JCL roundtable: Lessons from genetic variants altering lipoprotein metabolism

Because the Human Genome Project reached its first major milestone in completing the full sequence of human DNA, many new discoveries have been made relating genetic variants to disease. The new methodology that allows much more rapid and focused analyses of selected genes and the ability to screen the entire exome of any individual has provided tools to examine literally thousands of individuals for a given study. Genetic analysis has become a large-scale epidemiologic tool for examining variants in gene structure and correlating them with phenotypic markers of human disorders. These genome-wide association studies have been quite revealing about the mechanism of disorders of many types. These tools have been applied to the appearance of clinical atherosclerosis and to the chronic metabolic risk factors for this disease process. We are joined by 2 individuals who have made very significant contributions to this area of research: Dr Brian Ference of Wayne State University School of Medicine and Dr Sekar Kathiresan from Massachusetts General Hospital and Harvard Medical School. In our discussion, we are going to focus on genetic variants, which lead to changes in lipoprotein concentrations and those that have an association with earlier onset of clinical vascular disease. This roundtable was recorded during the November 2016 American Heart Association Scientific Sessions in Orlando, Florida.     

JCL roundtable: PCSK9 inhibitors in clinical practice

The roundtable this month will involve a discussion of two new drugs that have been approved by the Food and Drug Administration for the reduction of low-density lipoprotein cholesterol (LDL-C). The Food and Drug Administration approved the first of these, alirocumab as an “adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL [low-density lipoprotein]-cholesterol.” Evolucumab has similar indications plus an indication specifically for treatment of homozygous familial hypercholesterolemia. This sets the stage for their clinical use and in this roundtable, we will discuss with two experts, the implications of these indications for the practicing physician. Dr McKenney and Dr Moriarty have had extensive experience in the conduct of clinical trials that provided the evidence of safety and efficacy of these so called PCSK9 inhibitors.     

JCL Roundtable: HDL in the primary care setting

One of the most difficult and confusing issues for clinical lipidologists and physicians in general has been the management of low concentrations of high-density lipoprotein cholesterol. We know this to be a very powerful predictor of risk in scores of community-based and clinical trial cohorts. Raising this number in many patients would seem to provide a great therapeutic opportunity, but so far this concept has been very difficult to prove. I have been joined for this discussion by a cardiovascular epidemiologist, Dr. Rachel Mackey, from the University of Pittsburgh and two clinical lipidologists who have studied and written in depth about this problem. These are Dr. Benjamin Ansell from the University of California in Los Angeles and Dr. Peter Toth from Johns Hopkins University School of Medicine. Our objective in this discussion is to give primary care clinicians our thoughts about the recent research findings and the implications of these data on the best clinical practice.     

Roundtable discussion: Familial chylomicronemia syndrome: Diagnosis and management

Plasma triglyceride concentrations are normally below 150 mg/dL in the fasting state. However, these lipids can reach values of several thousand mg/dL. Elevations in this range are due to a massive retention of chylomicrons and usually result from multiple genetic variants with superimposed influences such as diabetes and immune disorders. Less commonly, major gene defects in lipoprotein metabolism can be the cause. These may present soon after birth with strong evidence of familial penetrance. The causes of this syndrome have been discussed in a Roundtable published in the most recent issue of this Journal. The polygenic etiology may also have a familial presentation with similar clinical import. The diagnosis and management of these disorders is of importance since they can lead to critical clinical syndromes including death from acute hemorrhagic pancreatitis. The chronic management requires a dedicated medical team and a patient committed to an effective regimen. We are joined in this discussion by Dr P. Barton Duell, University of Oregon Health Sciences Center, and Dr Daniel Gaudet of the Université de Montreal, Montreal, Quebec. All have had extensive personal experience in the diagnosis and management of patients with familial chylomicronemia. This Roundtable was recorded on November 11, 2017, during a meeting of the National Lipid Association in New Orleans, Louisiana.     

Clinical trial of argatroban, a direct thrombin inhibitor, as an anticoagulant in cardiopulmonary support and apheresis in emergency patients: a preliminary report

 To evaluate the safe and effective use of argatroban, a competitive direct thrombin inhibitor, as an alternative anticoagulant for percutaneous cardiopulmonary support (PCPS) and continuous hemofiltration or hemodiafiltration (CHF/CHDF), a preliminary multicenter clinical trial was conducted between October 1999 and September 2000. Nine patients who underwent PCPS and/or CHF/CHDF were enrolled in the study during this period. The dosage of argatroban was controlled so that the activated clotting time (ACT) was maintained at around 180 to 200 s. The mean duration of argatroban administration was 82 ± 92 h, and the mean dose was 0.67 ± 0.40 μg kg⁺¹ min⁻¹. Severe hemorrhagic complications requiring the discontinuation of argatroban administration were not observed in any of the patients. Platelet loss was prevented to some degree, and plasma levels of fibrinogen were well preserved during PCPS/CHDF. Except for two patients undergoing CHDF, clot formation within the extracorporeal circulation circuit was not identified macroscopically after the discontinuation of the procedures. We conclude that argatroban might be useful as an alternative anticoagulant in cases where heparin cannot be safely used because of the increased risk of bleeding complications, thrombocytopenia, and/or hypofibrinogenemia. Although the optimal dose of argatroban has not been established, we propose an initial starting dose of 0.7 to 1.0 μg kg⁻¹ min⁻¹, followed by adjustments to maintain an ACT of between 180 and 250 s. Received: December 17, 2001 / Accepted: June 1, 2002 Acknowledgments We thank Dr. S. Miyamoto (St. Marianna University School of Medicine), Dr. Y. Okada (Showa University School of Medicine), Dr. M. Shimizu, and Dr. J. Ishikawa (Yokohama City University School of Medicine) for providing data used in this study. We also thank Dr. S. Kanesaka (Showa University School of Medicine Fujigaoka Hospital) and Dr. S. Imaki (St. Marianna University School of Medicine, Yokohama City Seibu Hospital) for their helpful advice. Correspondence to:K. Akashi     

JCL Roundtable: Should we treat elevations in Lp(a)?

The focus of this Roundtable discussion is the mysterious lipoprotein Lp(a). There is growing evidence that it confers significant risk of vascular disease at high plasma concentrations. The concentration in plasma is highly variable from person to person but relatively stable in any given individual. The issue of defining this as a target of treatment has many facets, which have stymied clinicians in their management of this risk factor. The pertinent questions are many such as: “How does one obtain the most meaningful measure as there are so many components?” “What agents are truly effective in lowering this lipoprotein particle?” “Does direct treatment with reduction affect risk?” “How does low-density lipoprotein–cholesterol relate to the risk?” “If low-density lipoprotein-cholesterol is reduced, is there residual risk related directly to Lp(a)?” and “Are there effective therapies under development?” For this Roundtable, I am fortunate to have three experts that have studied these questions in various settings and have agreed to answer my questions relevant to these clinical issues. These include Dr Moriarty from the University of Kansas, Dr Remaley from the National Institutes of Health, and Dr Tsimikas from the University of California San Diego.     

Pioneer women in the development of toxicology in Brazil

Women have always played an important role in the development of toxicology all over the world. Specifically in Brazil, toxicology has had greater female representation than other countries, but women''s participation at high hierarchical levels is low. Although more than 62% of the members of the Brazilian Society of Toxicology are women, only 7 out of the 22 presidents have been women throughout its 48 years of existence. This article aims to celebrate women in the field of toxicology in Brazil, based on interviews with five of these scientists who have changed the field of toxicology in Brazil as we know it today, each in their specific sub-areas. These women are: Dr. Ester de Camargo Fonseca Moraes, Dr. Silvia Berlanga de Moraes Barros, Dr. Alice Aparecida da Matta Chasin, Dr. Gisela de Aragão Umbuzeiro, and Dr. Tania Marcourakis. They are not only pioneers but they are also examples of admirable persistence in fighting the adversities presented to them. They broke the glass ceiling and opened doors for future generations of women in science. We hope that this article helps inspire women in their careers in toxicology.     

Contraception during the perimenopause

Although the absolute risk of pregnancy is lower during the perimenopause due to decreased fertility and decreased coital frequency, unintended pregnancy occurs at ratios similar to those observed in young women, and pregnancies that do occur are at high risk for maternal complications and poor outcomes such as miscarriage or chromosomal abnormalities. Therefore all premenopausal women should receive counselling that includes discussion of sexual habits and contraception during routine health care encounters. The majority of US women in this age group use permanent contraception, but other methods can be safe and effective and can have non-contraceptive benefits.     

Rapid cyclic changes in density and accessibility of endometrial ligands for Escherichia coli Dr fimbriae.

The mechanisms of developing infection in young, noncompromised individuals are well understood. Colonization is prerequisite for the development of infection. In human, ligands serving bacterial colonization belong to common antigens. Consequently, a majority of individuals should be sensitive to infection at all times. We hypothesize that the temporal patterns of some infections and sensitivity to them are associated with sudden changes in the density and accessibility of common receptors. Endometrial samples from women having normal menstrual cycles were examined for histological location, receptor density, and in situ hybridization of Dr (decaying-accelerating factor) ligands for Escherichia coli Dr fimbriae. Significant up-regulation and luminal expression of Dr ligands occurred during the secretory phase, whereas receptors were expressed in the basement membrane and in smaller quantities during the proliferative phase. This observation agrees with our hypotheses that some ligands recognized by bacterial adhesins change their compartmentalization and, most importantly, that they up-regulate expression at specific times.     

The ontogeny of sex appeal inDrosophila melanogaster males

Drosophila melanogaster males are sexually attractive when they are young, but they elicit very little courtship when they are 2–3 days old. We have shown that males from a Canton-S stock start to lose their sex appeal between 3 and 4 h after they eclose from their pupal cases because they have begun to synthesizecis-vaccenyl acetate, an inhibitory pheromone, by that time. Later, when the young males are between 20 and 24 h old, mature males perform even less courtship because the young males have begun to produce less of a courtship-stimulating pheromone.This research was supported by U.S. Public Health Service Grant GM-33511 awarded to L.T. Most of the data are taken from P.G.C.'s honors research project report, submitted in partial fulfillment of the requirements for the bachelor of arts degree with honors awarded by Temple University.     

Polyvinylpyrrolidone Storage Disease: A Source of Error in the Diagnosis of Signet Ring Cell Gastric Adenocarcinoma

False-positive and false-negative diagnoses of cancer seldom occur during evaluation of gastric mucosal biopsy specimens obtained during flexible fiberoptic endoscopy of the stomach. When they do occur, false-negative diagnoses are usually the result of undersampling of the lesion, whereas false-positive diagnoses are the result of overinterpretation of benign histologic lesions. The diagnosis of diffuse signet ring cell adenocarcinoma is associated with both false-positive and false-negative diagnoses of cancer. The signet ring cell can be easily overlooked. Mucicarminophilic cells can be overinterpreted as diffuse signet ring cell adenocarcinoma. Polyvinylpyrrolidone is an unusual cause of this type of false-positive diagnosis of gastric adenocarcinoma. Judicious use of histochemical stains, immunohistochemistry, and electron microscopy plays a significant role in avoiding the false-positive diagnosis of diffuse signet ring cell adenocarcinoma.

The authors wish to acknowledge the diagnostic assistance provided by Dr Jan Kennedy, Department of Pathology, Grady Memorial Hospital; Dr Robert Pascal, Department of Pathology, Emory University; Dr Henry Appelman, Department of Pathology, University of Michigan Hospitals; Dr Frank B. Johnson, Chief, Chemical Pathology at the Armed Forces Institute of Pathology, Washington, DC, and Dr Leslie H. Sobin, Chief, Gastrointestinal Pathology at the Armed Forces Institute of Pathology, Washington, DC.     

Hostility-related differences in the associations between stress-induced physiological reactivity and lipid concentrations in young healthy women

We examined the relations of fasting lipid levels to stress-induced neuroendocrine and cardiovascular responses as a function of hostility in 36 healthy young women. Participants were women who scored above 17 (n = 23) or below 12 (n = 13) on the Cook-Medley Hostility (Ho) Inventory. Lipids were determined following an overnight fast. Individuals participated in a solvable anagram task, which evoked significant physiological responses in all participants. The Ho group by total serum cholesterol (TSC) and the Ho group by low-density lipoprotein (LDL) cholesterol interactions significantly predicted heart rate (HR) and norepinephrine (Ne) responses. For high Ho women, elevations in TSC and LDL cholesterol were associated with smaller HR responses and larger Ne responses. In contrast, for low Ho women, elevations in TSC and LDL cholesterol were associated with larger HR responses and smaller Ne responses. Results also indicated a significant Ho group by TSC to high density lipoprotein (HDL) cholesterol ratio interaction for Cortisol. For high Ho women, larger Cortisol responses were associated with a greater TSC to HDL cholesterol ratio. For low Ho women, larger Cortisol responses were associated with a smaller TSC to HDL cholesterol ratio. Lastly, higher TSC and LDL cholesterol levels were significantly associated with larger epinephrine responses. The findings suggest that stress-induced physiological responses are differentially associated with fasting lipids as a function of hostility in healthy young women. This work was supported by Grants HL- 46283 and HL-56105 from the National Heart, Lung, and Blood Institute. This study was conducted while Dr. Harralson was a post-doctoral fellow in the laboratory of Dr. Suarez.     

Management of emergencies. I. Management of the unconscious patient.

At the Boston City Hospital, with the arrival of each new generation of interns, a series of lectures is given on the management of medical emergencies. This series has been sponsored by the First and Third (Tufts) Medical Services under the direction of Dr. Fernando Biguria, and all the medical services have taken part. The lectures continue to be among the most popular and valuable conferences held during the year. Because of this, the Journal, has arranged a similar series, many of the articles being written by participants in the Boston City Hospital lecture course, with the hope that they may be helpful to all physicians, but especially to the young men and women who are now eagerly awaiting their internship this July.     

Social support and stress: Influences on lipid reactivity

Social support protects individuals from cardiovascular morbidity and mortality, possibly by attenuating physiological stress responses. The presence of supportive individuals during acute psychological stress has been shown to influence cardiovascular functioning, but in inconsistent directions. The purpose of this study was to test the notion that the presence of a supportive friend during an acute stressor would influence lipid reactivity. Forty healthy women participated in the study. One half engaged in a speech task while a friend was present; the other half participated in a speech task without a friend present. The speech stressor elicited elevations in total cholesterol and triglycerides under both conditions. Those with a friend present had greater total cholesterol reactivity to stress, relative to those without a friend present. These findings are similar to some studies in the cardiovascular literature, and may be due to increased threat appraisal among those with a friend present. This study was supported in part by National Institutes of Health grants HL-48363 and HL-48411, and by MO1-RR0034 to The Ohio State University General Research Clinical Research Center. We gratefully acknowledge the expert assistance of Karen Cook. The assays were performed in the laboratory of Dr. Linda Bausserman of the Division of Cardiology in the School of Medicine at Brown University.     

JCL Roundtable: Health information technology in the management of lipoprotein disorders

One of the most serious challenges to all physicians is the maintenance of therapy for those chronic disorders that at present cannot be cured. Elevations of low-density lipoprotein and very low-density lipoprotein are among the most common of those disorders. We are now in an era in which 2 fundamental developments of modern technology have come together. These are the supply of effective and safe lipid-lowering drugs as well as the ability to closely monitor pertinent measures in our patients. The rapid conversion of our health care systems into large teams of professionals with direct support from third-party payers has made it possible to coordinate chronic care through electronic medical records and electronic communication. As a result, with effective planning and organization, we can guide our patients toward better adherence to successful medical regimens. These issues are evolving rapidly and have been presented in some detail in the December 2013 issue of the Journal. I was joined in this Roundtable discussion by 3 health professionals who have had extensive experience with the application of health information technology. They are Dr. Karen Aspry and Dr. Alan Brown, both clinical cardiologists, and Dr. Matthew Ito, a Doctor of Pharmacy.     

Emerging adulthood and patterns of physical activity among Young Australian women

The transition from adolescence to young adulthood is associated with a sharp decline in physical activity, particularly for women. This article explores the relations between physical activity status and change and status and change in four life domains: residential independence, employment status, relationship status, and motherhood. Two waves of survey data from a representative sample of 8,545 Australian women, aged 18-23 at Survey 1 and 22-27 at Survey 2, were analyzed. Cross-sectionally, physical inactivity was most strongly related to being a mother, married, and not being in the labor force. Longitudinally, decreases in physical activity were most strongly associated with moving into a live-in relationship, with getting married, and with becoming a mother. When considered in combination, women who were married with children and not employed outside the home were the most likely to be physically inactive. The data suggest that adoption of adult statuses, particularly traditional roles involving family relationships and motherhood, is associated with reductions in physical activity for these women, although it is possible that the effect is driven by socioeconomic factors associated with early transitions. The data suggest a need for interventions to promote continued physical activity among young women who cohabit or marry and among those not in the workforce, in addition to those supporting young mothers to be physically active. The research on which this article is based was conducted as part of the Australian Longitudinal Study on Women’s Health, The University of Newcastle and The University of Queensland. We are grateful for the Commonwealth Department of Health and Ageing for funding and to the women who provided the survey data.     

Oocytes from younger women with increased serum FSH are superior to those from older women with hypergonadotrophism

Dear Sir, We thank Dr Check for his interest in our study and the issueshe raised in his letter. Firstly, Dr Check raised the issuewhether young women are protected from the adverse effects ofreduced ovarian reserve. He made reference to a study producedin 1997 (Check et al., 1998), where the authors evaluated pregnancyand on-going pregnancy rates in a small number of     

Increasing trend of spina bifida and decreasing birth weight in relation to declining body-mass index of young women in Japan

We analyzed the existing data from various surveys on the prevalence of spina bifida, birth weight, and body-mass index (BMI), dietary intake, and smoking habits of Japanese young women. We found that the increasing trend of the prevalence of spina bifida paralleled with the decrease in birth weight, and the decrease in BMI and dietary energy intake and the increase in smoking rate among women of childbearing age. The decreased energy intake is likely due to their distorted self-body image. Based on these findings, we hypothesize that lowering BMI in young women led to increasing prevalence of spina bifida and smaller babies in Japan. This low dietary intake possibly leads to poor folate nutritional status, a risk factor for the development of spina bifida, and increased smoking potentially accelerates these undesirable outcomes. Our hypothesis can be tested using two simultaneous approaches. The first step is an extensive educational campaign for young women to stop smoking, have a realistic body image and eat a sufficient balanced diet. Government officials and health-care workers are encouraged to establish an agenda to educate young women with emphasis on the importance of adequate nutrition during the critical period of reproduction. Together with this campaign, the distribution of folic acid tablets for the prevention of spina bifida can be tried in women of childbearing age through local health centers, which have been well established in Japan.     

Myths and realities of the menopause.

Menopause is a reproductive milestone in a woman's life around which many different myths have developed. We reviewed three sets of myths that middle-aged premenopausal women hold and evaluated those myths according to scientific data from our own work and that of others. First, middle-aged women expect to experience depression, irritability, and vasomotor symptoms during the menopause. It appears that the vast majority of postmenopausal women do not experience depression, but do experience vasomotor symptoms that are uncomfortable and may have secondary effects on psychological well being, especially during the perimenopause. Second, middle-aged women believe that holding negative expectations about the menopause affects the quality of the menopausal experience. Indeed, that appears to be the case, perhaps because myths can function as self-fulfilling prophecy. The third myth is that there are no important changes that occur during the menopause. That is incorrect. Estrogen deficiency during the menopause sets the stage for substantial changes in risk for CHD, which becomes clinically apparent later in life. We discussed how estrogen deficiency may influence both lipids and lipoprotein levels and the magnitude of neuroendocrine and cardiovascular respond to mental stress. That latter pathway is of particular interest because middle-aged women may be exposed more often to interpersonal stress and may respond more emotionally to it, relative to men, suggesting a potential interactive effect of the decline in reproductive hormones and co-occurring social and psychological changes during the menopausal period. This discussion of the myths and realities of the menopause has deliberately not been exhaustive.(ABSTRACT TRUNCATED AT 250 WORDS)     

Roundtable discussion: Dietary fats in prevention of atherosclerotic cardiovascular disease

This roundtable discussion on dietary fats was inspired by a recent Presidential Advisory from the American Heart Association giving recommendations about dietary fats for prevention of atherosclerotic cardiovascular disease. The Advisory clarifies a long-held position that saturated fat should be reduced in the American diet. New studies and meta-analyses have questioned the adverse role of saturated fat. The Advisory adds a crucial clarification based primarily on 4 randomized controlled diet trials, each conducted over 4 to 8 years during the 1960s extending to the 1970s. In each trial, saturated fat was reduced and replaced by vegetable oil rich in polyunsaturated fat (PUFA). Meta-analysis showed 29% reduction in major coronary events in the groups receiving PUFAs. Randomized clinical trials provide the best kind of evidence. Replacing saturated fat with PUFA reduces cardiovascular events. Replacing saturated fats with carbohydrates or trans fats does not reduce cardiovascular events. Cardiovascular risk reduction has also been seen in randomized trials with monounsaturated fat in the context of whole food diets, mostly plant based (Mediterranean diets). In this discussion, we additionally cover some of the roller-coaster history of recommendations concerning dietary fat and provide advice for practical counseling.