Extra-corporeal membrane oxygenation for the post-cardiotomy patient.

Extra-corporeal membrane oxygenation remains the last resort in keeping patients alive in those with profound cardiogenic shock following percutaneous interventions or open surgery on the heart. No guidelines exist on the management of patients on such a device despite a high mortality. We attempt to highlight some universal principles that would be relevant to the current practice of those exposed to this challenging field.

The effect of deep hypothermia on the human pulmonary circulation.

OBJECTIVE: Acute rises in pulmonary artery pressures following complex cardiac surgery are associated with high morbidity and mortality. We hypothesised that periods of deep hypothermia predispose to elevated pulmonary pressures upon rewarming. We investigated the effect of this hypothermic preconditioning on isolated human pulmonary arteries and isolated perfused lungs. METHODS: Isometric tension was measured in human pulmonary artery rings (n=24). We assessed the constriction and dilation of these arteries at 37 °C and 17 °C. Isolated perfused human lung models consisted of lobes ventilated via a bronchial cannula and perfused with Krebs via a pulmonary artery cannula. Bronchial and pulmonary artery pressures were recorded. We investigated the effect of temperature using a heat exchanger. RESULTS: Rewarming from 17 °C to 37 °C caused a 1.3 fold increase in resting tension (p<0.05). Arteries constricted 8.6 times greater to 30 nM KCl, constricted 17 times greater to 1 nM Endothelin-1 and dilated 30.3 times greater to 100 µM SNP at 37 °C than at 17 °C (p<0.005). No difference was observed in the responses of arteries originally maintained at 37 °C compared to those arteries maintained at 17 °C and rewarmed to 37 °C. Hypothermia blunted the increase in pulmonary artery pressures to stimulants such as potassium chloride as well as to H-R but did not precondition arteries to higher pulmonary artery pressures upon re-warming. CONCLUSIONS: Deep hypothermia reduces the responsiveness of human pulmonary arteries but does not, however, precondition an exaggerated response to vasoactive agents upon re-warming.

Worldwide survey on implantation of and outcomes for conduction system pacing with His bundle and left bundle branch area pacing leads.

BACKGROUND: Adoption and outcomes for conduction system pacing (CSP), which includes His bundle pacing (HBP) or left bundle branch area pacing (LBBAP), in real-world settings are incompletely understood. We sought to describe real-world adoption of CSP lead implantation and subsequent outcomes. METHODS: We performed an online cross-sectional survey on the implantation and outcomes associated with CSP, between November 15, 2020, and February 15, 2021. We described survey responses and reported HBP and LBBAP outcomes for bradycardia pacing and cardiac resynchronization CRT indications, separately. RESULTS: The analysis cohort included 140 institutions, located on 5 continents, who contributed data to the worldwide survey on CSP. Of these, 127 institutions (90.7%) reported experience implanting CSP leads. CSP and overall device implantation volumes were reported by 84 institutions. In 2019, the median proportion of device implants with CSP, HBP, and/or LBBAP leads attempted were 4.4% (interquartile range [IQR], 1.9-12.5%; range, 0.4-100%), 3.3% (IQR, 1.3-7.1%; range, 0.2-87.0%), and 2.5% (IQR, 0.5-24.0%; range, 0.1-55.6%), respectively. For bradycardia pacing indications, HBP leads, as compared to LBBAP leads, had higher reported implant threshold (median [IQR]: 1.5 V [1.3-2.0 V] vs 0.8 V [0.6-1.0 V], p = 0.0008) and lower ventricular sensing (median [IQR]: 4.0 mV [3.0-5.0 mV] vs. 10.0 mV [7.0-12.0 mV], p < 0.0001). CONCLUSION: In conclusion, CSP lead implantation has been broadly adopted but has yet to become the default approach at most surveyed institutions. As the indications and data for CSP continue to evolve, strategies to educate and promote CSP lead implantation at institutions without CSP lead implantation experience would be necessary.

2023 HRS/APHRS/LAHRS guideline on cardiac physiologic pacing for the avoidance and mitigation of heart failure.

Cardiac physiologic pacing (CPP), encompassing cardiac resynchronization therapy (CRT) and conduction system pacing (CSP), has emerged as a pacing therapy strategy that may mitigate or prevent the development of heart failure (HF) in patients with ventricular dyssynchrony or pacing-induced cardiomyopathy. This clinical practice guideline is intended to provide guidance on indications for CRT for HF therapy and CPP in patients with pacemaker indications or HF, patient selection, pre-procedure evaluation and preparation, implant procedure management, follow-up evaluation and optimization of CPP response, and use in pediatric populations. Gaps in knowledge, pointing to new directions for future research, are also identified.

2023 HRS/APHRS/LAHRS guideline on cardiac physiologic pacing for the avoidance and mitigation of heart failure.

Cardiac physiologic pacing (CPP), encompassing cardiac resynchronization therapy (CRT) and conduction system pacing (CSP), has emerged as a pacing therapy strategy that may mitigate or prevent the development of heart failure (HF) in patients with ventricular dyssynchrony or pacing-induced cardiomyopathy. This clinical practice guideline is intended to provide guidance on indications for CRT for HF therapy and CPP in patients with pacemaker indications or HF, patient selection, pre-procedure evaluation and preparation, implant procedure management, follow-up evaluation and optimization of CPP response, and use in pediatric populations. Gaps in knowledge, pointing to new directions for future research, are also identified.

The ionic atmosphere around A-RNA: Poisson-Boltzmann and molecular dynamics simulations.

The distributions of different cations around A-RNA are computed by Poisson-Boltzmann (PB) equation and replica exchange molecular dynamics (MD). Both the nonlinear PB and size-modified PB theories are considered. The number of ions bound to A-RNA, which can be measured experimentally, is well reproduced in all methods. On the other hand, the radial ion distribution profiles show differences between MD and PB. We showed that PB results are sensitive to ion size and functional form of the solvent dielectric region but not the solvent dielectric boundary definition. Size-modified PB agrees with replica exchange molecular dynamics much better than nonlinear PB when the ion sizes are chosen from atomistic simulations. The distribution of ions 14 Å away from the RNA central axis are reasonably well reproduced by size-modified PB for all ion types with a uniform solvent dielectric model and a sharp dielectric boundary between solvent and RNA. However, this model does not agree with MD for shorter distances from the A-RNA. A distance-dependent solvent dielectric function proposed by another research group improves the agreement for sodium and strontium ions, even for shorter distances from the A-RNA. However, Mg(2+) distributions are still at significant variances for shorter distances.

[Medical misinformation on social media: should it be corrected or not?] / Foute informatie op sociale media.

A lot of medical misinformation circulates on the Internet - especially social media. During the corona crisis, this became an acute and prominent problem. Countering medical misinformation can be done with debunking (refuting misinformation with fact checks) and prebunking (warning people about misinformation and teaching them to recognize it). Research shows that debunking helps correct misconceptions created by misinformation, although the effect is limited. Although this is sometimes suggested, it is not true that corrections or factchecks actually cause misconceptions to be reinforced. Prebunking is also effective, although it can also cause people to distrust reliable information as well.

Diamond nanopillar arrays for quantum microscopy of neuronal signals.

Significance: Wide-field measurement of cellular membrane dynamics with high spatiotemporal resolution can facilitate analysis of the computing properties of neuronal circuits. Quantum microscopy using a nitrogen-vacancy (NV) center is a promising technique to achieve this goal. Aim: We propose a proof-of-principle approach to NV-based neuron functional imaging. Approach: This goal is achieved by engineering NV quantum sensors in diamond nanopillar arrays and switching their sensing mode to detect the changes in the electric fields instead of the magnetic fields, which has the potential to greatly improve signal detection. Apart from containing the NV quantum sensors, nanopillars also function as waveguides, delivering the excitation/emission light to improve sensitivity. The nanopillars also improve the amplitude of the neuron electric field sensed by the NV by removing screening charges. When the nanopillar array is used as a cell niche, it acts as a cell scaffolds which makes the pillars function as biomechanical cues that facilitate the growth and formation of neuronal circuits. Based on these growth patterns, numerical modeling of the nanoelectromagnetics between the nanopillar and the neuron was also performed. Results: The growth study showed that nanopillars with a 2 - µ m pitch and a 200-nm diameter show ideal growth patterns for nanopillar sensing. The modeling showed an electric field amplitude as high as ≈ 1.02 × 10 10 mV / m at an NV 100 nm from the membrane, a value almost 10 times the minimum field that the NV can detect. Conclusion: This proof-of-concept study demonstrated unprecedented NV sensing potential for the functional imaging of mammalian neuron signals.

Proptosis--an uncommon presentation of orbital metastases secondary to prostate cancer.

We report the case of a man with advanced prostate cancer who presented as an emergency with proptosis of his right eye. Cross-sectional imaging of his head confirmed the cause to be orbital metastases secondary to his prostate cancer. The patient responded well to treatment with dexamethasone and palliative orbital radiotherapy.

Intensive care unit readmission after elective coronary artery bypass grafting.

Prospective data of 3,120 consecutive patients who had elective coronary artery bypass were analyzed to identify patient profile, cost, outcome and predictors of those readmitted to the intensive care unit. Group A (n=3,002) had a single intensive care unit admission and group B (n=118) were readmitted within 30 days after surgery. Parsonnet score, EuroSCORE, age, body mass index, chronic obstructive airway disease, peripheral vascular disease, renal dysfunction, unstable angina, congestive cardiac failure, and poor left ventricular function were higher in group B. Bypass and crossclamp times were longer, and the prevalence of inotropic and balloon pump support, arrhythmias, myocardial infarction, re-exploration, blood loss and transfusion, cerebrovascular accident, wound infection, sternal dehiscence, and multisystem failure were higher in group B. Despite a 4-fold increase in cost of care, the mortality rate (32.4%) of patients readmitted to intensive care was 23-times higher than routine patients (1.4%). Crossclamp time>80 min, Parsonnet score>10, EuroSCORE>9, sternal dehiscence, ventricular arrhythmias, and renal failure predicted readmission.

Immunological evidence for prothrombin in human platelets.

An attempt was made to isolate from plasma the platelet surface substrate for thrombin, glycoprotein V (GPV), because a GPV antigen was reported to be present in plasma. Plasma fractionation based on procedures for purification of GPV from platelets revealed a thrombin-sensitive protein with appropriate electrophoretic mobility. The protein was purified; an antiserum against it reacted with detergent-solubilized platelet proteins or secreted proteins in a double diffusion assay, adsorbed a protein from the supernatant solution of activated platelets, and inhibited thrombin-induced platelet activation, but the antiserum did not adsorb labeled GPV. The purified protein was immunochemically related to prothrombin rather than to GPV. Other antibodies against prothrombin were also able to adsorb a protein from platelets. It is concluded that plasma does not contain appreciable amounts of GPV, and platelets contain prothrombin or an immunochemically similar protein.

CXCR4 and CCR5 expression by H9 T-cells is downregulated by a peptide-nucleic acid immunomodulator.

Product R (Reticulose(TM)) is a peptide-nucleic acid immunomodulator with broad-spectrum antiviral activity that was recently shown to increase expression of mRNAs encoding the proinflammatory cytokines, IFN-gamma, IL-1beta, IL-6 and TNF-alpha. Since these cytokines induce expression of the chemokines, MIP-1alpha, MIP-1beta, RANTES, and SDF-1, all of which inhibit viral infectivity, we were interested to determine if Product R also alters chemokine expression. In addition, the finding, that Product R decreases HIV-1 RNA and extracellular p24 antigen in H9 T-lymphoma cells, suggested to us that this drug may block viral infection by reducing the expression of chemokine receptors on target cells. We have therefore utilized H9 cells to test the effects of Product R on expression of mRNAs encoding the chemokine receptors, CD4, CXCR4 and CCR5, as well as their ligands, IL-16, SDF-1, MIP-1alpha, MIP-1beta, and RANTES, by RT-PCR. We also assayed the effect of Product R on surface receptor expression by flow cytometry, and on the chemotactic activity of these cells towards the CXCR4 ligand, SDF-1, and the CCR5 ligands, MIP-1alpha and RANTES. H9 cells were cultured for 3-21 days in medium containing 5% or 10% Product R, or 5% or 10% PBS. We found that, compared to control cultures, cells cultured in media containing Product R expressed lower amounts of CXCR4 and CCR5 mRNA and surface antigen at all time points. Culture for 3 days in media containing Product R also reduced the ability of cells to migrate towards 10-20 ng/ml SDF-1 and 100-250 ng/ml RANTES. In contrast, Product R had no effect on the expression of CD4 mRNA and receptor protein, or on expression of IL-16 mRNA. These findings suggest that Product R may have clinical efficacy in HIV-1-infected patients by downregulating viral coreceptors on target T-cells.

Detection of transforming oncogenes in rat colon tumors induced by direct perfusion with N-methyl-N-nitrosourea.

We assayed rat colon tumors induced by N-methyl-N-nitrosourea (MNU) for transforming oncogenes by the NIH 3T3 transfection and nude mouse tumorigenicity assays. Transfection of DNA from 3 of 3 adenomas and 3 of 5 carcinomas induced transformed foci on NIH 3T3 cells. DNA from 2 of 3 primary foci also possessed focus-forming activity, and rat-specific sequences were observed in secondary focus DNAs. Furthermore, NIH 3T3 cells transfected with DNA from a carcinoma and from a primary focus derived from it, both positive in the focus-forming assay, induced tumors in nude mice. We found no evidence for rat H-ras, K-ras, or N-ras sequences in the DNA of any of 16 primary foci derived from 6 rat tumors; thus, in contrast to other animal tumor models induced by MNU, activation of the ras genes does not appear to predominantly occur in MNU-induced rat colon tumors. We also did not observe, in any of these foci, sequences corresponding to the rat neu, raf, fms, met, or hst genes, thus indicating that none of these is the transforming oncogene in our model. These results suggest that an as yet unidentified transforming oncogene may be activated in rat colon tumors induced by MNU.

Oncogene alterations in rat colon tumors induced by N-methyl-N-nitrosourea.

The authors assayed oncogene alterations in rat colon tumors induced by the direct-acting chemical carcinogen, N-methyl-N-nitrosourea (MNU). DNA isolated from 34 adenomas and eight carcinomas, as well as adjacent normal colon, of 11 rats was assayed by Southern blotting for restriction fragment length polymorphisms and gene amplifications and deletions in 13 oncogenes known to be involved in human or other animal tumors. In addition to finding apparent point mutations or other small alterations in the fos and abl genes in individual rat colon tumors, the authors observed what appear to be larger alterations (ie, rearrangements, or intragenic insertions or deletions) in the H-ras and myb loci in several tumors. In contrast, no changes in the K-ras, N-ras, myc, N-myc, neu, raf, fms, met, and hst genes were seen in any of these tumors. The frequency of myb gene alterations was higher in carcinomas than in adenomas, suggesting that these changes occurred relatively late during tumorigenesis and were not direct effects of the carcinogen. In addition, the finding of alterations in two or three oncogenes in several MNU-induced rat colon tumors suggests the possibility of more widespread genomic lesions in this model.

Enhanced expression of oncogene-encoded mRNA in a rat model of colon cancer.

We have studied the expression of oncogene-encoded mRNAs in a rat model of colon cancer. In this model, rats are intrarectally administered several low doses of the direct-acting carcinogen, N-methyl-N-nitrosourea (MNU). Tumors, predominantly adenomas, develop 5-7 months following administration of the carcinogen, and many of these progress to carcinomas. Upon assaying the steady-state levels of oncogene-encoded transcripts in normal rat colon, we found that fos and N-myc are highly expressed; H-ras, K-ras, myc, myb, and neu messages are present at lower levels; and N-ras, abl, and raf mRNAs are absent. When we compared transcript levels in rat tumors to those in normal colons from the same animal, we observed a 2-4 fold increase in both myc- and H-ras-encoded mRNAs and a 2-7 fold increase in myb message, but no change in expression of any of the 7 other genes. To test whether this increased expression is related to tumor production or is simply a result of the more rapid cellular turnover observed in tumor tissue, the level of oncogene-encoded transcripts was assayed in colonic mucosae of rats given two treatments known to enhance cell turnover and DNA synthesis in the colon. Neither acute application of MNU nor a diet containing 1% cholic acid caused any change in the level of oncogene-encoded mRNAs in rat colons, thus suggesting that the increased abundance of myc, myb, and H-ras messages in tumors is associated with tumor formation. The enhancement of expression of these genes in adenomas, as well as in carcinomas, further suggests that these alterations occur relatively early during the tumorigenic process.

Secondary post-tonsillectomy haemorrhage and informed consent.

This is a prospective incidence study of 250 secondary post-tonsillectomy haemorrhages from a population of 2706 tonsillectomies performed over a seven-year period, which aims to ascertain the incidence and character of post-tonsillectomy secondary haemorrhage. Out of 250 post-tonsillectomy secondary bleeds (9.2 per cent of total; 95 per cent CI = 8.2 per cent - 10.4 per cent), 39 patients had a severe bleed (1.4 per cent; 95 per cent CI = 1.2 per cent - 2.1 per cent). The incidence of secondary tonsillectomy haemorrhage increased with age, peaking at 30-34 years in both men and women (p < 0.001), with no statistically significant difference between the two sexes (p = 0.23). The incidence of serious haemorrhage increases in the older age categories (p = 0.005) but is not influenced by gender (p = 0.50). The majority of secondary tonsillectomy haemorrhages presented between the fourth and seventh day post-operation (69.8 per cent). These results now provide the basis for informed consent for a tonsillectomy in our department.

Complex aortic surgery in a regional center in the United Kingdom. Should the United Kingdom now adopt a United States-style supercenter model?

BACKGROUND: The United States has established aortic supercenters, which have demonstrated clear improvements in the short-term and long-term outcomes after surgery on the thoracic aorta. This model of care does not exist in the United Kingdom. We have looked at our recent experience of emergency and elective thoracic aortic surgery and describe and compare our operative outcomes and 10-year survival with other regional centers and supercenters worldwide. METHODS: This was a retrospective analysis of data collected prospectively from our cardiac database on patients who underwent surgery on the thoracic aorta (n=318) between November 1999 and November 2012. The outcome measures were adjusted operative mortality, postoperative complications, and long-term survival. RESULTS: Type A dissection was carried out on 23.90% of the patients and 76.10% had surgery on the aortic root and thoracic aorta for nondissection. The mean age of the patients was 62.21±14.1 years. The mean logistic EuroSCORE was 26 in the dissection group and 19 in the nondissection group. Hospital mortality was significantly greater (P<.05) in the dissection group compared with the nondissection group (23.7% vs 12.8%). Survival after dissection and nondissection surgery was 66.3%±5.6% versus 77.4%±2.8%, respectively, at 3 years, 63.9%±5.9% versus 71.8%±3.2% at 5 years, and 53.7%±7.4% versus 47.1%±6.0% at 10 years. CONCLUSIONS: Our outcomes are comparable with other regional centers worldwide; however, they are not as good as those reported from the aortic supercenters. There should be continued impetus regarding the establishment of thoracic aortic surgery guidelines and specialist aortic centers in the United Kingdom.

Hyperoxic vasoconstriction of human pulmonary arteries: a novel insight into acute ventricular septal defects.

Objectives. Acute rises in pulmonary artery pressures following postinfarction ventricular septal defects present a challenge. We hypothesised that the abnormally high oxygen content exposure to the pulmonary arteries may be a factor. We investigated the contractile responses of human pulmonary arteries to changes in oxygen tension. Methods. Isometric tension was measured in large and medium sized pulmonary artery rings obtained from lung resections for patients with bronchial carcinoma (n = 30). Fresh rings were mounted in organ baths bubbled under basal conditions with hyperoxic or normoxic gas mixes and the gas tensions varied during the experiment. We studied whether voltage-gated calcium channels and nitric oxide signalling had any role in responses to oxygen changes. Results. Hypoxia caused a net mean relaxation of 18.1% ± 15.5 (P < 0.005) from hyperoxia. Subsequent hyperoxia caused a contraction of 19.2% ± 13.5 (P < 0.005). Arteries maintained in normoxia responded to hyperoxia with a mean constriction of 14.8% ± 3.9 (P < 0.005). Nifedipine inhibited the vasoconstrictive response (P < 0.05) whilst L-NAME had no effect on any hypoxic vasodilatory response. Conclusions. We demonstrate that hyperoxia leads to vasoconstriction in human pulmonary arteries. The mechanism appears to be dependent on voltage-gated calcium channels. Hyperoxic vasoconstriction may contribute to acute rises in pulmonary artery pressures.

Understanding the physical basis of the salt dependence of the electrostatic binding free energy of mutated charged ligand-nucleic acid complexes.

The predictions of the derivative of the electrostatic binding free energy of a biomolecular complex, ΔG(el), with respect to the logarithm of the 1:1 salt concentration, d(ΔG(el))/d(ln[NaCl]), SK, by the Poisson-Boltzmann equation, PBE, are very similar to those of the simpler Debye-Hückel equation, DHE, because the terms in the PBE's predictions of SK that depend on the details of the dielectric interface are small compared to the contributions from long-range electrostatic interactions. These facts allow one to obtain predictions of SK using a simplified charge model along with the DHE that are highly correlated with both the PBE and experimental binding data. The DHE-based model developed here, which was derived from the generalized Born model, explains the lack of correlation between SK and ΔG(el) in the presence of a dielectric discontinuity, which conflicts with the popular use of this supposed correlation to parse experimental binding free energies into electrostatic and nonelectrostatic components. Moreover, the DHE model also provides a clear justification for the correlations between SK and various empirical quantities, like the number of ion pairs, the ligand charge on the interface, the Coulomb binding free energy, and the product of the charges on the complex's components, but these correlations are weak, questioning their usefulness.