Sex-specific responses to slow progressive pressure overload in a large animal model of HFpEF.

Approximately 50% of all heart failure (HF) diagnoses can be classified as HF with preserved ejection fraction (HFpEF). HFpEF is more prevalent in females compared with males, but the underlying mechanisms are unknown. We previously showed that pressure overload (PO) in male felines induces a cardiopulmonary phenotype with essential features of human HFpEF. The goal of this study was to determine if slow progressive PO induces distinct cardiopulmonary phenotypes in females and males in the absence of other pathological stressors. Female and male felines underwent aortic constriction (banding) or sham surgery after baseline echocardiography, pulmonary function testing, and blood sampling. These assessments were repeated at 2 and 4 mo postsurgery to document the effects of slow progressive pressure overload. At 4 mo, invasive hemodynamic studies were also performed. Left ventricle (LV) tissue was collected for histology, myofibril mechanics, extracellular matrix (ECM) mass spectrometry, and single-nucleus RNA sequencing (snRNAseq). The induced pressure overload (PO) was not different between sexes. PO also induced comparable changes in LV wall thickness and myocyte cross-sectional area in both sexes. Both sexes had preserved ejection fraction, but males had a slightly more robust phenotype in hemodynamic and pulmonary parameters. There was no difference in LV fibrosis and ECM composition between banded male and female animals. LV snRNAseq revealed changes in gene programs of individual cell types unique to males and females after PO. Based on these results, both sexes develop cardiopulmonary dysfunction but the phenotype is somewhat less advanced in females.NEW & NOTEWORTHY We performed a comprehensive assessment to evaluate the effects of slow progressive pressure overload on cardiopulmonary function in a large animal model of heart failure with preserved ejection fraction (HFpEF) in males and females. Functional and structural assessments were performed at the organ, tissue, cellular, protein, and transcriptional levels. This is the first study to compare snRNAseq and ECM mass spectrometry of HFpEF myocardium from males and females. The results broaden our understanding of the pathophysiological response of both sexes to pressure overload. Both sexes developed a robust cardiopulmonary phenotype, but the phenotype was equal or a bit less robust in females.

Quantum Relativity of Subsystems.

One of the most basic notions in physics is the partitioning of a system into subsystems and the study of correlations among its parts. In this Letter, we explore this notion in the context of quantum reference frame (QRF) covariance, in which this partitioning is subject to a symmetry constraint. We demonstrate that different reference frame perspectives induce different sets of subsystem observable algebras, which leads to a gauge-invariant, frame-dependent notion of subsystems and entanglement. We further demonstrate that subalgebras which commute before imposing the symmetry constraint can translate into noncommuting algebras in a given QRF perspective after symmetry imposition. Such a QRF perspective does not inherit the distinction between subsystems in terms of the corresponding tensor factorizability of the kinematical Hilbert space and observable algebra. Since the condition for this to occur is contingent on the choice of QRF, the notion of subsystem locality is frame dependent.

Cortical bone stem cells modify cardiac inflammation after myocardial infarction by inducing a novel macrophage phenotype.

Acute damage to the heart, as in the case of myocardial infarction (MI), triggers a robust inflammatory response to the sterile injury that is part of a complex and highly organized wound-healing process. Cortical bone stem cell (CBSC) therapy after MI has been shown to reduce adverse structural and functional remodeling of the heart after MI in both mouse and swine models. The basis for these CBSC treatment effects on wound healing are unknown. The present experiments show that CBSCs secrete paracrine factors known to have immunomodulatory properties, most notably macrophage colony-stimulating factor (M-CSF) and transforming growth factor-ß, but not IL-4. CBSC therapy increased the number of galectin-3+ macrophages, CD4+ T cells, and fibroblasts in the heart while decreasing apoptosis in an in vivo swine model of MI. Macrophages treated with CBSC medium in vitro polarized to a proreparative phenotype are characterized by increased CD206 expression, increased efferocytic ability, increased IL-10, TGF-ß, and IL-1RA secretion, and increased mitochondrial respiration. Next generation sequencing revealed a transcriptome significantly different from M2a or M2c macrophage phenotypes. Paracrine factors from CBSC-treated macrophages increased proliferation, decreased α-smooth muscle actin expression, and decreased contraction by fibroblasts in vitro. These data support the idea that CBSCs are modulating the immune response to MI to favor cardiac repair through a unique macrophage polarization that ultimately reduces cell death and alters fibroblast populations that may result in smaller scar size and preserved cardiac geometry and function.NEW & NOTEWORTHY Cortical bone stem cell (CBSC) therapy after myocardial infarction alters the inflammatory response to cardiac injury. We found that cortical bone stem cell therapy induces a unique macrophage phenotype in vitro and can modulate macrophage/fibroblast cross talk.

Cortical bone-derived stem cell therapy reduces apoptosis after myocardial infarction.

Ischemic heart diseases such as myocardial infarction (MI) are the largest contributors to cardiovascular disease worldwide. The resulting cardiac cell death impairs function of the heart and can lead to heart failure and death. Reperfusion of the ischemic tissue is necessary but causes damage to the surrounding tissue by reperfusion injury. Cortical bone stem cells (CBSCs) have been shown to increase pump function and decrease scar size in a large animal swine model of MI. To investigate the potential mechanism for these changes, we hypothesized that CBSCs were altering cardiac cell death after reperfusion. To test this, we performed TUNEL staining for apoptosis and antibody-based immunohistochemistry on tissue from Göttingen miniswine that underwent 90 min of lateral anterior descending coronary artery ischemia followed by 3 or 7 days of reperfusion to assess changes in cardiomyocyte and noncardiomyocyte cell death. Our findings indicate that although myocyte apoptosis is present 3 days after ischemia and is lower in CBSC-treated animals, myocyte apoptosis accounts for <2% of all apoptosis in the reperfused heart. In addition, nonmyocyte apoptosis trends toward decreased in CBSC-treated hearts, and although CBSCs increase macrophage and T-cell populations in the infarct region, the occurrence of apoptosis in CD45+ cells in the myocardium is not different between groups. From these data, we conclude that CBSCs may be influencing cardiomyocyte and noncardiomyocyte cell death and immune cell recruitment dynamics in the heart after MI, and these changes may account for some of the beneficial effects conferred by CBSC treatment.NEW & NOTEWORTHY The following research explores aspects of cell death and inflammation that have not been previously studied in a large animal model. In addition, apoptosis and cell death have not been studied in the context of cell therapy and myocardial infarction. In this article, we describe interactions between cell therapy and inflammation and the potential implications for cardiac wound healing.

Somatic mutation of the MEN1 gene in parathyroid tumours.

Primary hyperparathyroidism is a common disorder with an annual incidence of approximately 0.5 in 1,000 (ref. 1). In more than 95% of cases, the disease is caused by sporadic parathyroid adenoma or sporadic hyperplasia. Some cases are caused by inherited syndromes, such as multiple endocrine neoplasia type 1 (MEN1; ref. 2). In most cases, the molecular basis of parathyroid neoplasia is unknown. Parathyroid adenomas are usually monoclonal, suggesting that one important step in tumour development is a mutation in a progenitor cell. Approximately 30% of sporadic parathyroid tumours show loss of heterozygosity (LOH) for polymorphic markers on 11q13, the site of the MEN1 tumour suppressor gene. This raises the question of whether such sporadic parathyroid tumours are caused by sequential inactivation of both alleles of the MEN1 gene. We recently cloned the MEN1 gene and identified MEN1 germline mutations in fourteen of fifteen kindreds with familial MEN1 (ref. 10). We have studied parathyroid tumours not associated with MEN1 to determine whether somatic mutations in the MEN1 gene are present. Among 33 tumours we found somatic MEN1 gene mutation in 7, while the corresponding MEN1 germline sequence was normal in each patient. All tumours with MEN1 gene mutation showed LOH on 11q13, making the tumour cells hemi- or homozygous for the mutant allele. Thus, somatic MEN1 gene mutation for the mutant allele. Thus, somatic MEN1 gene mutation contributes to tumorigenesis in a substantial number of parathyroid tumours not associated with the MEN1 syndrome.

Quantum clocks observe classical and quantum time dilation.

At the intersection of quantum theory and relativity lies the possibility of a clock experiencing a superposition of proper times. We consider quantum clocks constructed from the internal degrees of relativistic particles that move through curved spacetime. The probability that one clock reads a given proper time conditioned on another clock reading a different proper time is derived. From this conditional probability distribution, it is shown that when the center-of-mass of these clocks move in localized momentum wave packets they observe classical time dilation. We then illustrate a quantum correction to the time dilation observed by a clock moving in a superposition of localized momentum wave packets that has the potential to be observed in experiment. The Helstrom-Holevo lower bound is used to derive a proper time-energy/mass uncertainty relation.

Comparability of subjective and objective measurements of nuclear density in cataract patients.

PURPOSE: To evaluate the relationship between subjective and objective measurements of lens density and the energy of phacoemulsification. SETTING: University Eye Clinic, Maastricht University Medical Centre, Maastricht, the Netherlands. DESIGN: Cross-sectional study. METHODS: The study population included 69 patients. Nuclear opalescence (NO) was graded with the Lens Opacities Classification System III (LOCS III). Thereafter, lens density was measured objectively with Scheimpflug imaging, anterior segment optical coherent tomography and spectral fundus reflectometry (SFR). Cumulative dissipative energy (CDE) and total ultrasound time (US t.t.) of the phacoemulsification were noted. The relationship between the different measurement techniques and energy of phacoemulsification was assessed using Spearman's correlation coefficients. RESULTS: We found moderate to strong correlations between LOCS III and objective measurements of the lens density (rho's from 0.53 to 0.78, p < 0.05) and a moderate correlation between three objective measurement techniques (rho's between 0.29 and 0.57, p < 0.05). There was a moderate correlation between CDE, US t.t. and lens density measurements (rho's from 0.29 to 0.55, p < 0.05), and the highest correlation was found between CDE and NO scores. Exclusion of patients with advanced cortical and posterior subcapsular opacities improved the correlation between SFR and lens density measurements but not the correlation with the energy of phacoemulsification. CONCLUSION: Lens Opacities Classification System III has shown the highest correlation with phacoemulsification energy and may be a preferred technique for prediction of use of phacoemulsification energy. Advanced cortical and posterior opacities may interfere with the quality of objective measurements but do not affect the correlation between lens density measurements and phacoemulsification energy.

Use of a parenteral propylene glycol-containing etomidate preparation for the long-term management of ectopic Cushing's syndrome.

Chronic severe hypercortisolism is associated with life-threatening infections, diabetes and a high surgical mortality rate. Oral medical therapy can inhibit steroidogenesis and reduce the risk of these complications. However, apart from a few reports using an ethyl alcohol formulation of the iv anesthetic etomidate, there is no well-tested parenteral steroidogenesis inhibitor. We used the propylene glycol preparation of etomidate available in the United States to control hypercortisolism in a 39-yr-old man with ectopic ACTH secretion who was unable to take oral medications. Etomidate was administered over a period of 5.5 months. We titrated the dose of etomidate daily using serum cortisol levels, to avoid steroid over replacement and allow for a response to ongoing stress. A reduced dose during a period of acute renal failure achieved adequate control of hypercortisolemia. Suppression of steroidogenesis persisted for at least 14 d and perhaps as long as 6 wk after cessation of the medication. Except for transient myoclonus, the patient tolerated this preparation well. Parenteral propylene glycol containing etomidate can be used safely for a prolonged period to reduce hypercortisolemia in patients unable to take oral medications.

Nonoperative observation of clinically occult arterial injuries: a prospective evaluation.

Forty-seven patients with 50 clinically occult injuries of major arteries were studied prospectively to determine the natural history of these lesions and the safety of nonoperative management. Penetrating trauma was the predominant mechanism and lower extremity arteries were most commonly involved. The morphology of these arterial injuries included 22 cases of intimal flaps, 21 cases of segmental arterial narrowing, 6 pseudoaneurysms, and 1 acute arteriovenous fistula. There was one death as a result of unrelated causes and another three injuries operated on immediately after arteriographic diagnosis. The remaining 46 injuries were followed up nonoperatively by serial arteriography (39) or clinical examination (7) during a mean interval of 3.1 months (range, 3 days to 27 months). Complete resolution was documented for 29 injuries (63%), whereas 3 improved, 9 remained unchanged, and 5 worsened during the period of follow-up. All worsened cases involved small or occult pseudoaneurysms that subsequently enlarged and then underwent immediate surgical repair without subsequent morbidity. Because 89% of the followed injuries never required surgery, nonoperative observation appears to be a safe and effective management option for clinically occult arterial injuries.

Determining the content of a surgical curriculum.

The purpose of undergraduate surgical education is to prepare the student for both the residency and eventual practice of medicine. To help determine the surgical knowledge and skills that would eventually the useful to the student, we conducted a survey of residents in training, physicians in practice, and surgical educators (department chairpersons and clerkship directors). Members of the Curriculum Committee of the Association for Surgical Education developed a questionnaire in which the respondents were asked to grade the functional importance of 84 areas of knowledge and 46 skills (0 = unnecessary, 3 = proficiency necessary). Using a modified Delphi technique to collect information, we sent the questionnaire to eight medical school graduation classes of 1975 (730 persons) and 1980 (776 persons) and all department chairpersons and/or clerkship directors (179). The results of the survey (46% response) revealed considerable agreement about the importance of certain skills and areas of knowledge, enabling us to rank order skills and knowledge based on mean responses (0.0 to 3.0). Physicians in practice, residents, and educators believed that certain areas of knowledge (e.g., acute abdominal problems, appendicitis, shock, cancer of the breasts) and skills (e.g., history taking and physical examination, gowning, suture removal) were very important (greater than 2.250, while other areas of knowledge (e.g., transplantation, liver abscess, soft tissue sarcomas) and skills (e.g., insertion of Swan-Ganz catheter, abdominal paracentesis, cricothyroidotomy) were less important (less than 1.3). This approach allows us to assign priorities to areas of knowledge and skills when determining curriculum content and to include functional criteria when developing educational objectives.

Computed tomographic diagnosis of acute aortoiliac catastrophes.

Whole-body computed tomography (CT) was used as an initial examination in stable patients whose symptoms were suggestive of aortoiliac emergencies. In three cases, CT provided highly specific diagnoses in three different aortoiliac complications. Computed tomography proved to be a fast and reliable diagnostic tool in emergency settings.

Effect of enteral and parenteral nutrition on amino acid levels in cancer patients.

BACKGROUND: The syndrome of cancer cachexia can have a significant impact on response to therapy as well as on survival in cancer patients. Therapies directed at metabolic perturbations in cachectic patients are dependent on nutritional repletion and maintenance of adequate amino acid substrate levels. This study compares the ability of oral feeding, enteral nutrition, and total parenteral nutrition to alter plasma amino acid levels in cancer patients. METHODS: Patients with esophageal cancer were stratified by weight loss. Patients with < 20% weight loss were randomized to continue an ad libitum oral diet (group I) or to receive total parenteral nutrition (group II) for 2 weeks; patients with > 20% weight loss were randomized to receive either enteral nutrition (group III) or total parenteral nutrition (group IV) for 2 weeks. Plasma amino acid levels were measured before the study and again after 2 weeks of nutrition support. RESULTS: Before therapy, there was no difference between the groups in total or essential amino acid levels; however, patients in all groups had significantly lower total amino acid levels compared with those of normal controls. After 2 weeks of treatment, patients in group I and III showed no difference in individual, essential, or total amino acid levels. However, patients in groups II and IV showed significant increases in a number of individual amino acids as well as in essential and total amino acid levels after 2 weeks of TPN. CONCLUSIONS: Patients with esophageal cancer demonstrated significant alterations in amino acid profiles compared with those of normal controls. Total parenteral nutrition was superior to ad libitum oral feeding and jejunostomy feeding in repleting plasma amino acid levels.

The 1983 Beirut Airport terrorist bombing. Injury patterns and implications for disaster management.

The casualty profile and results of the medical care provided for the survivors of the terrorist truck bombing of the U.S. Marine Corps facility in Beirut, Lebanon, in 1983 were reviewed to determine the factors that influenced casualty survival. This explosion resulted in 346 casualties, of whom 234 (68%) were immediately killed. The spectrum of injury was determined in 85 survivors using the Injury Severity Score (ISS). There were seven (6.3%) deaths among the 112 immediate survivors. All deaths occurred among the 19 (17%) victims who were critically injured (ISS greater than 15), giving a mortality in this population of 37 per cent. Six (86%) of the seven deaths were associated with an initial delay in treatment. Head injury was the most common fatal injury among both immediate fatalities (71.4%) and immediate survivors (57%). Thoracic injury and burns each accounted for 29 per cent of survivor deaths. Triage efficiency, as determined by the rates of overtriage (80%) and undertriage (0), did not appear adversely to affect mortality. Critical analysis of disasters such as this can contribute to improvements in preparation and casualty care in the event of future disasters.

Recurrent aortoduodenal fistula: a lesson in management.

Aortoenteric fistula (AEF) is a rare but often lethal complication of aortic reconstructive surgery. The diagnosis is often delayed due to the high percentage of false-negative using upper gastrointestinal series, angiography, and endoscopy. The diagnosis of AEF must be considered in any patient with a prosthetic graft and gastrointestinal bleeding. There are essentially two modalities of treatment: replacement of the graft or total removal of all prosthetic material and the construction of an extra anatomic bypass. A case report of a recurrent aortoduodenal fistula is presented that illustrated both delay in diagnosis and inappropriate treatment. We agree with the general trend in the literature that the appropriate management of this devastating complication is complete removal of the prosthetic graft, wide drainage, high-dose antibiotics, and extra anatomic bypass. Any deviation from these basic treatment steps - such as replacement of the graft - ignores the infectious component of this complication and can result in the devastating lethal complication seen in this patient. With appropriate suggested management this once uniformly fatal complication can be treated effectively, resulting in an acceptable morbidity and mortality.