Identifying and managing adverse environmental health effects: 2. Outdoor air pollution

AIR POLLUTION CONTRIBUTES TO PREVENTABLE ILLNESS AND DEATH. Subgroups of patients who appear to be more sensitive to the effects of air pollution include young children, the elderly and people with existing chronic cardiac and respiratory disease such as chronic obstructive pulmonary disease and asthma. It is unclear whether air pollution contributes to the development of asthma, but it does trigger asthma episodes. Physicians are in a position to identify patients at particular risk of health effects from air pollution exposure and to suggest timely and appropriate actions that these patients can take to protect themselves. A simple tool that uses the CH²OPD² mnemonic (Community, Home, Hobbies, Occupation, Personal habits, Diet and Drugs) can help physicians take patients'' environmental exposure histories to assess those who may be at risk. As public health advocates, physicians contribute to the primary prevention of illness and death related to air pollution in the population. In this article we review the origins of air pollutants, the pathophysiology of health effects, the burden of illness and the clinical implications of smog exposure using the illustrative case of an adolescent patient with asthma.Case A 16-year-old girl and her mother visit their family physician in July because the daughter woke up at 6 am that morning with shortness of breath, a cough and tightness in her chest. The girl has a history of asthma and used salbutamol soon after the onset of symptoms, with some but not total relief. She reports having had no symptoms during the previous month. She had a few episodes of wheezing the previous summer, which resolved with the use of salbutamol, and a cough that persisted for 2 weeks after an upper respiratory tract infection in the winter. She has no history of allergies, hayfever or other medical problems. She is a nonsmoker and has no family history of allergies. Audible wheezing is detected on physical examination, but the girl does not appear to be in distress. Her vital signs are normal, as are the results of the ear-nose-throat and cardiovascular examinations. Respiratory examination reveals wheezing throughout chest, no focal findings and a centrally placed trachea. The girl''s calves are soft and nontender, and there is no evidence of ankle edema. Her peak expiratory flow is 240 L/min (expected for height 400 L/min). Spirometry testing is unavailable. Fifteen minutes after 2 puffs of salbutamol her peak expiratory flow increases to 320 L/min. To identify possible exposures that may have contributed to the asthma episode, the physician quickly takes an environmental exposure history using the CH²OPD² mnemonic — Community, Home, Hobbies, Occupation, Personal habits, Drugs and Diet (1Table 1Open in a separate windowQuestions surrounding this case: What was the patient''s exposure to outdoor air pollutants? How should the patient and family be counselled about dealing with these trigger factors? What are the possible inducers and triggers from indoor air pollution? How can the patient and family find out about the status of outdoor air quality in their community?     

Exacerbation of demyelinating syndrome after exposure to wireless modem with public hotspot

ABSTRACT

In August 2003, 48-year-old JS of Colorado, USA, a fitness therapist and sports nutritionist, contracted neuroinvasive West Nile virus which left her with disabilities due to spinal axonal damage.In August 2014, she suddenly developed symptoms very much like her acute West Nile infection 11 years ago, including focal seizures, ataxia, vertigo and headaches. Her blood count looked normal so there was no obvious infection. What struck her as odd was that when she left her apartment for any length of time, the symptoms stopped. She found out that a new type of wireless modem, enabled for both personal use and functioning as a public hotspot designed to reach up to 100 m, had been installed in the flat under hers.Her neighbor replaced the modem with a router without the hotspot feature. After that, the seizures stopped immediately, and the other symptoms faded gradually, after which she was fine and again could sleep well. Later, when another activated hotspot was installed in an adjacent flat, JS once again noticed symptoms.A possible association between electrohypersensitivity, myelin integrity and exposure to low-intensity radiofrequency electromagnetic ?elds (RF-EMF) typical in the modern world has recently been proposed. Since the West Nile virus attacks both the nerve cells and the glial ones, one explanation to the above observed case effects is that the initial virus attack and the wireless modem’s RF-EMF affect the nervous system through the very same, or similar, avenues, and maybe both via the oligodendrocytes.     

Women's mating strategies

What does a woman want? The traditional evolutionist's answer to Freud's famous query is that a woman's extensive investment in each of her children implies that she can maximize her fitness by restricting her sexual activity to one, or at most, a few high-quality males. Because acquiring resources for her offspring is of paramount importance, a woman will try to attract wealthy, high-status men who are willing and able to help her. She must be coy and choosy, limiting her attentions to men who are worthy of her and emphasizing her chastity so as not to threaten the paternity confidence of her mate. The lady has been getting more complicated of late, however. As Sarah Hrdy¹ predicted, we now have evidence that women, like other female primates, are also competitive, randy creatures. Women have been seen competing with their rivals using both physical aggression^2,3 and more subtle derogation of competitors.⁴ While they are still sometimes coy and chaste, women have also been described recently as sexy and sometimes promiscuous creatures, manipulating fatherhood by the timing of orgasm^5,6 and using their sexuality to garner resources from men. The real answer to Freud's query, of course, is that a woman wants it all; a man with the resources and inclination to invest, and with genes that make him attractive to other women so that her sons will inherit his success. Her strategies for attaining these somewhat conflicting aims, and her success in doing so, are shaped by her own resources and options and by conflicts of interest with men and other women.     

Identifying and managing adverse environmental health effects: 5. Persistent organic pollutants

CONCERN AND AWARENESS IS GROWING about the health effects of exposures to environmental contaminants, including those found in food. Most primary care physicians lack knowledge and training in the clinical recognition and management of the health effects of environmental exposures. We have found that the use of a simple history-taking tool — the CH²OPD² mnemonic (Community, Home, Hobbies, Occupation, Personal habits, Diet and Drugs) — can help physicians identify patients at risk of such health effects. We present an illustrative case of a mother who is concerned about eating fish and wild game because her 7-year-old son has been found to have learning difficulties and she is planning another pregnancy. Potential exposures to persistent organic pollutants (POPs) and mercury are considered. The neurodevelopmental effects of POPs on the fetus are reviewed. We provide advice to limit a patient''s exposure to these contaminants and discuss the relevance of these exposures to the learning difficulties of the 7-year-old child and to the planning of future pregnancies.CaseA 27-year-old woman who lives in a town on the shore of Lake Huron wants to have a second child but has concerns. Her 7-year-old son is being assessed by the school psychologist for a learning disorder. She tells her family physician that she saw something on television about contaminants in fish affecting children''s intelligence. She is worried that her diet may have caused her son''s learning disorder and wants advice on how to protect her second child against environmental contaminants that may cause learning problems. Her past medical history is unremarkable. She is taking no medications other than folate (0.4 mg/d). She has had only the one pregnancy. Her pregnancy and delivery of her son were uncomplicated, and the boy met the developmental milestones. The concern about a learning disorder is recent. There is no family history of congenital anomalies, early deafness or twins. Her maternal grandmother had type 2 diabetes, and her father-in-law has hypertension; the rest of the family is healthy. Because the woman is worried about environmental exposures, you take an exposure history using the CH²OPD² mnemonic (Community, Home, Hobbies, Occupation, Personal habits, Diet and Drugs)¹ to identify possible sources of environmental contaminants (Open in a separate windowThe environmental contaminants that can affect the neurobehavioural development of the fetus include metals (lead, mercury and manganese), nicotine, pesticides (e.g., organophosphates), dioxins, polychlorinated biphenyls (PCBs) and solvents (e.g., alcohol).^2,3 In this article we focus on persistent organic pollutants (POPs) and mercury. These are the contaminants identified in the environmental exposure history of the case subject (4POPs are carbon-containing chemicals that share several properties. They are lipophilic, accumulating in the fat of living organisms, and increase in quantity up the food chain. Most are semivolatile, which means that they can travel in the air thousands of miles from their source before they settle. They resist photolytic, biological and chemical degradation and persist in the environment, taking as long as a century to degrade.⁵ Twelve POPs, including 9 pesticides, have been identified by the United Nations Environment Programme as powerful threats to the health of humans and wildlife and have been targeted for elimination (6 In the 1970s many countries banned or severely restricted the use of the 9 pesticides and PCBs and implemented pollution control strategies to reduce the amount of dioxin and furan released in the environment. However, it is thought that all 9 pesticides and PCBs are still used in many countries today.Table 2Open in a separate windowDespite significant achievements in reducing the production and use of POPs, these pollutants remain ubiquitous, as evident by the global distribution of PCBs and organochlorine pesticides in butter samples from around the world.⁷ Most human exposure comes from dietary sources. POPs are ingested, stored in fatty tissue and excreted in feces and breast milk. The concentration of certain chemical contaminants in breast milk serves as an indicator of population exposure. From 1967 to 1992, there was a downward trend in the concentrations of organochlorine pesticides and PCB hydrocarbons in samples of Canadian breast milk during the phase-out of these chemicals.⁸ The estimated daily intake of PCBs from the current diet of the average Canadian is less than 1 μg/d.⁹Although everyone is exposed to a background level of POPs, certain people may have higher levels of POPs exposure because of their eating habits. Some people eat more fish than the general population. Southeast Asian Canadians, Native Americans, sport anglers and hunters who regularly eat large amounts of Great Lakes fatty fish or wildlife from the top of the food chain, such as waterfowl and waterfowl eggs, turtles and turtle eggs, muskrat, otter, moose and deer, may be at risk of high exposure.¹⁰ Northern Aboriginals, such as the Inuit of Nunavik, who consume the fat of seals and beluga and narwhal whales, have been found to have higher body burdens of POPs.^11,12     

Succeeding in Science Despite the Odds; Studying Metabolism with NMR by Mildred Cohn

A Study of Oxidative Phosphorylation with O¹⁸-labeled Inorganic Phosphate(Cohn, M. (1953) J. Biol. Chem. 201, 735–750)Nuclear Magnetic Resonance Spectra of Adenosine Di- and Triphosphate. II. Effect of Complexing with Divalent Metal Ions(Cohn, M., and Hughes, T. R. (1962) J. Biol. Chem. 237, 176–181)Mildred Cohn was born in New York City in 1913. When she was young, her father told her she could achieve anything she chose to, but not without some difficulty because she was both female and Jewish. With her parents'' encouragement, Cohn moved rapidly through the New York public school system and graduated from high school at age 14. She decided to go to Hunter College in Manhattan, then an all-girls college, and majored in chemistry and minored in physics. Hunter''s attitude toward science education at that time can be summed up by the chairman of the chemistry department who declared that it was not ladylike for women to be chemists and that his sole purpose was to prepare his students to become chemistry teachers.When Cohn graduated from Hunter College in 1931 she tried to get a scholarship for graduate studies in chemistry but was unsuccessful. She enrolled in Columbia University nonetheless and used her savings to pay for her education. At Columbia, she studied under Nobel laureate Harold Urey but had to drop out after a year because of lack of money. She then took a job with the National Advisory Committee of Aeronautics and after a few years was able to earn enough money to return to Columbia. Working with Urey, she studied ways of separating different isotopes of carbon and received her Ph.D. in physical chemistry in 1937.Unfortunately, jobs were scarce in 1938, during the years of the Great Depression, and academic positions for women were even more scarce. Industrial recruiters regularly posted notices announcing that, “Mr. X of Y Company will interview prospective doctorate recipients—Male, Christian”(1).¹ With Urey''s help, Cohn was able to obtain a postdoctoral position at George Washington University with future Nobel prize winner Vincent du Vigneaud. In du Vigneaud''s laboratory, Cohn pioneered the effort to use isotopic tracers to follow the metabolism of sulfur-containing compounds, the subject of a previous Journal of Biological Chemistry (JBC) Classic (2). Cohn worked with du Vigneaud for 9 years and moved with him to New York when he went to Cornell Medical College.In 1946, Cohn went to Washington University in St. Louis to work with Carl and Gerty Cori, Nobel prize laureates and authors of a previous JBC Classic (3), who were studying biological catalysts. There, she did independent research, mainly focusing on using isotopes and NMR to study metabolic processes. Cohn was promoted to Associate Professor in Biochemistry in 1958 but left Washington University 2 years later to move to the University of Pennsylvania School of Medicine. She became a full Professor in 1961 and retired as Benjamin Rush Professor Emerita of Biochemistry and Biophysics in 1982.Once, when asked what her most exciting scientific moments were (4), Cohn replied, “In 1958, using nuclear magnetic resonance, I saw the first three peaks of ATP (5). That was exciting. [I could] distinguish the three phosphorus atoms of ATP with a spectroscopic method, which had never been done before. Another paper, in 1962 (the second JBC Classic reprinted here), was about the effect of metal ions on the phosphorus spectrum of ATP. And earlier, I found that oxygen in inorganic phosphate exchanged with water through oxidative phosphorylation (the first JBC Classic reprinted here).”Cohn''s study of oxidative phosphorylation came at a time when it was known that phosphorylation occurred concomitantly with oxidation in the electron transport chain. However, no one had yet discovered the nature of the interaction of the electron transport system with phosphate or any part of the phosphorylating system. Cohn approached this problem by tracking the loss of O¹⁸ from inorganic phosphate during oxidative phosphorylation in rat liver mitochondria. In the first JBC Classic reprinted here, she describes her findings as, “a new reaction which occurs in oxidative phosphorylation associated with the electron transport system has been observed in the rat liver mitochondria with α-ketoglutarate, â-hydroxybutyrate, and succinate as substrates. This reaction manifests itself by a replacement of O¹⁸ with normal O¹⁶ in inorganic phosphate labeled with O¹⁸ and parallels the phosphorylation which is associated with the oxidation.” Cohn concluded that water must be involved in this reaction because there was no other source of oxygen large enough to account for the amounts she saw introduced into inorganic phosphate. In the second JBC Classic Cohn describes her use of NMR to examine the structural changes in ADP and ATP caused by various divalent metal ions. Cohn knew that divalent ions were involved in enzymatic reactions of ADP and ATP but didn''t know their functions. Using NMR, she measured the changes in the chemical shifts in the peaks of the ATP and ADP phosphorus nuclei in the presence of Mg²⁺, Ca²⁺, and Zn²⁺ as well as the paramagnetic ions Cu²⁺, Mn²⁺, and Co²⁺. By analyzing the resultant spectra, she was able to determine which metals bound to which phosphate groups and thus gained insight into the nature of the metal complexes formed.Cohn received many awards and honors for her contributions to science, including the National Medal of Science in 1982, “for pioneering the use of stable isotopic tracers and nuclear magnetic resonance spectroscopy in the study of the mechanisms of enzymatic catalysis,” as well as election to the National Academies of Science in 1971. She also served the American Society of Biological Chemists (ASBC), now American Society for Biochemistry and Molecular Biology (ASBMB), in many ways. She was President of the Society in 1978 and was on the Federation of American Societies for Experimental Biology (FASEB) Board from 1978 to 1980 as ASBC representative. In addition, Cohn was the first woman to be appointed to the JBC Editorial Board.Despite her success, Cohn''s father was right about the difficulties she would encounter in her life. “My career has been affected at every stage by the fact that I am a woman, beginning with my undergraduate education, which was very inferior in chemistry, and physics was not even offered [as a major] at Hunter College, unlike the excellent science education that my male counterparts received at City College,” she notes. “In my day, I experienced discrimination in academia, government, and industry.”     

Gaia Pigino: Inside the cell

Gaia Pigino studies the molecular mechanisms and principles of self-organization in cilia using 3D cryo-EM.

Gaia Pigino was only 3 yr old when she became fascinated with nature in the beautiful countryside of Siena, Italy, where she grew up. The neighbor’s daughter showed her a hen in the chicken coop, and they caught it in the act of laying an egg. Gaia remembers, “This was for me almost a shock, as my experience about eggs was that they come directly out of paper boxes!” Her father was also an important part of awakening Gaia’s curiosity for the amazing things in nature. He used to bring home the award-winning magazine Airone, the Italian equivalent of National Geographic. Gaia never missed an issue; even before learning to read, she could spend hours looking at the captivating photos of the wildlife. She wanted to understand what she was seeing, and maybe because of that, she was determined to do science.Gaia Pigino. Photo courtesy of Human Technopole.Gaia took her first “scientific” steps with Professor Fabio Bernini and Professor Claudio Leonzio at the University of Siena, where she studied bioindicators of soil contamination and detoxification strategies of soil arthropods as part of her PhD project. But it was later, when she joined the laboratory of Professor Pietro Lupetti and met Professor Joel Rosenbaum, a pioneer of cilia research, that Gaia discovered the world of 3D EM and felt her place was “inside a single cell.” She solidified her interest in the structure of protein complexes of cilia and flagella and boosted her passion for cryo-electron tomography (ET) in the laboratory of Professor Takashi Ishikawa, first at the ETH Zurich and then at the Paul Scherrer Institut in Switzerland. In 2012, Gaia started her own laboratory at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany, with the vision of creating a truly interdisciplinary laboratory. Her team combines techniques from different fields such as biophysics, cell biology, and structural biology to answer open questions in the cilia field. Gaia recently moved countries again—this time to take over the position of Associate Head of the Structural Biology Research Centre, at the Human Technopole, Milan, Italy.We reached out to Gaia to learn more about her scientific journey and future research directions.What interested you about cilia?The first thing that attracted me toward cilia and flagella were some EM micrographs, by Professor Romano Dallai in Siena, that showed the beautiful geometrical microtubular structures of sperm flagella. I was intrigued by the apparent perfection of these organelles that clearly showed me that a cell is a coordinated system of complex molecular machines, the mechanism of many of which we do not understand. Soon after, Professor Joel Rosenbaum introduced me to the bidirectional transport of components inside cilia, which, he explained to me, is required for both assembly and function of virtually all cilia and flagella, from the motile cilia in our lungs to the primary cilium in our kidneys. He called it intraflagellar transport (IFT) and compared it to a Paternoster elevator, where the individual cabins were what we now call IFT trains. I was completely fascinated by the IFT system, the structure, the function, the dynamics, and the mechanism of which were still largely unknown. Quickly, I realized that in addition to IFT, cilia represent a virtually infinite source of open biological questions waiting to be solved, from the mechanics and regulation of the beating to the sensory function of primary cilia, and their importance for human health.What are some of the scientific questions currently of interest in your laboratory?In the past few years, we have made substantial contributions to the current understanding of the structure and the mechanism of the IFT (1, 2, 3). Currently, we are investigating how the structure of IFT trains relates to their functions by looking, in cryo-electron tomography, at how anterograde trains transform into retrograde trains and at how different ciliary cargoes are loaded on the trains. Beside this more classical line of research, we are exploring other approaches to study IFT, for instance we have developed a method to reactivate IFT trains in vitro on reconstituted microtubules. We want to use this approach to investigate the behavior of IFT trains, and their motors, in experimentally controllable conditions, e.g., in the presence of only certain tubulin posttranslational modifications. We have also made interesting discoveries about the distribution of tubulin posttranslational modifications on the microtubule doublets of the axoneme and how this spatially defined tubulin code affects the function of different ciliary components. We hope we will be able to share these new “stories” with the structural and cell biology community very soon!What kind of approach do you bring to your work?I believe that the main reason for why science became an integral, and dominant, part of my life is because it provides infinite riddles and continuous challenges. I have always been curious about how things work in nature, but I quickly realized that learning from books didn’t satisfy me. My desire was to be at the frontline, to be among the ones that see things happening in front of their eyes, at the microscope, for the first time. I wanted to be among the ones that make the discoveries that students read about in textbooks. Thus, what I bring to my work is an endless desire of solving biological riddles, curiosity, creativity, determination, and energy, with which I hope to inspire the members of my team. My laboratory uses an interdisciplinary approach; we use whatever method, technique or technology is needed to reach our goal, from the most basic tool to the most sophisticated cryo-electron microscope. And if the method we need does not yet exist, we try to invent it.A young Gaia Pigino (3 yr old) the day she discovered how eggs are made. Photo courtesy of Giancarlo Pigino.Could you tell us a bit about the Structural Biology Research Centre at the Human Technopole (HT)?At the HT Structural Biology Centre, we are working to create a vibrant and interdisciplinary scientific environment that will attract molecular, structural, cell, and computational biologists from all over the world. We are creating fantastic facilities, including one of the most well equipped and advanced electron microscopy facilities in Europe—and likely the world—headed by Paolo Swuec. My team, together with the teams of my colleague Alessandro Vannini and the research group leaders Ana Casañal, Francesca Coscia, and Philipp Erdmann, already cover a vast range of competences and know-how from classical molecular and structural biology approaches, such as crystallography and protein biophysics, to cryo-CLEM, cryo-FIB SEM and cryo-ET, all of which allow us to address questions in cell biology. Our goal is to create a scientific infrastructure and culture that will enable biologists to obtain a continuum of structural and functional information across scales.What did you learn during your PhD and postdoc that helped prepare you for being a group leader? What were you unprepared for?I learned that everyday research is mostly made of failures, but that with the right amount of obsession, persistence, curiosity, and creativity, it is always possible to succeed and discover new things. Being given the freedom to develop your own ideas and your own project very early in your career is a treat; science is not only about having good ideas! One needs to follow up on these ideas with intense work and troubleshooting to make them reality. In addition, I realized that being fearless and attempting what is considered too difficult by others, despite challenges, can turn into a worthy learning experience. Also, how you present your work to the scientific community matters for swinging the odds of success in your favor. Different places might work in very different ways, and conducting good science does not only depend on you, but also on the possibilities given to you by your environment.What was I unprepared for?—I guess several things, but one comes immediately to mind: I underestimated how much being responsible not only for my own life and career, but also the career of students, postdocs, and others in the laboratory, would affect me personally.Structure of the 96-nm axonemal repeat reconstructed by cryo-ET and subtomogram averaging. Image courtesy of Gonzalo Alvarez Viar, Pigino Lab.What has been the biggest accomplishment in your career so far?This is a tricky question for me... I tend to look into the future more than celebrating the past. I fight to succeed in something, but as soon as I conquer it, I find it less of an achievement than the thing I could conquer next. Nevertheless, I am happy about the discoveries and the papers published together with my students and postdocs (1, 2, 3, 4, 5). I am extremely excited about the fact that after many years of work I am now leading an interdisciplinary laboratory, where we combine techniques from different fields. I am also happy that three times my husband and I were able to move from one world class academic institution to the another to start exciting and fitting jobs and could still live together in the same place. We worked hard for this, but we also got lucky.What has been the biggest challenge in your career so far?I studied French in school; I had almost no exposure to spoken English until the end of my PhD. To avoid having to show my English insufficiencies, I did hide beside the board of my poster at the first international conference I attended in 2004! It took me a while to overcome this barrier and feel confident to express my thoughts and ideas in English.What do you think you would be if you were not a scientist?I had been a good fencer during my youth. I was a member of the Italian National Team between ages 14 and 19 and saw quite a bit of the world, which was cool! When my sporting career failed, due to diabetes, I was torn between art and science. I guess that in a parallel universe, I am a wildlife photographer and a potter specialized in wood kiln firing. [Gaia confesses that she misses “the amazing and addictive adrenaline rush of a good fencing match!”]Any tips for a successful research career?Do not compare your performances to the ones of the people at your career stage; compare yourself with people that are already successful one level higher than you currently are at. For example, if you are a PhD student, ask yourself what in your current performance separates you from being a good postdoc—once a postdoc, what is missing to be a good PI.     

Louisa May Alcott: her mysterious illness

Louisa May Alcott (1832-1888), famous in her own time and immortalized in ours as a major figure of the "American Renaissance," died at the age of 55 after intermittent suffering over 20 years. Her illnesses evoked intense interest in her time and in ours. Alcott tracked her signs and symptoms (in letters and journal entries), which included headaches and vertigo, rheumatism, musculo-skeletal pain, and skin rashes; in her final years she recorded severe dyspepsia with symptoms of obstruction, and headaches compatible with severe hypertension. Her death came suddenly with a stroke. Standard biographies propose that her illnesses were due to acute mercury poisoning from inorganic mercury medication she received for a bout of typhoid in 1863, a cause she herself believed. We have reviewed Alcott's observations, as well as those of others, and have determined that acute mercury poisoning could not have caused her long-term complaints. We propose instead that Alcott suffered a multi-system disease, possibly originating from effects of mercury on the immune system. A portrait of Alcott raises the possibility that she had systemic lupus erythematosus (SLE).     

A case of giardiasis expressing severe systemic symptoms and marked hypereosinophilia

An 88-year-old Japanese woman was referred to our hospital due to a one-month history of face edema, aphagia, shortness of breath, and skin rush over almost her entire skin. She had no abdominal symptoms. Her peripheral blood count showed a white blood cell (WBC) count of 27.1 × 10⁹/L with 82.1% eosinophils. Serum non-specific Immunoglobulin E was within a normal range. Soluble interleukin-2 receptor was elevated to 4200 U/mL. At first, her eosinophil count was so high that we suspected she had an eosinophilic leukemia or hypereosinophilic syndrome. After admission, cysts of Giardia duodenalis (G. duodenalis) were detected in the patient's feces by microscopic analysis, then she was diagnosed with giardiasis, and 750 mg per day of metronidazole was administered for seven days. Her WBC count decreased to 6.0 × 10⁹/L with 10% eosinophils, and her systemic symptoms improved. At that time her serum IL-5 was within a normal range. A few months later, the patient again complained of skin rush, and G. duodenalis was once again found in her feces. Her serum IL-5 was elevated to 751 pg/mL. Metronidazole was administered for two weeks, and her eosinophil count decreased. G. duodenalis is a protozoan parasite, and it is one of the most common waterborne transmission gastrointestinal parasites in the world. G. duodenalis rarely causes hypereosinophilia. To our knowledge, this is the first case report of giardiasis with extreme hypereosinophilia and severe systemic symptoms.     

It's a Wonderful Life: A Career as an Academic Scientist

Many years of training are required to obtain a job as an academic scientist. Is this investment of time and effort worthwhile? My answer is a resounding “yes.” Academic scientists enjoy tremendous freedom in choosing their research and career path, experience unusual camaraderie in their lab, school, and international community, and can contribute to and enjoy being part of this historical era of biological discovery. In this essay, I further elaborate by listing my top ten reasons why an academic job is a desirable career for young people who are interested in the life sciences.Students are attracted to careers in academic science because of their interest in the subject rather than for financial reward. But then they hear messages that make them think twice about this career choice. It is difficult to find a job: “Hear about Joe? Three publications as a postdoc and still no job offers.” The NIH pay line is low: “Poor Patricia, she is now on her third submission of her first NIH grant.” Publishing is painful: “Felix''s grad school thesis work has been rejected by three journals!” Academic jobs are demanding: “Cathy has spent her last three weekends writing grants rather than being with her family.”Such scenarios do take place, but if you think that this is what a career in academic science is about, then you need to hear the other side of the story. And this is the purpose of this article—a chance to reflect on the many good things about the academic profession. In the classic movie It''s a Wonderful Life, George Bailey is at the point of despair but regains his confidence through the wisdom and perspective of a guardian angel, Clarence. Doubt and setbacks also are bound to happen in science (as is true of other careers), but pessimism should not rule the day. It is a great profession and there are many happy endings. I would like to share my top ten reasons of why being an academic professor is a “wonderful life,” one that bright and motivated young people should continue to aspire to pursue.     

Ye Tian: Surveilling stress to live longer

Ye Tian investigates how mitochondrial stress signaling pathways regulate longevity using C. elegans as a model system.

An avid reader, Ye Tian used to save up her child allowance with the sole purpose of buying science fiction books. Reading and solving mathematical problems were her favorite hobbies; indeed, she liked mathematics so much that she was about to enroll herself as an architecture major but finally chose biotechnology. Ye moved from her hometown in the Northwest of China, Baoji—famous for housing the Zhou dynasty’s bronzeware and being close to the Terracotta Army—to Beijing for her college and graduate studies.Ye is proud of being among the earliest researchers working on Caenorhabditis elegans in her country; for her PhD studies, she joined the lab of Hong Zhang, who at that time has just established the first C. elegans lab in China at the National Institute of Biological Sciences in Beijing. Ye identified epg-2 as an adaptor for cargo recognition during autophagy. In 2010, she crossed the Pacific toward the U.S. West Coast for her postdoctoral training in the aging field with Andrew Dillin, first at the Salk Institute in San Diego and then at the University of California, Berkeley. There, she discovered that mild mitochondrial stress during development in worms rewires their chromatin landscape to establish specific gene expression patterns throughout the lifespan and promote longevity.Ye Tian. Photo courtesy of Ye Tian.Ye came back to China at the end of 2016 to start her own lab at the Institute of Genetics and Developmental Biology of the Chinese Academy of Sciences. Her research team studies mitochondrial stress signaling pathways and their interplay with aging. We chatted with her to learn more about her next scientific plans.What interested you about the interplay between mitochondria and aging?I became interested in mitochondrial biology during my postdoc in Andrew Dillin’s lab. Since the origin of eukaryotic cells, mitochondria have been a driving force of evolution. During reproduction, mitochondria are passed from the mother to the offspring through egg cells and they exhibit a unique inheritance pattern. As essential hubs that dictate cellular metabolism, it is clear now that mitochondria and the nucleus maintain a bidirectional communication. Early life “stressed” mitochondria communicate with the nucleus to induce gene expression changes that are beneficial on longevity and persist throughout the lifespan. The fact that mitochondrial function is crucial to aging fascinated me; I wanted to continue exploring that topic further, and that’s why I established my lab around the question of how mitochondrial surveillance mechanisms regulate the aging process.What are you currently working on? What is up next for you?My research team focuses on the interplay between mitochondrial stress signaling pathways and aging. The first work that my lab published was a project that I started during my postdoc. The Dillin lab reported a phenomenon in which perturbations of mitochondria in neurons induced a mitochondrial stress response in the peripheral tissues and hypothesized that a secreted signal molecule, named after mitokine, is required for the cell non-autonomous regulation (1). The identity of this molecular signal remained elusive for almost ten years until we found that a secreted Wnt ligand, EGL-20, functions as the mitokine to coordinate mitochondrial stress signaling across tissues and promote longevity of the organism (2). We are also interested in how the crosstalk between mitochondria and the nucleus influences lifespan. We found that mitochondrial perturbations alter the nuclear epigenome to induce longevity via the histone deacetylation complex NuRD in response to cellular acetyl-CoA levels, the key metabolite at the entry point of the Krebs cycle (3).Lab group picture; current lab members (2021). Photo courtesy of Ye Tian.Our latest work stemmed from a serendipitous observation that neuronal mitochondrial stress is sensed by and transmitted through the mitochondria in the germline. Intergenerational, maternal inheritance of elevated levels of mitochondrial DNA via the mitokine Wnt/EGL-20, which causes the activation of the mitochondrial unfolded protein response (UPR^mt), provides descendants with a greater tolerance to environmental stress. This makes the offspring live longer (4).Among our short-term scientific plans, we’re determining how mitochondria functions during the aging process at both the genetic and biochemical levels and searching for ways to apply our findings from C. elegans to neurodegenerative disease models in mammals.What kind of approach do you bring to your work?The curiosity about how things work drives me; what I enjoy the most is when I see things happening in front of my eyes and when I figure out why they occur that way. That enthusiasm is what I try to spread to my team every day. In the lab, we rely on C. elegans as our model system and on genetics to dissect complex biological processes like aging. We have also adapted modern biochemical and imaging techniques as well as bioinformatics to complement our genetic studies. I’m a geneticist at heart, and I like to initiate a project with a well-designed genetic screen. The best part is that the screen often leads me to answers I was not expecting, and that’s genuinely inspiring!What did you learn during your PhD and postdoc that helped prepare you for being a group leader? What were you unprepared for?Like most scientists, my research career has gone through ups and downs. I had to change my research project in the last year of my graduate school; that was nerve-racking, but I eventually managed to redirect my thesis and get exciting results under time pressure, thanks in large to the support of my parents, mentors, and lab mates. That helped me prepare to become a principal investigator; I gained confidence in problem solving, and since I’ve experienced the stress of dealing with last-minute scope changes firsthand, I connect better with my students.I guess, as many other non-native English speakers, I wasn’t prepared for writing grants and papers fluently in English. This issue wasn’t obvious during my graduate and postdoctoral studies, as my mentors were always there for me and proofread and edited my writing. Now I have to stand up for myself. I spend most of my time writing; I’ve improved my writing skills but it’s still an ongoing process.Reconstruction of the nerve system of C. elegans by confocal microscopy. Green corresponds to YFP-labeled neuronal specific marker Q40, and red labels germline specific mitochondrial outer membrane protein TOMM-20::mkate2. Image courtesy of Ye Tian’s lab.What has been the biggest accomplishment in your career so far?My very first PhD student, Qian Zhang, graduated with two first-author papers and decided to pursue a research career in academia. Being responsible for someone else’s career is challenging but also rewarding.What has been the biggest challenge in your career so far?I use the model organism C. elegans for my research in aging, so from time to time, peers criticize the relevance of my work to human health. I’m used to justifying my scientific approach to funding agencies and peers in other fields, but sometimes it’s exhausting or not pleasant.Who were your key influences early in your career?My PhD mentor, Hong Zhang. He is very passionate about the science he does, and he is courageous to shift his research directions to answer new biological questions.What is the best advice you have been given?I think the best advice I’ve gotten is that “tomorrow is another day.” It reminds me to keep going and be optimistic.What hobbies do you have?I love art and music. When I was in San Diego, I used to play in the Chinese Music Band; I miss my musician friends over there. In my teens, I used to hike mountainside trails along the river with my parents. Now, running has become my new favorite hobby. I enjoy the tranquility and peace of mind while running; it’s soothing.     

Reemergence of the bedbug Cimex lectularius in Seoul, Korea

A healthy 30-yr-old woman carrying an insect that had been caught in her living room visited the International Clinic at Severance Hospital, Seoul, in December 2007. The insect she brought was identified to be a nymph of a bedbug, Cimex lectularius, and her skin rashes looked typical bedbug''s bites. Her apartment was investigated, and a dead body of a bedbug, cast skins, and hatched eggs were found in her rooms and neighbors'' rooms in the same building. She was living in that apartment in Seoul for 9 months since she had moved from New Jersey, USA. We assume that the bedbugs were introduced from abroad, since there had been no report on bedbugs in Seoul for more than 2 decades at least. This is a report of a reemergence of the common bedbug, C. lectularius in Seoul, Korea.     

Raissa L. Berg's contributions to the study of phenotypic integration,with a professional biographical sketch

Raissa L. Berg had a remarkable career in many respects and an impact on the study of phenotypic integration that continues to increase over 50 years after the publication of her seminal paper in that area. She was born and lived most of her life in Russia, with most of her research focused on measuring spontaneous mutation rates in Drosophila. She was forced to abandon this work during the height of Lysenko''s power in Russia, so she turned temporarily to the study of correlation patterns in plants; ironically, this work has had a more enduring impact than her main body of research. She showed that floral and vegetative traits become decoupled into separate correlation ‘pleiades’ in plants with specialized pollinators, but floral and vegetative traits remain correlated in plants that have less specialized pollination. Unfortunately, her plant work is often mis-cited as providing evidence for increased correlations among floral traits due to selection by pollinators for functional integration, a point she never made and one that is not supported by her data. Still, many studies of correlation pleiades have been conducted in plants, with the results mostly supporting Berg''s hypothesis, although more studies on species with generalized pollination are needed.     

A Reflection of Joan

A case history is reported to demonstrate a simple psychotherapeutic approach in family practice to patients with psychoneurotic illness with somatic complaints. The patient had a two-year history of multiple aches and pains, particularly centred on her abdomen. In two interviews, a total of one and a half hours, her problem was isolated more definitely and relief was provided for her symptoms. It is suggested that this is a practical approach to such patients, who are probably a large factor in any “overutilization” of physician''s services.     

Salt and water: a simple approach to hyponatremia

HYPONATREMIA IS COMMON IN BOTH INPATIENTS and outpatients. Medications are often the cause of acute or chronic hyponatremia. Measuring the serum osmolality, urine sodium concentration and urine osmolality will help differentiate among the possible causes. Hyponatremia in the physical states of extracellular fluid (ECF) volume contraction and expansion can be easy to diagnose but often proves difficult to manage. In patients with these states or with normal or near-normal ECF volume, the syndrome of inappropriate secretion of antidiuretic hormone is a diagnosis of exclusion, requiring a thorough search for all other possible causes. Hyponatremia should be corrected at a rate similar to that at which it developed. When symptoms are mild, hyponatremia should be managed conservatively, with therapy aimed at removing the offending cause. When symptoms are severe, therapy should be aimed at more aggressive correction of the serum sodium concentration, typically with intravenous therapy in the inpatient setting. CaseA 72-year-old woman presents to your office with a 2-day history of presyncope when rising from a chair. She has been taking hydrochlorothiazide, 25 mg/d, for 5 years for systolic hypertension. Over the last week she has had a bout of viral gastroenteritis with marked diarrhea. She has been trying to replace the lost fluids by drinking 2–3 L of water per day. You determine that when she rises from a seated position, her blood pressure drops 20 mm Hg; her jugular venous pressure is low. Serum levels are as follows: sodium 128 mmol/L, potassium 3.1 mmol/L, creatinine 125 mmol/L and urea nitrogen 10 mmol/L.What is your approach to this woman''s hyponatremia?Hyponatremia is common in both inpatients and outpatients. Its causes are numerous and often elusive. Having a simple approach to assessment and treatment can be helpful in most cases that present in clinical practice. This review is meant to be a simplified, clinically based overview of the diagnosis and management of hyponatremia. Pathophysiological details of common and rare causes of hyponatremia and a detailed laboratory approach to diagnosis can be found elsewhere.¹     

Resting tachycardia, a warning sign in anorexia nervosa: case report

Background

Among psychiatric disorders, anorexia nervosa has the highest mortality rate. During an exacerbation of this illness, patients frequently present with nonspecific symptoms. Upon hospitalization, anorexia nervosa patients are often markedly bradycardic, which may be an adaptive response to progressive weight loss and negative energy balance. When anorexia nervosa patients manifest tachycardia, even heart rates in the 80–90 bpm range, a supervening acute illness should be suspected.

Case presentation

A 52-year old woman with longstanding anorexia nervosa was hospitalized due to progressive leg pain, weakness, and fatigue accompanied by marked weight loss. On physical examination she was cachectic but in no apparent distress. She had fine lanugo-type hair over her face and arms with an erythematous rash noted on her palms and left lower extremity. Her blood pressure was 96/50 mm Hg and resting heart rate was 106 bpm though she appeared euvolemic. Laboratory tests revealed anemia, mild leukocytosis, and hypoalbuminemia. She was initially treated with enteral feedings for an exacerbation of anorexia nervosa, but increasing leukocytosis without fever and worsening left leg pain prompted the diagnosis of an indolent left lower extremity cellulitis. With antibiotic therapy her heart rate decreased to 45 bpm despite minimal restoration of body weight.

Conclusions

Bradycardia is a characteristic feature of anorexia nervosa particularly with significant weight loss. When anorexia nervosa patients present with nonspecific symptoms, resting tachycardia should prompt a search for potentially life-threatening conditions.     

Severe self-mutilation of hands in a nonpsychotic, nonretarded patient

A case report of a young female teenager with a long history of self-destruction of her hands by chewing, scratching, and gnawing is presented. This habit was related to her successfully repaired cervical meningomyelocele in infancy. Not only did she first present with ulcerations and osteomyelitis, but also with distal autoamputation and severe iron deficiency anemia. A team approach with a pediatrician, neurologist, psychiatrist, and plastic surgeon was employed for her treatment. Behavior modification was moderately successful. Her hands and forearms were reconstructed with arthrodesis, local and distant flaps, and skin grafting without incident. She has been followed now for 4 years.     

Elda Grabocka: Stress-buffering comes in granules

Elda Grabocka investigates the role of stress granules in obesity and cancer.

When one thinks of high school, sharing hallways with students from 80 different countries is not the usual image that springs to mind. This was indeed Elda Grabocka’s experience. She grew up in Pogradec, a remote town in Albania—her parents, both physicians, were assigned to this location by the state. Elda won one of the two spots available for Albanian students in a national competition to attend the United World College of the Adriatic in Trieste, Italy, a high school focused on social change that brings together students from around the globe to promote intercultural understanding. Elda still remembers, with a smile on her face, the first glimpse at the laboratories as the senior students were working on their thesis projects: “That was exactly what I wanted to do!” She barely spoke English at the time and had to catch up to the level of her peers, but her perseverance and passion prevailed, and she obtained the International Baccalaureate Diploma (IBD). For the independent study of the IBD program, she submitted a research project in chemistry, which ended up being an important learning and life lesson: “That helped me understand that I was more suited to biology! In hindsight, it was great to have that experience so early; I certainly had no awareness then how essential failing and then learning from your failures is to science, but having a level of comfort with it from the beginning was probably a bonus.”Elda Grabocka. Photo courtesy of Chris Hamilton Photography.But science was not the only professional option Elda contemplated—her volunteering experience with relief organizations in various refugee camps made her consider a career in public health and humanitarian relief efforts. She finally sought a PhD degree in molecular pharmacology and structural biology in the laboratory of Phil Wedegaertner at Thomas Jefferson University. After studying heterotrimeric G-proteins and how the subcellular localization of their exchange factors regulates function, Elda felt the need to seek greener pastures. She went on to do a postdoc on one of longest-studied oncogenes, RAS—her choice wasn’t motivated by the field, but by the mentor, Dafna Bar-Sagi. Elda’s admiration for Dafna is notable when she speaks about her time at the New York University Langone Medical Center: “It’s remarkable how many novel aspects of RAS biology that have shaped and then re-shaped our thinking about this oncogene have come out of her lab; I felt there was a depth and breadth to her approach to scientific research that if I could learn, I’d be able to see more of the angles, so to speak, ask better questions; she has really expanded my mind in all those aspects.” Elda’s work focused on the interplay between the mutated forms of RAS and the wild-type isoforms, which she and others have shown is context dependent, with the wild-type isoforms acting as both tumor suppressors and tumor promoters (1). While still in Dafna’s laboratory, Elda pursued a more independent scientific interest: the role of stress granules in mutant KRAS cells. In 2016, Elda returned to her alma mater, joining the Department of Cancer Biology at the Sidney Kimmel Cancer Center at Jefferson as an assistant professor, with stress granules in cancer as the focus of her laboratory. We contacted her to learn more about her research journey.What interested you about stress granules and their connection with obesity and cancer?I became interested in stress granules and their potential role in cancer early in my postdoc. I read a review by Stephen Elledge’s group where they described the “stress phenotype” of cancer as an important player in tumorigenesis. I realized that cancer cells exist mostly in a state of stress—for example, mutated genes, like oncogenic RAS, are potent inducers of many types of cellular stresses. I was working on a RAS ubiquitination project, and one of the candidates for a RAS de-ubiquitinating enzyme we were looking at was implicated in stress granule formation. Little was known about stress granules at the time—they are induced by types of stresses associated with tumors (hypoxia, oxidative stress, osmotic pressure, proteotoxic stress, metabolic stress, etc.), so the question I asked was whether stress granules could function as a stress coping/adaptation mechanism in cancer. Indeed, I found that stress granules are prevalent in tissues from patients with pancreatic cancer and mouse models of pancreatic cancer. Remarkably, not all cancer cells are the same in their capacity to form stress granules—all cells will make stress granules under stress, but KRAS mutant cancer cells have a heightened ability to do so because signaling from mutant KRAS enhances the levels of a critical molecule to stress granule formation, 15-deoxy-prostaglandin J2 (2). This enhanced capacity to make stress granules, in turn, renders KRAS mutant cells more resistant to stress and more dependent on stress granules; inhibition of stress granules leads to increased cell death in KRAS mutant versus KRAS wild-type cancer cells.Immunofluorescence staining of pancreatic ductal adenocarcinoma tissue showing cancer cells in red, stress granules in green, and nuclei in blue. Image courtesy of the Grabocka laboratory.The work establishing this dependence was in vitro, so the primary goal when I started my laboratory was to determine their relevance in tumorigenesis, which led me to explore their connection to obesity and cancer for several reasons. First, obesity is a major predisposing factor for several cancers, including pancreatic and colon, which are prevalent KRAS-driven cancers for which treatment options are limited. Second, obesity is a complex pathology which likely impacts the pathobiology, the therapy response, and even the evolution of cancers that arise in this setting. Given that cell stress and inflammation are key features in obesity, this would make the ideal background to study the contribution of stress granules in tumorigenesis. I think this pre-existing stress [obesity] might necessitate the engagement of stress adaptive mechanisms from the early stages of tumorigenesis and may also lead to a high dependence on these processes.What are you currently working on, and what is up next for you?It’s a very exciting time to be working on stress granules! The field has grown significantly over the past 10 yr or so, especially with the renewed interest in phase separation. As organelles that form via phase separation when a cell is under stress, stress granules are perhaps one of the best examples of phase separation in vivo and a great platform to understand its relevance. The recent advances in defining the composition, as well as key molecular drivers and their functional domains in stress granule assembly, have been of great benefit. We are now better positioned to define the stress granule–specific functions in health and disease. Because stress granules are induced by various types of stresses, they could function as a pan-stress adaptation mechanism in cancer. This is a very appealing angle, as if we can solve how stress granules enable stress adaptation, which is a major focus of my laboratory, we could have better anti-cancer therapies.The composition of stress granules, comprising hundreds of proteins and mRNAs involved in several aspects of cell biology, prompted me to ask whether cytoprotection under stress is their main and/or only function. What other cellular processes stress granules regulate, whether these vary with the type of stress, and how such processes are integrated into the stress response of cancer cells are burning questions we are currently working on, as the answers will advance our understanding of the role of stress granules in cancer. The “chronic stress” of cancer is heterogenous in both spatial and temporal terms, as well as in the type of stress and intensity. I am also very curious to see if and how heterogeneity in stress stimuli impact the composition of stress granules and the processes they regulate, and how this may affect tumor evolution. Also, cancer cells are not the only cells in the tumor that make stress granules. As a matter of fact, we reported that KRAS mutant cells can stimulate stress granule formation in a paracrine manner. An ongoing project in the laboratory that I’m very excited about is focused on understanding the contribution of stress granules to the pro-tumorigenic microenvironment.What kind of approach do you bring to your work?My approach is very hypothesis and observation driven; the latter in the sense that it can often be that initial spark that inspires an idea, draws connections, and looks for context and meaning. I also find that sometimes the answer to my next question or the question I don’t know to ask yet is hidden right in front of my eyes, so paying careful attention to the data is key. It is also where objective and critical evaluation of experimental results starts. There’s one line that’s firmly ingrained in my mind from my postdoctoral training, which is “Science is self-correcting.” It’s a note of caution that if you don’t pay attention and see only what you want to see, it will still eventually prove you wrong, and you’d have wasted a lot of time in the process. So I try to minimize that waste as much as possible—unavoidable entirely, having a favorite hypothesis is part of the scientific thinking process, but crucial to remember to follow the data and not just convince yourself.What has been the biggest accomplishment in your career so far?I’m still quite early in my career to start listing accomplishments. I feel privileged to do the work I do; I essentially get funded to pursue ideas that I find interesting. So I have a hard time with this question because it has a hint of pride, and when you start adding pride to privilege, as a junior principal investigator especially, it gets a bit too self-serving. I hope that the work we are doing stands the test of time and leads to or helps lead to a meaningful impact on patients’ lives—that would be a great accomplishment.What has been the biggest challenge in your career so far?The past two years of COVID have certainly been a different reality, and a constantly shifting one at that. From a career perspective, so much of a scientific career happens at the bench: experiments happen at the bench, we train at the bench, animal work is long and requires multiple dedicated essential personnel and facilities, so inevitably, remote work, or shift work, limited occupancy, and the shortages we are now seeing in the supply chain have been a major challenge for everyone. I do think junior laboratories like mine experience that a bit harder. The bandwidth to absorb these challenges is much smaller if you’re just starting out, or if you’ve had a laboratory for a couple of years and are just ramping up. I must say though that it has made for stronger teamwork in the laboratory, and we’ve had to be really focused and efficient—so there’s an upside!Out for a paddle. Photo courtesy of Elda Grabocka.Any tips for a successful research career?Hard to say, because certainly it means different things to different people. The only tip I would give perhaps is to define what that means, what that success looks like for oneself, and be true to that. I expect how each one defines it also changes with time and experience, but I do think it’s very important to identify what success means as early as possible and let that be what you measure your efforts against. It’s easy to get distracted, overwhelmed, or even disheartened otherwise. My own definition is quite simple: success is doing what I love to do, working toward answering a meaningful scientific question, and enabling/supporting my trainees to reach their potential—keeping that in mind has been very important and helpful.     

Europe and ESTRO moving East. A story of betrayal and redemption—Candid observations by a privileged witness

After briefly looking into the dramatic twist of history that caused Central- and Eastern Europe to be separated from the West, the author observes the impact of 40 years of cold war and isolation on the state of radiotherapy (RT) in Central Europe. From her privileged position as a staff member in charge of public relations and society development at the European Society for Therapeutic Radiology and Oncology (ESTRO), she witnesses and helps drive the “rapprochement” between radiation oncology professionals from both sides of the former iron curtain. Thanks to substantial support from target tailored EU projects, ESTRO was in a position to give a powerful impulse to the re-integration of Central European RT in the mainstream of European health care. The author describes from her own and privileged perspective the excitement of discovering the rich heritage of a shared common past and expresses her concern that in the dynamic repositioning of Europe''s point of gravity towards the East, the multiple but still fragile links between Central- and West European radiotherapy, tied within ESTRO, should not get dissolved in transition.