Mechanisms of intestinal failure in Crohn's disease

PURPOSE: The purpose of this study was to determine the mechanisms by which patients with Crohn's disease develop intestinal failure and, in particular, to assess the relative importance of severe primary disease, repeated uncomplicated elective small intestine resection, and resection performed as a consequence of intra-abdominal septic surgical complications. METHODS: This was a retrospective analysis of 41 patients with Crohn's disease referred to a specialized intestinal failure unit between January 1987 and September 1998 for permanent home parenteral nutrition. To compare the surgical activity in patient groups, a resection index was calculated by dividing the number of intestinal resections by the interval in years between the first resection for Crohn's disease and referral for management of intestinal failure. RESULTS: Extensive primary Crohn's disease was responsible for intestinal failure in 7 cases (17 percent). The remainder (n=34, 83 percent) developed intestinal failure after intestinal resection. Nine of the surgical Crohn's patients developed intestinal failure after uncomplicated sequential resection, (median small-bowel length 65 (range, 60–120) cm) after a median of 3 (range, 2–8) operations over a median of 17 (range, 3–27) years. By contrast, the other 25 surgical Crohn's patients developed intestinal failure after multiple unplanned laparotomies for intra-abdominal sepsis (median small-bowel length 70 (range, 60–200) cm), with a median of 4 (range, 2–7) laparotomies performed over a median of 0.5 (range, 0.1 to 1.5) years (P<0.001). The resection index for the 25 Crohn's patients undergoing laparotomies for intra-abdominal sepsis was significantly greater than that of the 9 patients who had planned sequential resections (2.1 (0.27–25)vs. 0.23 (0.1–1.0);P < 0.002, Mann-WhitneyU test). CONCLUSION: Intestinal failure develops in Crohn's disease primarily as a result of complications of surgical treatment. The largest group of patients at risk consists of those who are undergoing multiple unplanned laparotomies to control intra-abdominal sepsis.     

Milky Spots Promote Ovarian Cancer Metastatic Colonization of Peritoneal Adipose in Experimental Models

The goal of controlling ovarian cancer metastasis formation has elicited considerable interest in identifying the tissue microenvironments involved in cancer cell colonization of the omentum. Omental adipose is a site of prodigious metastasis in both ovarian cancer models and clinical disease. This tissue is unusual for its milky spots, comprised of immune cells, stromal cells, and structural elements surrounding glomerulus-like capillary beds. The present study shows the novel finding that milky spots and adipocytes play distinct and complementary roles in omental metastatic colonization. In vivo assays showed that ID8, CaOV3, HeyA8, and SKOV3ip.1 cancer cells preferentially lodge and grow within omental and splenoportal fat, which contain milky spots, rather than in peritoneal fat depots. Similarly, medium conditioned by milky spot–containing adipose tissue caused 75% more cell migration than did medium conditioned by milky spot–deficient adipose. Studies with immunodeficient mice showed that the mouse genetic background does not alter omental milky spot number and size, nor does it affect ovarian cancer colonization. Finally, consistent with the role of lipids as an energy source for cancer cell growth, in vivo time-course studies revealed an inverse relationship between metastatic burden and omental adipocyte content. Our findings support a two-step model in which both milky spots and adipose have specific roles in colonization of the omentum by ovarian cancer cells.CME Accreditation Statement: This activity (“ASIP 2013 AJP CME Program in Pathogenesis”) has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians.The ASCP designates this journal-based CME activity (“ASIP 2013 AJP CME Program in Pathogenesis”) for a maximum of 48 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose.It is estimated that 22,240 women will be diagnosed with and 14,030 women will die of cancer of the ovary in 2013 (http://seer.cancer.gov/csr/1975_2009_pops09, last accessed June 18, 2013). The majority of patients present with metastases or eventually die of metastatic disease within the abdominal cavity. After escape from the primary tumor, ovarian cancer cells in the peritoneal fluid have access to and can potentially lodge within a variety of tissues.^1,2 In both clinical disease and experimental models, however, the omentum is the site of prodigious metastasis formation.^3–6 Thus, attachment of ovarian cancer cells to the omentum represents an early step in the development of widespread peritoneal disease.^7,8 Although the importance of the omentum is widely acknowledged, there still is no consensus on its role in metastasis formation. This raises the question of what components of the omental tissue microenvironment participate in, or facilitate, ovarian cancer metastatic colonization.Studies of omental function date back to the early 19th century. Jobert de Lamballe, a 19th-century surgeon in France, was reportedly the first to recognize the curious ability of this organ to fight infection and form adhesions to help control injuries.⁹ After nearly two centuries of investigation, a great deal is known about the physiology and surgical applications of the omentum.^9–12 As the central regulator of peritoneal homeostasis, its functions include regulating fluid and solute transport, sensing and repairing injuries, promoting angiogenesis, fighting infection, serving as a source of stem cells, producing regulatory molecules, and storing and supplying lipids. These diverse functions are conferred by the cellular composition and architecture characteristic of human omenta.Aside from the clear collagenous membrane that acts as a scaffold for the organ, the majority of the omentum is composed of bands of adipose tissue that contain adipocytes, blood and lymph vessels, immune cells, stromal cells, and connective matrix components that lie beneath an irregular mesothelium.¹³ In general, adipocytes have a variety of functions, ranging from lipid storage to production of endocrine molecules, and can serve as an integrating hub for inflammation, metabolism, and immunity.^2,14–23 A distinctive feature of the omental vasculature is the presence of numerous branching blood vessels ending in tortuous glomerulus-like capillary beds near the tissue periphery.^24–28 Immune cells aggregate around and within these capillary beds to form milky spots, which are the major immune structure for host defense of the peritoneal cavity.^24,29–36 In milky spots, both the endothelial lining of the capillaries and the overlying mesothelium are specially adapted to facilitate transmigration of immune cells.^24,37,38 Additional structural elements include plasmocytes, fibroblasts, and mesenchymal cells, as well as collagen and reticular and elastic fibers.^29,34,37,39A comprehensive literature review showed that studies examining the role of the omentum in metastasis focus on the contribution of its individual components, and not on the tissue as a whole. In our view, results from the majority of studies support models in which ovarian cancer metastatic colonization is driven either purely by milky spots or purely by adipocytes. The milky spot–driven model is based on a large body of in vivo data showing that, on intraperitoneal injection, cancer cells rapidly and specifically localize, invade, and proliferate within omental milky spots.^{3,6,24,28,40–44} In contrast, the adipocyte-driven model is based on the observation that, in its resting state, the omentum is composed predominantly of adipose and that cultured adipocytes can produce adipokines capable of promoting ovarian cancer cell migration and invasion in vitro.⁴⁵ Adipocytes can also provide a proliferative advantage by transferring fatty acids to ovarian cancer cells.⁴⁵ Although both models have clear strengths, neither addresses the intimate and dynamic interaction among milky spots, surrounding adipocytes, and other components of omental tissues.Taking tissue architecture and function as a guide, we propose that an alternative, more fully integrated model of metastatic colonization is needed. To test this idea, we identified peritoneal fat depots (omentum, mesentery, and uterine, gonadal, and splenoportal fat) that are accessible to ovarian cancer cells after intraperitoneal injection.² Of these, the omentum and splenoportal fat are reported to contain milky spot structures.^24,46 We reasoned that a comparison of peritoneal adipose that either contains or lacks milky spots could be used to determine the contributions of adipocytes and milky spots to the lodging and progressive growth of ovarian cancer cells in physiologically relevant tissues. In vivo studies using a panel of ovarian cancer cell lines showed that milky spots dramatically enhance early cancer cell lodging on peritoneal adipose tissues. Consistent with this finding, conditioned medium from milky spot–containing adipose tissue had a significantly increased ability to direct cell migration, compared with conditioned medium from milky spot–deficient adipose tissue. Studies using a panel of immunodeficient mice showed that the number and size of omental milky spots is not dependent on the mouse genetic background and, similarly, that ovarian cancer cell colonization does not depend on the immune composition of the milky spot. Finally, consistent with the role for lipids as an energy source for ovarian cancer cell growth, in vivo time-course studies revealed an inverse relationship between metastatic burden and adipocyte content in the omentum. Our findings support a two-step model in which both milky spots and adipose have specific roles in colonization of the omentum by ovarian cancer cells.     

Using Natural Language Processing on Electronic Health Records to Enhance Detection and Prediction of Psychosis Risk

BackgroundUsing novel data mining methods such as natural language processing (NLP) on electronic health records (EHRs) for screening and detecting individuals at risk for psychosis. MethodThe study included all patients receiving a first index diagnosis of nonorganic and nonpsychotic mental disorder within the South London and Maudsley (SLaM) NHS Foundation Trust between January 1, 2008, and July 28, 2018. Least Absolute Shrinkage and Selection Operator (LASSO)-regularized Cox regression was used to refine and externally validate a refined version of a five-item individualized, transdiagnostic, clinically based risk calculator previously developed (Harrell’s C = 0.79) and piloted for implementation. The refined version included 14 additional NLP-predictors: tearfulness, poor appetite, weight loss, insomnia, cannabis, cocaine, guilt, irritability, delusions, hopelessness, disturbed sleep, poor insight, agitation, and paranoia. ResultsA total of 92 151 patients with a first index diagnosis of nonorganic and nonpsychotic mental disorder within the SLaM Trust were included in the derivation (n = 28 297) or external validation (n = 63 854) data sets. Mean age was 33.6 years, 50.7% were women, and 67.0% were of white race/ethnicity. Mean follow-up was 1590 days. The overall 6-year risk of psychosis in secondary mental health care was 3.4 (95% CI, 3.3–3.6). External validation indicated strong performance on unseen data (Harrell’s C 0.85, 95% CI 0.84–0.86), an increase of 0.06 from the original model. ConclusionsUsing NLP on EHRs can considerably enhance the prognostic accuracy of psychosis risk calculators. This can help identify patients at risk of psychosis who require assessment and specialized care, facilitating earlier detection and potentially improving patient outcomes.     

Defects in Mitochondrial Efficiency and H2O2 Emissions in Obese Women Are Restored to a Lean Phenotype With Aerobic Exercise Training

The notion that mitochondria contribute to obesity-induced insulin resistance is highly debated. Therefore, we determined whether obese (BMI 33 kg/m²), insulin-resistant women with polycystic ovary syndrome had aberrant skeletal muscle mitochondrial physiology compared with lean, insulin-sensitive women (BMI 23 kg/m²). Maximal whole-body and mitochondrial oxygen consumption were not different between obese and lean women. However, obese women exhibited lower mitochondrial coupling and phosphorylation efficiency and elevated mitochondrial H₂O₂ (mtH₂O₂) emissions compared with lean women. We further evaluated the impact of 12 weeks of aerobic exercise on obesity-related impairments in insulin sensitivity and mitochondrial energetics in the fasted state and after a high-fat mixed meal. Exercise training reversed obesity-related mitochondrial derangements as evidenced by enhanced mitochondrial bioenergetics efficiency and decreased mtH₂O₂ production. A concomitant increase in catalase antioxidant activity and decreased DNA oxidative damage indicate improved cellular redox status and a potential mechanism contributing to improved insulin sensitivity. mtH₂O₂ emissions were refractory to a high-fat meal at baseline, but after exercise, mtH₂O₂ emissions increased after the meal, which resembles previous findings in lean individuals. We demonstrate that obese women exhibit impaired mitochondrial bioenergetics in the form of decreased efficiency and impaired mtH₂O₂ emissions, while exercise effectively restores mitochondrial physiology toward that of lean, insulin-sensitive individuals.     

Expression of BCR/ABL and BCL-2 in myeloid progenitors leads to myeloid leukemias

Chronic myelogenous leukemia is a myeloproliferative disorder (MPD) that, over time, progresses to acute leukemia. Both processes are closely associated with the t(9;22) chromosomal translocation that creates the BCR/ABL fusion gene in hematopoietic stem cells (HSCs) and their progeny. Chronic myelogenous leukemia is therefore classified as an HSC disorder in which a clone of multipotent HSCs is likely to be malignantly transformed, although direct evidence for malignant t(9;22)+ HSCs is lacking. To test whether HSC malignancy is required, we generated hMRP8p210BCR/ABL transgenic mice in which expression of BCR/ABL is absent in HSCs and targeted exclusively to myeloid progenitors and their myelomonocytic progeny. Four of 13 BCR/ABL transgenic founders developed a chronic MPD, but only one progressed to blast crisis. To address whether additional oncogenic events are required for progression to acute disease, we crossed hMRP8p210BCR/ABL mice to apoptosis-resistant hMRP8BCL-2 mice. Of 18 double-transgenic animals, 9 developed acute myeloid leukemias that were transplantable to wild-type recipients. Taken together, these data indicate that a MPD can arise in mice without expression of BCR/ABL in HSCs and that additional mutations inhibiting programmed cell death may be critical in the transition of this disease to blast-crisis leukemia.     

Effects of skeletal muscle protein phosphatase inhibitor-2 on protein synthesis and protein phosphorylation in rabbit reticulocyte lysates

Reticulocyte lysates contain two major classes of protein phosphatase activities, designated type 1 and type 2. These designations are based on criteria derived from the analyses of protein phosphatase species in other tissues. The criteria include (i) chromatographic elution profiles on DEAE-cellulose; (ii) specificity of lysate phosphatases toward [(32)P]phosphorylase a and [(32)P]phosphorylase kinase; (iii) sensitivity of lysate phosphatases to Mg(2+) ATP; and (iv) sensitivity to the heat-stable protein phosphatase inhibitor-2. The lysate phosphatase species are similar to those described in rabbit skeletal muscle and rabbit liver. Reticulocyte protein phosphatase type 1, but not type 2, is inhibited by heat-stable protein phosphatase inhibitor-1 and -2 which have been characterized from rabbit skeletal muscle. We have initiated a study on the function and specificity of lysate protein phosphatase activities involved in the regulation of protein synthesis by examining the effects of protein phosphatase inhibitor-2 on reticulocyte protein synthesis and protein phosphorylation. Our findings are as follows. (a) Protein phosphatase inhibitor-2 inhibits protein chain initiation in hemin-supplemented lysates. (b) Inhibition is characterized by biphasic kinetics and is reversed by the delayed addition of purified reticulocyte eukaryotic initiation factor 2 (eIF-2). (c) Inhibition of protein synthesis by inhibitor-2 is accompanied by the phosphorylation of the alpha-subunit (38,000 daltons) of eIF-2 (eIF-2alpha) and of two heat-stable polypeptides of 29,000 and 44,000 daltons. (d) The 29,000-dalton component is phosphorylated in lysates under conditions of protein synthesis and appears to be inhibitor-2, but the physiological significance of this modification of inhibitor-2 is not clear. (e) Inhibitor-2 has no effect on the activation in vitro of isolated heme-regulated or double-stranded RNA-dependent eIF-2alpha kinases. We propose that the inhibition of protein synthesis in hemin-supplemented lysates by added inhibitor-2 is due at least in part to the inhibition of a type 1 eIF-2alpha phosphatase activity, which permits a basal eIF-2alpha kinase activity to be expressed leading to the accumulation of phosphorylated eIF-2alpha and an inhibition of protein synthesis.     

Effects of sustained isometric handgrip on praecordial accelerocardiogram in normal subjects and in patients with heart disease.

The effects of isometric exercise on the maximum amplitude of the praecordial accelerocardiogram (as represented by the DE deflection) have been compared in 6 normal subjects (group 1), 12 patients with aortic stenosis (group 2), and 16 patients with myocardial disease (group 3). Whereas the tachycardia and pressor effects of isometric exercise were identical in all three groups, the normal subjects showed a significant decrease in DE during handgrip of 10 +/- 4 per cent (P less than 0.05) as compared with the insignificant increases of 8.5 +/- 6 per cent (P greater than 0.5), and 4 +/- 3.5 per cent (P greater 0.3) observed in the patients in groups 2 and 3. This response in the normal subjects differed significantly from the responses observed in the patients in groups 2 (P less than 0.02) and 3 (P less than 0.01). Of the patients in each of groups 2 and 3, 50 per cent responded abnormally to handgrip in that they showed a significant increase in DE. In the patients with aortic stenosis this subgroup of patients differed from the remainder in that they had a higher resting cardiac index (P less than 0.05). In the patients with myocardial disease this subgroup was characterized by a significantly lower resting left ventricular end-diastolic pressure (P less than 0.02). It seems, therefore, that those patients who increase DE in response to handgrip tend to have better left ventricular function at rest than those who do not. We suggest that this may be because of increased beta adrenergic activity at rest and during isometric exercise in the subgroup who respond to handgrip with an increase in DE.