a mechanism by which CBS is allosterically activated by AdoMet under normal conditions but is destabilized under pathological conditions, for redirecting the metabolic flux toward methionine conservation. A mechanistic basis for the coordinate changes in redox and methylation metabolism that are a hallmark of several complex diseases is explained by these observations. glutathione ͉ liver disease C ellular methylation and antioxidant metabolism are linked by the transsulfuration pathway, which converts the methionine cycle intermediate, homocysteine, to cysteine, the limiting reagent in glutathione synthesis. The balance between conserving methionine via transmethylation under conditions of methionine restriction and committing it to transsulfuration under conditions of plenty is regulated at two key control points, methionine adenosyltransferase (MAT) and cystathionine ␤-synthase (CBS) (Fig. 1). Aberrations in methylation and redox homeostasis are common to a number of chronic diseases including pathologies of the liver. In alcoholic liver disease and in hepatocellular carcinoma an increase in markers of oxidative stress is observed (1, 2). Furthermore, there is a switch in the expression of MAT genes from MAT1A to MAT2A in liver cancer, which correlates with lower S-adenosylmethionine (AdoMet) levels (3).Under normal conditions, coordinate regulation of methylation and antioxidant metabolism is achieved by the allosteric activation of CBS by AdoMet (Fig. 1). AdoMet is a V-type allosteric effector that increases CBS activity 2-to 3-fold (4, 5). Under conditions of plenty, methionine is directed toward cysteine synthesis via the transsulfuration pathway for use in glutathione and other cellular functions or directed toward catabolism. Cysteine is the limiting reagent in glutathione synthesis and in liver; Ϸ50% of the cysteine in glutathione is derived from methionine via the transsulf...

Intestinal volvulus, regardless of location, is a rare disease process, but one that requires high suspicion and timely diagnosis given the increased incidence of intestinal necrosis and potential mortality. Most patients with intestinal volvulus require some form of surgical intervention. However, over the last few decades, the work-up and management of intestinal volvulus has changed given constant advancements in technology and patient care. Most importantly, however, is recognizing the need for emergent versus more elective surgery because this influences the morbidity and mortality for the individual patient.

PCs had similar outcomes to CTs in terms of failure rate and tube insertion-related complications, and the initial drainage output from PCs was not inferior to that of CTs. The usage of PCs was, however, selective. A future multi-center study is needed to provide additional support and information for PC usage in traumatic HTX/HPTX.

Background Cardiac output (CO) measurement in the intensive care unit (ICU) requires invasive devices such as the pulmonary artery (PA) catheter or arterial waveform pulse contour analysis (PCA). This study tests the accuracy and feasibility of point of care ultrasound (POCUS) of the common carotid artery to estimate the CO non-invasively and compare it to existing invasive CO measurement modalities. Methods Patients admitted to the surgical and cardiothoracic ICU in a tertiary university-affiliated academic center during a 4-month period, with invasive hemodynamic monitoring devices for management, were included in this cohort study. Common carotid artery POCUS was performed to measure the CO and the results were compared to an invasive device. Results Intensivists and ICU fellows, using ultrasound of the common carotid artery, obtained the CO measurements. Images of the Doppler flow and volume were obtained at the level of the thyroid gland. Concurrent CO measured via invasive devices was recorded. The patient cohort comprised 36 patients; 52 % were females. The average age was 59 ± 13 years, and 66 % were monitored via PCA device and 33 % via PA catheter. Intraclass correlation coefficient (ICC) analysis demonstrated almost perfect correlation (0.8152) between measurements of CO via ultrasound vs. invasive modalities. The ICC between PO-CUS and the invasive measurement via PCA was 0.84 and via PA catheter 0.74, showing substantial agreement between the ultrasound and both invasive modalities. Conclusions Common carotid artery POCUS offers a non-invasive method of measuring the CO in the critically ill population.Keywords Cardiac output Á Ultrasound Á Carotid doppler Á Pulmonary artery catheter Á Pulse contour analysis Á Point of care ultrasound Abstract Background La misurazione della gittata cardiaca (CO) in Unità di Terapia Intensiva (ICU) richiede dispositivi invasivi come il cateterismo dell'arteria polmonare (PA) o l'analisi dell'onda dell'impulso arterioso (PCA). Questo studio si propone di valutare l'accuratezza e la fattibilità dell'ecografia (POCUS) della carotide comune per stimare la CO in modo non invasivo e confrontarla con le modalità esistenti di misurazione della CO effettuate in maniera invasiva. Metodi I pazienti ricoverati in terapia intensiva chirurgica e cardiotoracica in un centro accademico, affiliato con l'università, nel corso di un periodo di quattro mesi, sottoposti a dispositivi di monitoraggio emodinamico invasivo sono stati inclusi in questo studio. E' stata eseguita l'ecografia dell'arteria carotide comune per misurare la CO ed i risultati sono stati confrontati con una tecnica invasiva. Risultati Medici di terapia intensiva e borsisti, utilizzando l'ecografia della carotide comune, hanno ottenuto le misurazioni della CO. Immagini del flusso Doppler e di volume sono state ottenute a livello della ghiandola tiroidea. Contemporaneamente è è stata registrata la CO mediante dispositivi invasivi. Il gruppo era costituito da 36 Ultrasound (2015) 18:127-133 DOI 10.1007 pazien...

Prognostic study, level III.

The traditional treatment of traumatic hemothorax (HTX) has been an insertion of a large-bore 36-to 40-Fr chest tube. Our previous single-center randomized controlled trial (RCT) had shown that 14-Fr percutaneous catheters (PCs) (pigtail) were equally as effective as chest tube. We performed a multicenter RCT, hypothesizing that PCs are as equally effective as chest tubes in the management of patients with traumatic HTX (NCT03546764). METHODS:We performed a multi-institution prospective RCT comparing 14-Fr PCs with 28-to 32-Fr chest tubes in the management of patients with traumatic HTX from July 2015 to September 2020. We excluded patients who were in extremis and required emergent tube placement and those who refused to participate. The primary outcome was failure rate, defined as a retained HTX requiring a second intervention. Secondary outcomes included daily drainage output, tube days, intensive care unit and hospital length of stay, and insertion perception experience (IPE) score on a scale of 1 to 5 (1, tolerable experience; 5, worst experience). Unpaired Student's t test, χ 2 , and Wilcoxon rank sum test were used with significance set at p < 0.05. RESULTS:After exclusion, 119 patients participated in the trial, 56 randomized to PCs and 63 to chest tubes. Baseline characteristics between the two groups were similar. The primary outcome, failure rate, was similar between the two groups (11% PCs vs. 13% chest tubes, p = 0.74). All other secondary outcomes were also similar, except PC patients reported lower IPE scores (median, 1: "I can tolerate it"; interquartile range, 1-2) than chest tube patients (median, 3: "It was a bad experience"; interquartile range, 2-5; p < 0.001). CONCLUSION:Small caliber 14-Fr PCs are equally as effective as 28-to 32-Fr chest tubes in their ability to drain traumatic HTX with no difference in complications. Patients reported better IPE scores with PCs over chest tubes, suggesting that PCs are better tolerated.

Clearance of homocysteine via the transsulfuration pathway provides an endogenous route for cysteine synthesis and represents a quantitatively significant source of this amino acid needed for glutathione synthesis. Men have higher plasma levels of total homocysteine than do women, but the mechanism of this sex-dependent difference is not known. In this study, we investigated regulation by testosterone of cystathionine beta-synthase (CBS), which catalyzes the committing step in the transsulfuration pathway. We report that testosterone downregulates CBS expression via a posttranscriptional mechanism in the androgen-responsive prostate cancer cell line, LNCaP. This diminution in CBS levels is accompanied by a decrease in flux through the transsulfuration pathway and by a lower intracellular glutathione concentration. The lower antioxidant capacity in testosterone-treated prostate cancer cells increases their susceptibility to oxidative stress conditions. These results demonstrate regulation of the homocysteine-clearing enzyme, CBS, by testosterone and suggest the potential utility of targeting this enzyme as a chemotherapeutic strategy.

Introduction Traditional management of traumatic hemothorax/hemopneumothorax (HTX/HPTX) has been insertion of large-bore 32-40 French (Fr) chest tubes (CTs). Retrospective studies have shown 14Fr percutaneous pigtail catheters (PCs) are equally effective as CTs. Our aim was to compare effectiveness between PCs and CTs by performing the first randomized controlled trial (RCT). We hypothesize PCs work equally as well as CTs in management of traumatic HTX/HPTX. Methods Prospective RCT comparing 14Fr PCs to 28-32Fr CTs for management of traumatic HTX/HPTX from 07/2015 to 01/2018. We excluded patients requiring emergency tube placement or who refused. Primary outcome was failure rate defined as retained HTX or recurrent PTX requiring additional intervention. Secondary outcomes included initial output (IO), tube days and insertion perception experience (IPE) score on a scale of 1-5 (1 = tolerable experience, 5 = worst experience). Unpaired Student's t-test, chi-square and Wilcoxon rank-sum test were utilized with significance set at P \ 0.05. Results Forty-three patients were enrolled. Baseline characteristics between PC patients (N = 20) and CT patients (N = 23) were similar. Failure rates (10% PCs vs. 17% CTs, P = 0.49) between cohorts were similar. IO (median, 650 milliliters[ml]; interquartile range[IR], 375-1087; for PCs vs. 400 ml; IR, 240-700; for CTs, P = 0.06), and tube duration was similar, but PC patients reported lower IPE scores (median, 1, ''I can tolerate it''; IR, 1-2) than CT patients (median, 3, ''It was a bad experience''; IR, 3-4, P = 0.001). Conclusion In patients with traumatic HTX/HPTX, 14Fr PCs were equally as effective as 28-32Fr CTs with no significant difference in failure rates. PC patients, however, reported a better insertion experience. www.ClinicalTrials.gov Registration ID: NCT02553434