Comprehensive epigenomic profiling of human alveolar epithelial differentiation identifies key epigenetic states and transcription factor co-regulatory networks for maintenance of distal lung identity.

BACKGROUND: Disruption of alveolar epithelial cell (AEC) differentiation is implicated in distal lung diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and lung adenocarcinoma that impact morbidity and mortality worldwide. Elucidating underlying disease pathogenesis requires a mechanistic molecular understanding of AEC differentiation. Previous studies have focused on changes of individual transcription factors, and to date no study has comprehensively characterized the dynamic, global epigenomic alterations that facilitate this critical differentiation process in humans. RESULTS: We comprehensively profiled the epigenomic states of human AECs during type 2 to type 1-like cell differentiation, including the methylome and chromatin functional domains, and integrated this with transcriptome-wide RNA expression data. Enhancer regions were drastically altered during AEC differentiation. Transcription factor binding analysis within enhancer regions revealed diverse interactive networks with enrichment for many transcription factors, including NKX2-1 and FOXA family members, as well as transcription factors with less well characterized roles in AEC differentiation, such as members of the MEF2, TEAD, and AP1 families. Additionally, associations among transcription factors changed during differentiation, implicating a complex network of heterotrimeric complex switching in driving differentiation. Integration of AEC enhancer states with the catalog of enhancer elements in the Roadmap Epigenomics Mapping Consortium and Encyclopedia of DNA Elements (ENCODE) revealed that AECs have similar epigenomic structures to other profiled epithelial cell types, including human mammary epithelial cells (HMECs), with NKX2-1 serving as a distinguishing feature of distal lung differentiation. CONCLUSIONS: Enhancer regions are hotspots of epigenomic alteration that regulate AEC differentiation. Furthermore, the differentiation process is regulated by dynamic networks of transcription factors acting in concert, rather than individually. These findings provide a roadmap for understanding the relationship between disruption of the epigenetic state during AEC differentiation and development of lung diseases that may be therapeutically amenable.

Primary colorectal linitis plastica presenting as rapid acute deterioration: a diagnostic dilemma.

We present a rare case of primary colorectal linitis plastica presenting as an acute admission to hospital with a wide range of systemic symptoms, sudden rapid deterioration and subsequent mortality. A postmortem examination revealed a primary linitis plastica of the colon and rectum with diffuse metastatic disease. To our knowledge, this is the first report of primary colorectal linitis plastica presenting as an acute deterioration as a result of extensive metastatic disease.

Improving diagnostic accuracy in clinically ambiguous paediatric appendicitis: a retrospective review of ultrasound and pathology findings with focus on the non-visualised appendix.

OBJECTIVE: To compare pre-operative ultrasound to histopathological results and retrospectively assess the diagnostic accuracy of ultrasound in paediatric appendicitis. METHODS: 5 year review of all appendectomies performed in patients <16 years old in a tertiary referral university hospital. 983 patients had an appendicectomy over the time period while 189 patients had a preoperative ultrasound. We retrospectively reviewed all of the preoperative imaging in conjunction with the reports for the 189 patients; our aim was to determine the sensitivity of preoperative ultrasound for the diagnosis of acute appendicitis. RESULTS: Of the 189 patients who had an ultrasound, 102 had histology positive for appendicitis and 87 had normal histology. Sensitivity overall was 72.55% [95% confidence interval (CI) 62.82 to 80.92] and specificity was 77.01% (95% CI 66.75 to 85.36). A suggested ultrasound diagnosis of appendicitis made positive pathology three times more likely and a normal ultrasound made positive pathology three times less likely [positive-predictive value 3.16 (95% CI 2.11 to 4.72) negative predictive value 0.36 (95% CI 0.25 to 0.50)]. 77% (67/87) of the patients whose pathology was ultimately normal had an ultrasound which was either normal or suggested an alternative diagnosis. However, in the 33 (17%) of patients with a non-visualised appendix, no secondary signs of inflammation or alternative diagnosis 16 (48%) had pathologically confirmed appendicitis. CONCLUSION: Ultrasound has the potential to improve diagnostic accuracy in clinically ambiguous appendicitis. ADVANCES IN KNOWLEDGE: This paper furthers the evidence on the efficacy of ultrasound as a diagnostic tool in acute appendicitis in children, especially when the diagnosis is clinically equivocal. It also sheds further light on the "non-visualized appendix" with almost half of these patients having pathologically confirmed appendicitis; meaning advanced imaging with CT or MR may be indicated in this cohort.

Magnetic Resonance Image-Guided Radiotherapy (MRIgRT): A 4.5-Year Clinical Experience.

AIMS: Magnetic resonance image-guided radiotherapy (MRIgRT) has been clinically implemented since 2014. This technology offers improved soft-tissue visualisation, daily imaging, and intra-fraction real-time imaging without added radiation exposure, and the opportunity for adaptive radiotherapy (ART) to adjust for anatomical changes. Here we share the longest single-institution experience with MRIgRT, focusing on trends and changes in use over the past 4.5 years. MATERIALS AND METHODS: We analysed clinical information, including patient demographics, treatment dates, disease sites, dose/fractionation, and clinical trial enrolment for all patients treated at our institution using MRIgRT on a commercially available, integrated 0.35 T MRI, tri-cobalt-60 device from 2014 to 2018. For each patient, factors including disease site, clinical rationale for MRIgRT use, use of ART, and proportion of fractions adapted were summated and compared between individual years of use (2014-2018) to identify shifts in institutional practice patterns. RESULTS: Six hundred and forty-two patients were treated with 666 unique treatment courses using MRIgRT at our institution between 2014 and 2018. Breast cancer was the most common disease, with use of cine MRI gating being a particularly important indication, followed by abdominal sites, where the need for cine gating and use of ART drove MRIgRT use. One hundred and ninety patients were treated using ART in 1550 fractions, 67.6% (1050) of which were adapted. ART was primarily used in cancers of the abdomen. Over time, breast and gastrointestinal cancers became increasingly dominant for MRIgRT use, hypofractionated treatment courses became more popular, and gastrointestinal cancers became the principal focus of ART. DISCUSSION: MRIgRT is widely applicable within the field of radiation oncology and new clinical uses continue to emerge. At our institution to date, applications such as ART for gastrointestinal cancers and accelerated partial breast irradiation (APBI) for breast cancer have become dominant indications, although this is likely to continue to evolve.

Juvenile papillomatosis (Swiss cheese disease) of the breast.

Thirty-seven cases of juvenile papillomatosis of the breast were reviewed. The average age was 19 years (range 10-44 years). On examination the patients usually had a localized, multinodular mass that was interpreted as a fibroadenoma. Microscopically, typical lesions featured papillomatosis, sometimes with severe atypia, cysts with or without apocrine metaplasia, duct stasis, and sclerosing adenosis. In one case the breast with papillomatosis adenosis. In one case the breast with papillomatosis has remained free of carcinoma, but at the time of biopsy the patient had secretory carcinoma of the other breast. Papillomatous changes were not observed in the breast with carcinoma. Another woman had lobular carcinoma in situ coexisting with juvenile papillomatosis. After an average follow-up of 8 years, no subsequent carcinoma has been found. Thus, there appears to be little risk for early onset of carcinoma, but without additional follow-up the long-term assessment of this disorder remains uncertain. We recommend that a patient with juvenile papillomatosis have a thorough clinical examination of the breasts at least once a year.

Design and synthesis of novel cyclic RGD-containing peptides as highly potent and selective integrin alpha IIb beta 3 antagonists.

Utilizing conformational constraints in conjunction with various structural considerations, we have synthesized a series of cyclic disulfide peptides that are highly potent and selective antagonists for the platelet integrin alpha IIb beta 3 (GPIIb/IIIa). The affinities of the peptides for alpha IIb beta 3 were determined by platelet aggregation assays and an alpha IIb beta 3 ELISA. Their affinities for alpha 5 beta 1 and alpha v beta 5 integrins were also determined in respective ELISA assays. Structure-activity relationship studies suggest that R-G-D-Ar-R (Ar = hydrophobic residue) is the essential pharmacophore that is responsible for their high alpha IIb beta 3 binding affinity, very high selectivity, and distinct biological properties. One of these analogues, TP9201, has been shown to inhibit platelet-mediated thrombus formation without associated prolongation of template bleeding time. The arginine residue adjacent the carboxy terminus of the R-G-D-Ar sequence could function as the biological effector element that determines this distinct and unexpected biological property.

6-substituted 1,3,4,5-tetrahydrobenz[cd]indol-4-amines: potent serotonin agonists.

A series of 6-substituted tricyclic ergoline partial structures has been synthesized and found to possess very strong serotonin agonist activity. A methoxy group at the 6-position greatly enhances activity, but at the expense of compound stability. Substituting the 6-position with protophyllic groups that are also electron-withdrawing in character enhances both activity and stability.

Cardiac aneurysm complicated by E. coli abscess.

An E. coli myocardial abscess developed in the region of an old aneurysmal myocardial scar. In spite of vigorous antibiotic therapy fever and positive blood cultures persisted. A combination of In-111 WBC scanning and Tc-99m RBC gated heart imaging located the infection in the aneurysmal scar. The abscess was resected and the patient survived.

Beneficial metabolic effects of methylprednisolone sodium succinate in acute myocardial ischemia.

The metabolic and hemodynamic effects of methylprednisolone sodium succinate (40 mg/kg body weight) after acute myocardial ischemia were determined in 24 heparinized mongrel dogs. Myocardial ischemia was produced by ligation of the left anterior descending coronary artery. Catheters in the coronary sinus and the vein draining the left anterior descending coronary arterial area were used to collect blood samples from nonischemic and ischemic myocardium. Lactate, pyruvate, glucose, free fatty acids and oxygen were measured in arterial and venous blood from ischemic and nonischemic areas before and 3, 30 and 60 minutes after myocardial ischemia in animals with (Group II) and without (Group I) steroid treatment. In both Groups I and II glucose, lactate, free fatty acids, oxygen and coronary blood flow in nonischemic areas were not significantly changed, whereas glucose uptake in ischemic areas was significantly increased with myocardial ischemia and remained elevated. In Group I lactate uptake in ischemic areas became negative after coronary arterial ligation and remained so; in Group II, it increased after 30 (70%) and 60 (111%) minutes. Free fatty acid uptake in ischemic areas was reduced after myocardial ischemia in Group I, but in Group II it increased after 30 (224%) and 60 minutes (173%), and there was a concomitant increase in oxygen uptake. Pyruvate uptake in nonischemic areas decreased after 60 minutes in Group I, whereas it was reduced after 30 (68%) and 60 minutes (513%) in Group II. The changes were similar in ischemic myocardium. There were no significant changes in hemodynamic indexes. Coronary blood flow in ischemic areas decreased in Group I after myocardial ischemia and further after 30 and 60 minutes, but in Group II it increased after 30 (82%) and 60 minutes (53%). The data indicate that administration of methylprednisolone results in improved collateral blood flow into the infarcted area and a significantly improved metabolic response of ischemic myocardium. The glucocorticoid may also have a direct benefical effect on carbohydrate metabolism and cause the increased pyruvate neccesary to maintain the generation of energy-producing substrates. The results also suggest that methylprednisolone increases cell survival time and results in greater salvage of ischemic myocardium.

Effect of intra-aortic balloon pumping on nutrient coronary flow in normal and ischemic myocardium.

The effects of intra-aortic balloon pumping (IABP) on myocardial flow distribution were studied in 50 dogs. Cardiac output was controlled by right heart bypass. In each dog the following parameters were measured with and without IABP during normal coronary perfusion and after regional ischemia was induced by anterior descending coronary vein flow by timed collection, and endocardial/epicardial flow ratios by a previously reported thermal washout technique. In nonischemic myocardium, IABP significantly (p less than 0.05) increased mean coronary sinus flow 11.5 percent +/- 5.8 percent (S.D.) and the mean endocardial/epicardial ratio, 17.3 percent +/- 0.28 percent. In the regionally ischemic myocardium, IABP significantly (p less than 0.05) increased mean segmental coronary vein flow 13.9 percent +/- 1.23 percent but decreased the endocardial/epicardial ratio 29.9 percent +/- 1.1 percent. We conclude that in the dog, IABP enhances subendocardial blood flow in perfused but not in ischemic myocardium. Contrary to common suppositions, the increase in collateral blood flow with IABP preferentially supplies epicardial layers in segmental ischemic zones, but may be shunted from the subendocardium.

Management of long-standing cardiocutaneous fistulas after resection of left ventricular aneurysms.

Cardiocutaneous fistulas arising from pledgets used in the closure of resected left ventricular aneurysms are rare but have serious implications. The case histories of four patients, each managed in a somewhat different manner, are presented. From this experience we recommend an aggressive approach to remove the infected pledgets once scar formation is complete and before erosion of the pledgets into the left ventricular cavity can occur.

The effect of continued cigarette smoking on the patency of synthetic vascular grafts in Leriche syndrome.

The effects of continued smoking were studied in 187 consecutive patients who underwent aorto-iliac or aorto-femoral grafting because of Leriche disease and who left the hospital with well-functioning grafts. The patients were divided into the following groups: (1) never smoked, (2) stopped smoking after the operation, (3) continued to smoke less than a pack a day and (4) continued to smoke more than a pack a day. The patency of the grafts was evaluated at regular intervals during a follow-up period ranging from 6 months to 10 years. A significant difference in the patency in the favor of the nonsmokers was found, with the "more than one pack a day" group having more than triple the occlusion rate of the nonsmokers, both absolutely and in month-patency time. We recommend that the surgeon make a most sincere effect to induce patients undergoing vascular operations for occlusive vascular diseases to give up smoking. Failure to promise to stop the smoking habit should be regarded as a relatively strong contraindication for surgery in patients not directly threatened with loss of an extremity.

Left ventricular myotomy. Physiologic approach to surgical therapy for IHSS.

Twenty patients were operated on for idiopathic hypertrophic subaortic stenosis (IHSS) between 1966 and 1980. All were in New York Heart Association functional class 3 or 4, and 17 had overt congestive failure. The mean resting gradient across the left ventricular (LV) outflow tract preoperatively was 78 mm Hg. Seventeen patients underwent transaortic LV myotomy, one had mitral valve replacement (MVR), and two patients with rheumatic mitral insufficiency (MI) and IHSS underwent myotomy and MVR. There was one operative death (5 percent). Mean follow-up was 5.8 years. Eighteen of 19 survivors were improved to class 1 or 2. One patient whose gradient and symptoms were not relieved by myotomy was improved by myectomy and MVR. The MI was abolished or reduced by myotomy in ten of 13 patients. There were six late deaths, five of which are known or assumed to be cardiac related. We concluded that LV myotomy is a safe and effective technique for surgical management of IHSS. Left ventricular myectomy, MVR, or both are indicated in selected cases.

Tricuspid valve replacement for Ebstein's anomaly in childhood with a Starr-Edwards caged-ball prosthesis. 21-year follow-up.

A 21-year follow-up after tricuspid valve replacement (TVR) with a Starr-Edwards caged-ball prosthesis in a ten-year old boy is described. TVR is performed for Ebstein's anomaly, with strict indications in childhood. Despite the current preference for bioprostheses, good performance can be expected from the Starr-Edwards caged-ball valve.

Strut failure of the Starr-Edwards cloth-covered metallic ball prosthesis. Report of two asymptomatic cases and review of the overall experience.

Two cases of asymptomatic strut failure of an aortic Starr-Edwards cloth-covered metallic ball prosthesis are reported. Strut failure can be asymptomatic for years. Available information on the overall worldwide experience of six cases is reviewed and suggestions made for early diagnosis and treatment of this rare complication.

Application of region of interest definition to quadtree-based compression of CT images.

A quadtree-based data compression algorithm can provide different levels of compression within and outside of regions of interest (ROIs). The current study shows whether ROI compression can provide greater compression or diagnostic accuracy than uniform quadtree compression. In 75 single CT images from 75 consecutive abdominal examinations, 43 abnormalities were identified and surrounded by ROIs. Three radiologists interpreted the images following (1) 50:1 compression of the entire image; (2) ROI compression at five decreasing compression ratios (with 50:1 compression outside the ROI); and (3) reversible (lossless) compression of the entire image. Reversible compression (compression ratio 3:1) yielded a sensitivity of 96%. ROI compression of 15:1 was achieved with no loss of sensitivity; ROI compression of 28:1 yielded a sensitivity of 91% (not significantly different). At any given compression ratio, diagnostic sensitivity was greater with ROI compression than with uniform quadtree compression. For purposes of image archiving, quadtree-based ROI compression is superior to uniform compression of CT images.

Caloric restriction lowers blood pressure in the spontaneously hypertensive rat.

In the spontaneously hypertensive rat (SHR), caloric restriction without sodium restriction is associated with reduced blood pressure. Four days of fasting lowered blood pressure 19% while 4 days of eating 50% of ad lib intake reduced blood pressure 10%. Similar dietary changes had less effect on blood pressure in normotensive rats of the same strain (Wistar-Kyoto--WKY). These data are consistent with the hypothesis that caloric restriction lowers sympathetic activity.

Coronary artery surgery without global ischemia.

A simple technique for local occlusion of the coronary artery without aortic cross-clamping during the distal anastomosis has been developed. The use of this internal coronary artery occluder, which we developed, represents another step forward in myocardial protection during coronary bypass procedures.

A comparative synchronous coronary surgery survival study.

Utilizing patient criteria published by the Veterans Administration Cooperative (VAC) Study, a cohort of 229 surgically treated patients was retrieved from the Milwaukee Cardiovascular Data Registry. These patients were all operated on by one surgeon during 1972 to 1974. Four-year survival of this group was compared with that of the medically treated cohort of 310 patients from the VAC Study. Operative mortality was included in all surgical groups. The cumulative 4-year survival of both groups revealed a 95 to 85% advantage for surgical therapy. In patients with three-vessel disease, the cumulative survival favored surgical therapy--94% compared with 80% in the medically terated cohort--and in patients with triple-vessel disease and a normal left ventricle, surgical therapy again showed better results: 100% compared with 88%. Patients with two-vessel disease and a normal left ventricle who underwent surgical intervention had slightly better 4-year survival than those who had medical treatment--100% versus 95%--and those with two-vessel disease and an abnormal left ventricle had a 93% survival after surgical treatment compared with 84% for those with medical treatment. For patients with single-vessel disease, there was no difference in survival between the surgical and medical cohorts.