Cyanotic congenital heart disease and coronary artery atherogenesis

Hypoxemic erythrocytotic residents of high altitudes lack coronary atherosclerosis and have low cholesterol levels. It was postulated that hypoxemic erythrocytotic adults with cyanotic congenital heart disease (CCHD) might be analogous. The incidence of coronary atherosclerosis in this patient population has not been established, and hypocholesterolemia has not previously been recognized. Accordingly, 279 patients were divided into 4 groups: group A: 143 cyanotic patients not operated on (54 men and 89 women, aged 18 to 69 years); group B: 47 cyanotic patients (28 men and 19 women rendered acyanotic by operation at age 22 to 69 years); group C: 41 acyanotic patients not operated on (22 men and 19 women, aged 22 to 75 years); and group D: 48 patients acyanotic before and after operation (24 men and 24 women, aged 21 to 70 years). Coronary arteries were studied angiographically in 59 patients and at necropsy in 5 subjects aged 37 to 56 years. Total cholesterol was <160 mg/dl in 58% of group A, 52% of group B, 10% of group C, and 12% of group D (p <0.000001, chi-square analysis). Angiograms disclosed dilated coronary arteries without obstruction. Necropsy disclosed ectatic coronary arteries with structural abnormalities of the media. In conclusion, this study provides the first quantitative and qualitative data on antiatherogenic changes in lipoproteins in adults with CCHD. The coronary arteries are atheroma free because hypocholesterolemia acts in concert with the antiatherogenic properties of upregulated nitric oxide, hyperbilirubinemia, hypoxemia, and low platelet counts. The persistence of hypocholesterolemia after the surgical elimination of cyanosis suggests a genetic determinant.     

Worsening of cerebral hyperemia by the administration of terlipressin in acute liver failure with severe encephalopathy

There is increasing evidence that terlipressin is useful in patients with cirrhosis and hepatorenal syndrome, but there are no data of its use in patients with acute liver failure (ALF) in whom hepatorenal syndrome is common. Although terlipressin produces systemic vasoconstriction, it produces cerebral vasodilatation and may increase cerebral blood flow (CBF). Increased CBF contributes to intracranial hypertension in patients with ALF. The aim of this study was to evaluate the safety of terlipressin in patients with ALF with respect to cerebral hemodynamics. Six successive patients with ALF were ventilated electively for grade IV hepatic encephalopathy. Patients were monitored invasively and CBF was measured (Kety-Schmidt technique). Measurements were made before and at 1, 3, and 5 hours after intravenous (single bolus) administration of terlipressin (0.005 mg/kg), median, 0.25 mg (range, 0.2-0.3 mg). There was no significant change in heart rate, mean arterial pressure, or cardiac output. CBF and jugular venous oxygen saturation both increased significantly at 1 hour (P = 0.016). Intracranial pressure increased significantly at 1 hour (P = 0.031), returning back to baseline values at 2 hours. In conclusion, administration of terlipressin, at a dose that did not alter systemic hemodynamics, resulted in worsening of cerebral hyperemia and intracranial hypertension in patients with ALF and severe hepatic encephalopathy. These data suggest the need to exercise extreme caution in the use of terlipressin in these patients in view of its potentially deleterious consequences on cerebral hemodynamics.     

Fully-automated left ventricular mass and volume MRI analysis in the UK Biobank population cohort: evaluation of initial results

UK Biobank, a large cohort study, plans to acquire 100,000 cardiac MRI studies by 2020. Although fully-automated left ventricular (LV) analysis was performed in the original acquisition, this was not designed for unsupervised incorporation into epidemiological studies. We sought to evaluate automated LV mass and volume (Siemens syngo InlineVF versions D13A and E11C), against manual analysis in a substantial sub-cohort of UK Biobank participants. Eight readers from two centers, trained to give consistent results, manually analyzed 4874 UK Biobank cases for LV end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), ejection fraction (EF) and LV mass (LVM). Agreement between manual and InlineVF automated analyses were evaluated using Bland–Altman analysis and the intra-class correlation coefficient (ICC). Tenfold cross-validation was used to establish a linear regression calibration between manual and InlineVF results. InlineVF D13A returned results in 4423 cases, whereas InlineVF E11C returned results in 4775 cases and also reported LVM. Rapid visual assessment of the E11C results found 178 cases (3.7%) with grossly misplaced contours or landmarks. In the remaining 4597 cases, LV function showed good agreement: ESV ?6.4?±?9.0 ml, 0.853 (mean?±?SD of the differences, ICC) EDV ?3.0?±?11.6 ml, 0.937; SV 3.4?±?9.8 ml, 0.855; and EF 3.5?±?5.1%, 0.586. Although LV mass was consistently overestimated (29.9?±?17.0 g, 0.534) due to larger epicardial contours on all slices, linear regression could be used to correct the bias and improve accuracy. Automated InlineVF results can be used for case-control studies in UK Biobank, provided visual quality control and linear bias correction are performed. Improvements between InlineVF D13A and InlineVF E11C show the field is rapidly advancing, with further improvements expected in the near future.     

‘The team for both sides?’ A qualitative study of change in heart failure services at three acute NHS Trusts

Heart failure (HF) is an increasingly prevalent long‐term condition that affects around 900,000 people in the United Kingdom (National Institute for Health and Clinical Excellence). The study examined how HF services in the English National Health Service (NHS) were changing, focusing particularly on the primary/secondary care interface. The maintenance of continuity in care in the face of increasing demand and financial pressures on health and social care was a key concern. Semi‐structured interviews were conducted with 22 members of staff working in HF services in three NHS acute Trusts in the West Midlands of England. Interviews were conducted between April and December 2011 with purposively selected participants and data were analysed using the Framework Method. Four main themes emerged from the analysis: service context, capacity, the primary/secondary interface and communication across boundaries. Barriers to, and facilitators of, continuity of care for patients with HF were identified within these themes. The findings provide insights into the structure, management and work of HF services in the acute and community settings. They highlight how local systems for the management of HF patients are developing in ways which are not necessarily consistent with national policy.     

Early PREdiction of sepsis using leukocyte surface biomarkers: the ExPRES-sepsis cohort study

Purpose

Reliable biomarkers for predicting subsequent sepsis among patients with suspected acute infection are lacking. In patients presenting to emergency departments (EDs) with suspected acute infection, we aimed to evaluate the reliability and discriminant ability of 47 leukocyte biomarkers as predictors of sepsis (Sequential Organ Failure Assessment score?≥?2 at 24 h and/or 72 h following ED presentation).

Methods

In a multi-centre cohort study in four EDs and intensive care units (ICUs), we standardised flow-cytometric leukocyte biomarker measurement and compared patients with suspected acute infection (cohort-1) with two comparator cohorts: ICU patients with established sepsis (cohort-2), and ED patients without infection or systemic inflammation but requiring hospitalization (cohort-3).

Results

Between January 2014 and February 2016, we recruited 272, 59 and 75 patients to cohorts 1, 2, and 3, respectively. Of 47 leukocyte biomarkers, 14 were non-reliable, and 17 did not discriminate between the three cohorts. Discriminant analyses for predicting sepsis within cohort-1 were undertaken for eight neutrophil (cluster of differentiation antigens (CD) CD15; CD24; CD35; CD64; CD312; CD11b; CD274; CD279), seven monocyte (CD35; CD64; CD312; CD11b; HLA-DR; CD274; CD279) and a CD8 T-lymphocyte biomarker (CD279). Individually, only higher neutrophil CD279 [OR 1.78 (95% CI 1.23–2.57); P?=?0.002], higher monocyte CD279 [1.32 (1.03–1.70); P?=?0.03], and lower monocyte HLA-DR [0.73 (0.55–0.97); P?=?0.03] expression were associated with subsequent sepsis. With logistic regression the optimum biomarker combination was increased neutrophil CD24 and neutrophil CD279, and reduced monocyte HLA-DR expression, but no combination had clinically relevant predictive validity.

Conclusions

From a large panel of leukocyte biomarkers, immunosuppression biomarkers were associated with subsequent sepsis in ED patients with suspected acute infection.

Clinical trial registration

NCT02188992.

     

Tumor trapping of 5-fluorouracil: in vivo 19F NMR spectroscopic pharmacokinetics in tumor-bearing humans and rabbits.

The pharmacokinetics of 5-fluorouracil (5FU) were studied in vivo in patients with discrete tumors and in rabbits bearing VX2 tumors by using 19F NMR spectroscopy. The human studies were conducted in a 1.5-T Magnetom magnetic resonance imager (Siemens), and the rabbit studies were conducted in a 4.7-T GE/Nicolet 33-cm bore magnet. Free 5FU was detected in the tumors of four of the six patients and in all VX2 tumors but not in normal rabbit tissues. No other metabolites were seen in these tumors, contrary to the extensive catabolism we had previously documented using 19F NMR spectroscopy in both human and animal livers. The tumor pool of free 5FU in those human tumors that trapped 5FU was determined to have a half-life of 0.4-2.1 hr, much longer than expected and significantly longer than the half-life of 5FU in blood (5-15 min), whereas the half-life of trapped 5FU in the VX2 tumors ranged from 1.05 to 1.22 hr. In this initial experience, patient response to chemotherapy may correlate with extent of trapping free 5FU in the human tumors. These studies document that NMR spectroscopy is clinically feasible in vivo, allows noninvasive pharmacokinetic analyses at a drug-target tissue in real time, and may produce therapeutically important information at the time of drug administration. Demonstration of the trapping of 5FU in tumors provides both a model for studying metabolic modulation in experimental tumors (in animals) and a method for testing modulation strategies clinically (in patients).     

When continuous surgical site infection surveillance is interrupted: the Royal Hobart Hospital experience

BACKGROUND: The prevalence of surgical site infections (SSI) is second only to urinary tract infections in hospitalized patients. They continue to threaten the health of hospitalized patients and impact negatively on the financial solvency of hospitals through prolonged hospitalization, increased rates of rehospitalization, and significantly increased health care costs. METHODS: We describe the effect of a 12-year surveillance program that included postdischarge follow-up and feedback to clinicians on the rate of SSI and the effect when surveillance is interrupted. Surgical procedures performed at the Royal Hobart Hospital (RHH), a university teaching hospital in Australia, between 1988 and 2001 were monitored for evidence of SSI in hospitals and for up to 30 days postoperatively. The surveillance program was inadvertently disrupted for 15 months from October 1990 to January 1992 and then recommenced. It has been ongoing since that time, apart from a 3-month interruption in 1998. Infection rates were determined on a regular basis, and these results were provided to surgeons, theatre staff, and surgical ward staff every 6 months. Patients included all adult surgical patients with an incisional wound, excluding burn patients and day-only surgical patients. RESULTS: Over the 12-year active surveillance period, 47,581 surgical procedures were followed for SSI. In-hospital SSI rates declined significantly over the study period from 4.7% (95% CI: 3.9%-5.6%) in 1988-1989 to 1.2% (95% CI: 0.8%-1.7%) in 2001 (P < .0001). Infection rates fell rapidly following the commencement of the program. This decline was halted during the period from October 1990 to January 1992 when the program was suspended. In-hospital SSI rates declined once again following the recommencement of the surveillance program, and these lower rates have been maintained. In contrast, postdischarge infection rates rose significantly from 1.2% (95% CI: 0.8%-1.7%) in 1988-1989 to 2.1% (95% CI: 1.6%-2.7%) in 2001 (P < .0001). CONCLUSION: The introduction of a program of continuous SSI surveillance at the RHH was associated with a reduction in the in-hospital and total SSI rate. This phenomenon was repeated following the recommencement of the program after a temporary interruption. Increasing numbers of SSIs are arising after hospital discharge. Many of these patients are readmitted to the hospital for further management of the SSI. Surveillance programs that do not perform postdischarge surveillance will have difficulty in capturing this data. Our experience supports the Study on the Efficacy of Nosocomial Infection Control (SENIC) findings, showing that health care facilities can achieve improved levels of infection management with active surveillance programs.     

Prostaglandin E2 mediates phosphorylation and down-regulation of the tuberous sclerosis-2 tumor suppressor (tuberin) in human endometrial adenocarcinoma cells via the Akt signaling pathway

Prostaglandin (PG) E2 promotes tumor growth via interaction with its G protein-coupled receptors and activation of intracellular signaling. Tuberous sclerosis 2 (tuberin) is a tumor suppressor, which negatively regulates cell growth. Its phosphorylation results in its inactivation and targeted down- regulation, thus lifting the growth inhibition effects. This study investigated the expression and localization of tuberin in neoplastic and normal endometrium and the effect of PGE2 on phosphorylation of tuberin via the Akt pathway. Quantitative RT-PCR and Western blot analysis demonstrated reduced expression of tuberin in neoplastic tissue, compared with normal endometrial tissue. Tuberin expression was localized by immunohistochemistry to the glandular epithelial compartment in neoplastic and normal endometrium. We investigated the effect of PGE2 on phosphorylation of tuberin via the Akt pathway. Treatment of neoplastic and normal endometrium with 100 nm PGE2 enhanced phosphorylated tuberin immunoreactivity in the glandular epithelium. PGE2 also phosphorylated Akt and tuberin in Ishikawa endometrial adenocarcinoma cells, leading to a reduction in expression of total tuberin protein. Cotreatment of cells with wortmannin or LY294002 inhibited the PGE2-induced phosphorylation of Akt and tuberin. These data suggest that PGE2 signaling may promote endometrial tumorigenesis by inactivation of tuberin after its phosphorylation via the Akt signaling pathway.