Cherish the Capacity to Change

The following address was given at the Gold-Headed Cane Ceremony, University of California School of Medicine, on 3 June 1966. At this event on the eve of Commencement Day, the senior student who has been chosen by his classmates and professors in the Department of Medicine as the one who best exemplifies the qualities of a true physician is given a gold-headed cane. This carries on the English tradition of a cane which was passed from physician to physician from 1689 to 1825, and was carried successively by Drs. John Radcliffe, Richard Mead, Anthony Askew, David Pitcairn and Matthew Baillie. The original cane now rests in the Hall of the Royal College of Physicians in London.     

Type of Practice of Physicians in California,Report of the Bureau of Research and Planning

The total number of non-federal^* physicians in California rose from 23,065 in mid-1959 to 26,271 in January, 1962, an 11.3 per cent increase. The proportion of physicians in private active practice remained almost constant during this period.A significant rise, both in number and proportionally, took place in the full-time specialty category, offset by losses in the general practice-part-time specialty group. While specialists increased by over 30 per cent, general practitioners, who made up 31.7 per cent of all non-federal physicians in 1959, were only 24.7 per cent of the total in early 1962.     

The Role of Hemoglobin's C-terminal Region: the Work of Eraldo Antonini

Studies on Carboxypeptidase Digests of Human Hemoglobin(Antonini, E., Wyman, J., Zito, R., Rossi-Fanelli, A., and Caputo, A. (1961) J. Biol. Chem. 236, PC60–PC63)The Effect of Oxygenation on the Rate of Digestion of Human Hemoglobins by Carboxypeptidases(Zito, R., Antonini, E., and Wyman, J. (1964) J. Biol. Chem. 239, 1804–1808)Eraldo Antonini (1931–1983) received his degree in Medicine and Surgery from the University of Rome in 1955. He then began studying hemoglobin and myoglobin with Alessandro Rossi-Fanelli at the Institute of Biochemistry of the University of Rome and at the Regina Elena Institute for Cancer Research.Open in a separate windowEraldo Antonini (right) in Caprarola in 1971 for Jeffries Wyman''s (left) birthday party, with Robert W. Noble (back).In 1961, Antonini and Rossi-Fanelli published a paper describing the effect on human hemoglobin''s activity when the C-terminal amino acid residues are removed from the molecule''s α and/or β chains. This paper is reprinted here as a Journal of Biological Chemistry (JBC) Classic. In the study, the scientists used carboxypeptidase A to digest the C-terminal tyrosine and histidine on the molecule''s β chain and carboxypeptidase B to remove the C-terminal lysine, tyrosine, and arginine on the molecule''s α chain. The resulting protein appeared intact but had an increased oxygen affinity, lowered cooperativity, and dramatically reduced Bohr effect.This observation inspired Max Perutz, who wrote: “Several years later, my electron density maps showed that these residues form salt bridges with neighboring subunits in deoxyhaemoglobin which get broken on transition to oxyhaemogloblin. Remembering Antonini''s observation, I realized at once that these bridges must represent the additional bonds between the subunits in the T structure predicted by Monod, Wyman and Changeux''s theory of allostery. Antonini had also demonstrated that the release of Bohr protons is colinear with oxygen uptake. When Kilmartin''s and my work proved that most of the Bohr protons originate from the salt bridges, it became clear to me that oxygen uptake is linked to the rupture of these bridges” (1).In the second JBC Classic reprinted here, Antonini follows up on the first paper by doing a reciprocal experiment in which he looks at differences in digestion rates of oxy- and deoxyhemoglobin, reasoning, “If enzymatic modification can affect conformation and changes of conformation resulting from combination with ligand (oxygen), one might expect that the rate of attack on the hemoglobin by the enzymes should depend on the presence or absence of ligand; this would determine conformation, and conformation, in turn, would control the rate.” Again using carboxypeptidases A and B, he showed that the rate of digestion is different for the oxy- and deoxy- forms of the molecule, indicating a differential accessibility of the C-terminal residues to these enzymes.This work was later extended and perfected by John V. Kilmartin on a suggestion by Perutz, who pointed out the crucial role of the C-terminal residues for the molecular mechanism of cooperativity and the Bohr effect. Kilmartin was able to differentiate the role of the C-terminal histidine from that of tyrosine by preparing and characterizing a modified hemoglobin devoid of histidine.Over the next several years, Antonini continued to study hemoglobin, looking at the properties of the α and β chains, the acid-base equilibria of hemoglobin, the Bohr effect and its dependence on temperature, the oxidation-reduction equilibria, ligand-induced conformational changes in hemoglobin, and the kinetics of the reaction of myoblogins and hemoglobins with ligands. This work culminated in the publication of Hemoglobin and Myoglobin in Their Reactions with Ligands in 1971 (2), which was a landmark in the field.In the 1970s, Antonini expanded his scientific interests and started focusing on electron-transfer metalloproteins (such as cytochrome c oxidase) and on proteolytic enzymes. He eventually became Professor of Molecular Biology at the University of Camerino and was later made Professor of Chemistry and Director of the Institute of Chemistry in the Faculty of Medicine and Surgery at the University of Rome. He also received the Feltrinelli Prize from the Accademia Nazionale dei Lincei in 1974.One of Antonini''s coauthors on the two JBC Classics reprinted here is JBC Classic author Jeffries Wyman (3) who came to Rome in 1961 for a week-long visit and ended up remaining for 25 years and working with Antonini. This collaboration produced a series of outstanding papers and conceptual advancements that have had a long lasting influence on protein chemistry.^1,2     

Treatment of Acromegaly,Cushing Disease and Nelson Syndrome

Since 1957 we have treated more than 429 patients who had pituitary neoplasms, most of which were hormone-secreting tumors. Long-term follow-up in the large group of patients treated for acromegaly shows a median survival of better than 16 years, with improvement over time. The short-term follow-up results in patients with Cushing^* disease, Nelson syndrome and chromophobe adenoma are very encouraging. To compare these excellent results with those following surgical procedures, a large study of patients followed for a long period after the operations is needed.     

Protecting Reproductive Health and Choice

Women and men have special needs in rehabilitation. Women''s needs, however, have received far less attention in the scientific community and medical literature. This section, edited by Sandra Cole, PhD,^* highlights some of the unique concerns of women who live with physical disabilities.     

The characterization of restriction endonucleases: the work of Hamilton Smith

Purification of the HhaII Restriction Endonuclease from an Overproducer Escherichia coli Clone(Kelly, S., Kaddurah-Daouk, R., and Smith, H. O. (1985) J. Biol. Chem. 260, 15339–15344)Catalytic Properties of the HhaII Restriction Endonuclease(Kaddurah-Daouk, R., Cho, P., and Smith, H. O. (1985) J. Biol. Chem. 260, 15345–15351)Hamilton Othanel Smith was born in 1931 in New York City. In 1937, he and his family moved to Champaign-Urbana, Illinois, because his father had joined the faculty of the department of education at the University of Illinois. As a boy, Smith was interested in chemistry, electricity, and electronics, and he spent many hours with his brother in their basement laboratory, which was stocked with supplies purchased from their paper route earnings. Smith attended a small college preparatory school called the University Laboratory High School and graduated in 3 years largely due to his science teacher who allowed him to complete chemistry and physics during the summer.Open in a separate windowHamilton O. SmithAfter finishing high school, Smith enrolled at the University of Illinois, majoring in mathematics. During his sophomore year, his brother showed him a book on mathematical modeling of central nervous system circuits by Nicolas Rashevsky. This caught his interest, and after transferring to the University of California, Berkeley, Smith immersed himself in courses in cell physiology, biochemistry, and biology. A guest lecture by Journal of Biological Chemistry (JBC) Classic author George Wald (1) describing his studies of retinal biochemistry soon converted Smith into a devoted student of visual physiology and eventually motivated him to apply to medical school.In 1952, Smith began his studies at the Johns Hopkins University Medical School. He received his M.D. 4 years later and went to Barnes Hospital in St. Louis for a medical internship. However, in 1957, Smith was called up in the Doctor Draft and joined the U.S. Navy. He finished his Navy service in 1959 and moved to Detroit to begin a medical residency training at the Henry Ford Hospital. There he became interested in bacteriophage and decided that this would be the focus of his research.So, in 1962, Smith began his research career with Myron Levine in the department of human genetics at the University of Michigan in Ann Arbor. He and Levine carried out a series of studies demonstrating the sequential action of the phage P22 C-genes, which controlled lysogenization. They also discovered the gene controlling prophage attachment, now known as the int gene, and carried out a study of defective transducing particles formed after induction of int mutant prophage.In 1967, Smith joined the faculty of Johns Hopkins University as an assistant professor of microbiology and continued his bacteriophage research. A year later, working with Thomas J. Kelly, Jr. and Kent W. Wilcox, Smith isolated and characterized the first Type II restriction endonuclease (HindII) from Haemophilus influenzae and determined the sequence of its cleavage site (2, 3). In recognition of this discovery, he was awarded the 1978 Nobel Prize in Physiology or Medicine with Werner Arber and Daniel Nathans.These studies led to Smith''s subsequent research on DNA methylases and nucleases in H. influenzae. The two JBC Classics reprinted here detail Smith''s efforts to discover the rules governing sequence recognition in the Type II restriction endonuclease HhaII via x-ray crystallography. To facilitate these studies, Smith and his colleagues engineered a two-plasmid system in Escherichia coli that overproduced HhaII on induction with isopropylthiogalactoside (IPTG). The first paper describes the induction characteristics of the two-plasmid overproducer clone and purification of the endonuclease. The second paper, published back-to-back with the first, details the catalytic properties of the endonuclease. Smith used two methods to follow the reactions: 1) gel electrophoretic analysis of nicked circular and linear DNA products, and 2) release of ³²P-labeled inorganic phosphate from specifically labeled HhaII sites in a reaction coupled with bacterial alkaline phosphatase. Smith''s two-plasmid system eventually allowed him to obtain crystals of the HhaII endonuclease with a heptanucleotide DNA duplex (4).Smith served on the faculty at Johns Hopkins for 30 years before retiring as American Cancer Society Distinguished Research Professor Emeritus of Molecular Biology and Genetics in 1998. In 1993, he accepted an appointment to the scientific advisory council of The Institute for Genomic Research, which led to his collaboration with J. Craig Venter in the sequencing of H. influenzae by whole genome shotgun sequencing and assembly. Five years later, Smith joined Celera Genomics, where he was senior director of DNA Resources and aided in the sequencing of the Drosophila and human genomes. In 2005, he co-founded Synthetic Genomics, an off-shoot of Celera. He also serves as scientific director of the Synthetic Biology & Biological Energy Groups at the J. Craig Venter Institute. In addition to the Nobel Prize, Smith has received several honors including election to the National Academy of Sciences in 1980.¹     

Impact of physician continuity on death or urgent readmission after discharge among patients with heart failure

Background:

Early physician follow-up after discharge is associated with lower rates of death and readmission among patients with heart failure. We explored whether physician continuity further influences outcomes after discharge.

Methods:

We used data from linked administrative databases for all adults aged 20 years or more in the province of Alberta who were discharged alive from hospital between January 1999 and June 2009 with a first-time diagnosis of heart failure. We used Cox proportional hazard models with time-dependent covariates to analyze the effect of follow-up with a familiar physician within the first month after discharge on the primary outcome of death or urgent all-cause readmission over 6 months. A familiar physician was defined as one who had seen the patient at least twice in the year before the index admission or once during the index admission.

Results:

In the first month after discharge, 5336 (21.9%) of the 24 373 identified patients had no follow-up visits, 16 855 (69.2%) saw a familiar physician, and 2182 (9.0%) saw unfamiliar physician(s) exclusively. The risk of death or unplanned readmission during the 6-month observation period was lower among patients who saw a familiar physician (43.6%; adjusted hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.83–0.91) or an unfamiliar physician (43.6%; adjusted HR 0.90, 95% CI 0.83–0.97) for early follow-up visits, as compared with patients who had no follow-up visits (62.9%). Taking into account all follow-up visits over the 6-month period, we found that the risk of death or urgent readmission was lower among patients who had all of their visits with a familiar physician than among those followed by unfamiliar physicians (adjusted HR 0.91, 95% CI 0.85–0.98).

Interpretation:

Early physician follow-up after discharge and physician continuity were both associated with better outcomes among patients with heart failure. Research is needed to explore whether physician continuity is important for other conditions and in settings other than recent hospital discharge.Hospital care accounts for almost one-third of health care spending, and unplanned readmissions within 30 days after discharge cost more than $20 billion each year in the United States and Canada.¹ Heart failure is one of the most common reasons for admission to hospital and is associated with a high risk of readmission.¹ Although the prognosis for patients with heart failure has improved over the past decade, the risk of early death or readmission after discharge is still high and is increasing.² Prompt follow-up of patients with heart failure has been associated with lower rates of death and readmission,^3,4 and 30-day follow-up has been included as a quality-of-care indicator in Canada.⁵It is unclear, however, whether the postdischarge visits should be with the physician who previously saw the patient or with any physician. Results of studies exploring the association between provider continuity and postdischarge outcomes have been inconclusive and the studies have included few patients with heart failure.^6–9 Intuitively, one might consider physician continuity important for patients with heart failure discharged from hospital, given their age, high comorbidity burdens and complex treatment regimens. However, a robust evidence base and multiple guidelines with consistent messaging on key management principles have made physician continuity potentially less important.We designed this study to determine whether physician continuity influenced postdischarge outcomes among patients with heart failure beyond the influence of early physician follow-up.     

Factors associated with physician follow-up among patients with chest pain discharged from the emergency department

Background:

Many patients with chest pain do not receive follow-up from a physician after discharge from the emergency department despite significant survival benefit associated with follow-up care. Our objective was to evaluate factors associated with physician follow-up to understand this gap in practice.

Methods:

We conducted an observational study involving patients at high risk who were assessed for chest pain and discharged from an emergency department in Ontario between April 2004 and March 2010. We used multivariable logistic regression to determine the association of clinical and nonclinical characteristics with physician follow-up.

Results:

We identified 56 767 patients, of whom 25.1% did not receive any follow-up by a physician, 69.0% were seen by their primary care physician, and 17.3% were seen by a cardiologist within 30 days. Patients who had medical comorbidities and cardiac conditions such as myocardial infarction or heart failure were less likely to have follow-up. In contrast, a previous visit to a primary care physician was associated with the highest odds of having physician follow-up (odds ratio [OR] 6.44, 95% confidence interval [CI] 5.91–7.01). Similarly, a previous visit to a cardiologist was strongly associated with follow-up by a cardiologist (OR 3.01, 95% CI 2.85–3.17). Patients evaluated in emergency departments with the highest tertile of chest pain volume were more likely to receive follow-up from any physician (OR 1.52, 95% CI 1.31–1.77) and from a cardiologist (OR 2.04, 95% CI 1.61–2.57).

Interpretation:

Nonclinical factors are strongly associated with physician follow-up for patients with chest pain after discharge from the emergency department. However, patients with comorbidities and at higher risk for future adverse events are less likely to receive follow-up care.Chest pain is one of the most common presenting symptoms in emergency departments. In Canada, about 500 000 visits to the emergency department are related to chest pain assessment each year.¹ Most of these visits result in discharge after excluding a cardiac diagnosis with an immediate risk of adverse effect.² Current clinical guidelines strongly advocate for patients with chest pain who have been discharged from the emergency department to receive outpatient follow-up with a physician within 72 hours for further assessment or treatment, because many patients remain at risk for future events.³Among patients at high baseline cardiovascular risk who were discharged from the emergency department after assessment of chest pain, our group has previously shown significantly reduced hazard of death or myocardial infarction associated with follow-up with either a primary care physician or a cardiologist within 30 days.² At 1-year postassessment, the rate of death or myocardial infarction was 5.5% among patients who received cardiologist follow-up, 7.7% with primary care follow-up and 8.6% with no physician follow-up.² In addition, we found a considerable gap in practice, with 1 in 4 high-risk patients with chest pain failing to follow-up with a physician within 30 days of assessment in Ontario, Canada.² A better understanding of why physician follow-up does not occur in accordance with guidelines is essential to improve the transition of care from the emergency department to home. Thus, the main objective of our study was to evaluate clinical and nonclinical factors associated with physician follow-up among patients with chest pain after discharge from the emergency department.     

From Chattel to Consenter: Adolescents and Informed Consent: 2009 Grover Powers Lecture

Angela Holder was to give the Grover Powers Memorial Lecture at the weekly Grand Rounds conducted by the Yale Department of Pediatrics on Wednesday, May 27, 2009, but unfortunately, she died one month earlier, on April 22, leaving behind her prepared address, “From Chattel to Consenter: Adolescents and Informed Consent,” which she had regarded as the pinnacle of a remarkable career, much of it spent at Yale. As the Grover Powers honoree, the department’s highest honor, Ms. Holder was only the fourth woman of 46 recipients and the first who was not a physician. On the date scheduled for her address, tributes were presented by her son, John Holder, and her longtime colleague, Dr. Robert Levine, co-founder of Yale’s Interdisciplinary Bioethics Center. Their comments follow Angela Holder’s completed but undelivered Grover Powers address. — Myron Genel, MD, Professor Emeritus of PediatricsUnder the common law of England and in the early years of the United States, a minor (defined as anyone under 21) was a chattel or possession of his or her father [1-4]. A father had the right to sue a physician who treated his son or daughter perfectly properly but without the father’s permission because such an intervention contravened the father’s right to control the child. Beginning in the early years of the 20th century, by the end of World War II and into the 1950s, the notion that a 16-year-old was a legally different entity from a 6-year-old gradually became law in all states.¹ The first hospital unit for adolescents was created in 1951 at Boston Children’s Hospital, and the concept of “adolescent medicine” was born [5].As the law in this area currently defines “adolescent,” we are discussing someone 14 or older who may be (1) living at home with his or her parents; (2) Not living at home but still dependent on parents (i.e., a 16-year-old college freshman living in a dorm); (3) an “emancipated minor” who is married, emancipated by a court order, or a parent (other than in North Carolina), living away from home and self-supporting; or (4) a runaway or throwaway. At any time in this country, there are about 200,000 adolescents living on the streets with no adult supervision or involvement [6].Regardless of the age of the patient, informed consent consists of five elements: (1) An explanation of what will happen; (2) explanation of the risks; (3) explanation of the projected benefits; (4) alternatives (including doing nothing); and (5) why the physician thinks it should be done, which I interpret as a right to know one’s diagnosis. While the doctrine of “therapeutic privilege” means that in rare cases a physician may withhold some information from an adult patient if she or he believes the patient cannot “deal with the information,” there can never be any withholding of information from an adolescent. If the patient can’t deal with the information to be presented, then parents have to be involved and give permission to treat the adolescent.In some cases, when parents are involved, they do not want their adolescent to know his or her diagnosis. While this is usually not a good idea, it normally falls under the rubric of “professional judgment,” and the physician has every right to decide to follow the parents’ instruction if she agrees with it. In some situations, however, the adolescent must be told what his or her illness is, whether parents like it or not. For example, if a teenager is HIV positive, he or she must be told, must be instructed about safe sex, and must be asked to divulge the names of any sex partners. Parents who say, “Oh, no, don’t tell him, he would never do anything like that, so it doesn’t matter,” should be tactfully but firmly led to accept the fact that he may well have and if he hasn’t yet, he will certainly in the future. There has been at least one successful malpractice case in which the physician did not, at the request of the parents, tell his adolescent patient that he had HIV. The patient’s girlfriend caught it and sued the physician [7]. I feel sure there are many more cases like this that have been quietly settled and no one will ever hear about.Usually, questions about adolescents giving consent to treatments that their parents don’t know about involve outpatient treatment. In the first place, hospital administrators, who are much more interested in getting paid than they are in advancing the rights of autonomous adolescents, are not going to admit for a non-emergency problem a minor whose parent has not made some sort of financial arrangement to pay for it. Secondly, in most households, if Little Herman doesn’t show up for supper or throughout the evening, someone notices and a few telephone calls later discovers that Little Herman is in the hospital.     

Announcing the call for the Issue Focus on the 2nd Costa Rican Biophysics Symposium—virtual meeting,March 2021

This Commentary is a call for submissions for the upcoming Issue Focus that will highlight some of the scientific topics discussed during the 2^nd Costa Rica Biophysics Symposium.

The Second Costa Rican Biophysics Symposium¹ was organized on March 11^th and March 12^th of 2021. The first edition of this symposium was organized in 2019 at the National Academy of Sciences in Costa Rica (Solís et al. 2020). Due to the success of this event, the organizers decided to pursue a second edition of this scientific meeting. However, the global emergency of COVID-19 forced to keep social distancing as part of the sanitary measures and therefore, the second edition was held virtually. Nevertheless, the event was a great success as measured by the number of registrations near to 130, the quality of the presentations of the 15 speakers from 5 different countries (Costa Rica, Switzerland, USA, France, and Germany), and the level of participation during the Q & A sessions of each talk. As the highlight of the symposium, we had the pleasure to host Dr. Francisco Bezanilla as the keynote speaker and who highlighted some of his recent work on non-canonical mechanisms of voltage sensor domain coupling to pore domains in voltage-gated potassium channels (Carvalho-de-Souza and Bezanilla 2019).In commemoration of the 2^nd Costa Rica Biophysics Symposium, Biophysical Reviews will publish an Issue Focus in 2022 highlighting some of the scientific topics discussed during the event. Review articles from speakers and attendees who were part of the event are solicited. The format for the review articles is similar to those submitted for the special issue of the 20^th International Congress of the International Union of Pure and Applied Biophysics (IUPAB) (Itri et al. 2021). The Special Issue for the 20^th IUPAB International Congress will be prepared and edited by the current authors (Christopher Solís, Gustavo Chaves, and José Ángel Rodriguez-Corrales).     

Rehabilitation in the Philippines

The international community has perspective and experience that will freshen our approaches to rehabilitation. Martin Grabois, MD^*, editor of this special section, has gathered articles written by experts from other countries. The intention is to stimulate thought, discussion, and action—and to broaden horizons.     

Umashtanchaeviella plethotricha,a new genus and species of the family Tetracondylidae (Acari,Oribatida)

A new genus of oribatid mites of the family Tetracondylidae, Umashtanchaeviella gen. n., with type species Umashtanchaeviella plethotricha sp. n., is proposed and described from forest litter, the Bu Gia Map National Park, southern Vietnam. The new genus is distinguishable from other otocepheoid genera by the presence of notogastral plethotrichy.¹     

Ecological networks: delving into the architecture of biodiversity

In recent years, the analysis of interaction networks has grown popular as a framework to explore ecological processes and the relationships between community structure and its functioning. The field has rapidly grown from its infancy to a vibrant youth, as reflected in the variety and quality of the discussions held at the first international symposium on Ecological Networks in Coimbra—Portugal (23–25 October 2013). The meeting gathered 170 scientists from 22 countries, who presented data from a broad geographical range, and covering all stages of network analyses, from sampling strategies to effective ways of communicating results, presenting new analytical tools, incorporation of temporal and spatial dynamics, new applications and visualization tools.¹ During the meeting it became evident that while many of the caveats diagnosed in early network studies are successfully being tackled, new challenges arise, attesting to the health of the discipline.     

Yasutomi Nishizuka's Discovery of Protein Kinase C

Studies on a Cyclic Nucleotide-independent Protein Kinase and Its Proenzyme in Mammalian Tissues. I. Purification and Characterization of an Active Enzyme from Bovine Cerebellum (Takai, Y., Kishimoto, A., Inoue, M., and Nishizuka, Y. (1977) J. Biol. Chem. 252, 7603–7609)Direct Activation of Calcium-activated, Phospholipid-dependent Protein Kinase by Tumor-promoting Phorbol Esters (Castagna, M., Takai, Y., Kaibuchi, K., Sano, K., Kikkawa, U., and Nishizuka, Y. (1982) J. Biol. Chem. 257, 7847–7851)Yasutomi Nishizuka (1932–2004) was born in Ashiya-city, Japan. He attended Kyoto University and obtained his M.D. in 1957 and his Ph.D. in 1962, working with Journal of Biological Chemistry (JBC) Classic author Osamu Hayaishi (1). He then spent a year as a postdoctoral fellow at Rockefeller University with Fritz Lipmann (also featured in a JBC Classic (2)) before returning to Kyoto University to resume work with Hayaishi. During this time, Nishizuka studied the biosynthesis of nicotinamide adenine dinucleotide (NAD), the involvement of GTP in ribosomal protein translation, and ADP-ribosylation by diphtheria toxin.Open in a separate windowYasutomi NishizukaIn 1969, Nishizuka accepted the position of full professor and head of the department of biochemistry at the Kobe University School of Medicine. There, Nishizuka became interested in the role of protein kinases in the regulation of cell functions. This led to his discovery of a novel protein kinase, which he published in the first paper reprinted here as the JBC Classic. As Nishizuka reported in that paper, he and his colleagues partially purified the kinase from bovine cerebellum. They found that the enzyme was capable of phosphorylating histone and protamine and that it probably was produced from its precursor protein by a limited proteolytic reaction. The detailed properties of the proenzyme and its conversion to active protein kinase were reported in a subsequent JBC paper (3). Nishizuka named this new enzyme “protein kinase C (PKC).”A paper published by Nishizuka two years later in the JBC (4) showed that PKC was activated without limited proteolysis by a membrane-associated factor in the presence of a low concentration of Ca²⁺. In 1980, he published another paper in the JBC (5) showing that the membrane-associated factor was diacylglycerol, which suggested that the lipid could be a novel second messenger generated by receptor-stimulated phosphoinositide hydrolysis. Nishizuka validated this idea by showing that treating platelets with a combination of a Ca²⁺ ionophore and membrane-permeant short chain diacylglycerol mimicked stimulation by the aggregating agent thrombin (6). This discovery was a major advance in the understanding of cell signaling.Nishizuka and his colleagues then discovered that PKC is the biological target of tumor-promoting phorbol esters. At that time, it was well known that croton oil augmented carcinogenesis when it was applied at weekly intervals to the skin of mice in conjunction with a very dilute solution of benz[a]pyrene in acetone. The oil contained phorbol ester, a powerful tumor promoter, and caused a wide variety of cellular responses that were similar to those seen with hormones. Nishizuka speculated that the phorbol ester was producing diacylglycerol to activate PKC. However, upon further investigation, he realized that the phorbol ester contained a diacylglycerol-like structure and thus might activate PKC directly. In a series of experiments, published in the second JBC Classic reprinted here, Nishizuka was able to show that the phorbol ester activated PKC directly. This discovery showed that PKC was important for cell proliferation and cancer. It also established the use of phorbol esters as crucial tools for the manipulation of PKC activation in intact cells, eventually allowing the elucidation of the wide range of cellular processes regulated by this enzyme.This research laid the foundation for an enormous number of studies on the complex PKC family, many of them from Nishizuka''s group.In 1975, Nishizuka became president of the University of Kobe, a position that he held until 2001. He received numerous awards and honors for his research, including the Gairdner Foundation International Award (1988), the Alfred P. Sloan Jr. Prize (1988), the Japan Order of Culture (1988), the Albert Lasker Basic Medical Research Award (1989), the Kyoto Prize (1992), the Wolf Prize in Medicine (1995), the Jimenez Diaz Award (1995), and the Schering Prize (1995). He also served as a foreign member and honorary fellow of various academies, including the National Academies of Science, the Royal Society, l''Academie des Sciences, die Deutsche Akademie der Naturforscher Leopoldina, le Real Academia de Ciencias, the Asiatic Society, and the Japan Academy.¹     

Gender-based differences in physician payments within the fee-for-service system in Ontario: a retrospective,cross-sectional study

Background:Differences in physician income by gender have been described in numerous jurisdictions, but few studies have looked at a Canadian cohort with adjustment for confounders. In this study, we aimed to understand differences in fee-for-service payments to men and women physicians in Ontario.Methods:We conducted a cross-sectional analysis of all Ontario physicians who submitted claims to the Ontario Health Insurance Plan (OHIP) in 2017. For each physician, we gathered demographic information from the College of Physicians and Surgeons of Ontario registry. We compared differences in physician claims between men and women in the entire cohort and within each specialty using multivariable linear regressions, controlling for length of practice, specialty and practice location.Results:We identified a cohort of 30 167 physicians who submitted claims to OHIP in 2017, including 17 992 men and 12 175 women. When controlling for confounding variables in a linear mixed-effects regression model, annual physician claims were $93 930 (95% confidence interval $88 434 to $99 431) higher for men than for women. Women claimed 74% as much as men when adjusting for covariates. This discrepancy was present in nearly all specialty categories. Men claimed more than women throughout their careers, with the greatest gap 10–15 years into practice.Interpretation:We found a gender gap in fee-for-service claims in Ontario, with women claiming less than men overall and in nearly every specialty. Further work is required to understand the root causes of the gender pay gap.

A gender pay gap in physician incomes has been described across numerous jurisdictions.¹ Previous analyses have found income differences between women and men in the general physician population, among academic physicians and among physicians within the same specialty, ^2–8 and when controlling for years of experience, hours worked, geographic location, race and practice type.^9–13Although the difference in physician income between women and men is well described in the United States, fewer studies have looked at a Canadian cohort. An analysis of surgeons in Ontario found that female surgeons earned less per hour spent operating than male surgeons, and suggested that female physicians were more likely to perform less lucrative procedures than male physicians.¹⁴ A recent report released by the Ontario Medical Association highlighted income disparity between men and women physicians in Ontario, but did not provide a detailed breakdown by specialty.¹⁵ Transparent and detailed reporting on gender differences in physician payments can provide data to guide advocacy for greater pay equity.In this study, we aimed to describe payments to physicians across the province of Ontario by gender when controlling for specialty choice, career stage and physician demographics.     

The 2009 Lindau Nobel Laureate Meeting: Werner Arber,Physiology or Medicine 1978

Swiss microbial geneticist, Werner Arber shared the 1978 Nobel Prize in Physiology or Medicine with Hamilton Smith and Daniel Nathans for their discovery of restriction endonucleases.Werner Arber was born in Granichen, Switzerland in 1929. Following a public school education, he entered the Swiss Polytechnical School in Zurich in 1949, working toward a diploma in natural sciences. There, his first research experience involved isolating and characterizing an isomer of chlorine. Following graduation in 1953, Arber joined a graduate program at the University of Geneva, taking on an assistanceship in electron microscopy (EM), in which he studied gene transfer in the bacterial virus (bacteriophage) lambda. Eventually encountering limitations with EM as a tool, he began using microbial genetics as a methodology for his studies. The study of microbial genetics had been possible for a relatively short time: DNA had been discovered to carry genetic information only a decade before he d entered the field.After earning his Ph.D. in 1958, Arber continued to develop skills in microbial genetics, working with colleagues in the United States for a short time before returning to Geneva at beginning of 1960. There, he continued working on lambda transduction in E. coli, but found that the virus would not efficiently propagate. Recalling research done seven years earlier by Joe Bertani and Jean Weigle on "host-controlled restriction-modification", he realized there must be a host-controlled modification of the invading DNA, and sought to identify the mechanism. Based on Grete Kallengerger s work that demonstrated degradation of both irradiated and non-irradiated phage lambda following injection in a host, Arber and his graduate student, Daisy Dussoix further investigated the fate of DNA, and found that restriction and modification (later determined to be postreplicative nuclotide methylation) directly affected DNA, but did not cause mutations. They also found that theses were properties of the bacterial strains, and that both viral and cellular DNA were degraded. Together, Arber and Dussoix reported their findings to scientific community in 1961 at the First International Biophysics Congress in Stockholm. Aber also presented the research to the Science Faculty of University of Geneva in 1962, earning the Plantamour-Prevost prize. Based on his work and the work of others, he hypothesized that an enzyme in the host bacterium cut DNA into smaller pieces at specific sites, and methylase modified the host DNA to protect it from the digestive enzyme. These theories were later confirmed by Urs Kuhnlein, who found that mutation of specific sites rendered the phage resistant to cleavage; Hamilton smith, who identified Type II endonuclease HindII; and Daniel Nathans, who used HindII to break the SV40 virus into 11 fragments, allowing him to determine its method of replication.Since the discovery of restriction endonucleases, researchers have used them as tools to study the functions of genes of all types of organisms. Restriction enzymes have also facilitated the study of gene functions and enabled production of substances of medical and nutritional importance. Arber feels that in the next few decades we will learn much from the study of epigentics --factors that can affect the phenotype of an organism without changing the genetic information--. He is proud that, in that studying restriction degradation and DNA methylation in the 1960s, he was among the first in studying epigenetic phenomenon.Download video file.^{(118M, mp4)}     

Synthesis and Properties of Modified Oligodeoxyribonucleotides Containing 9-(2-Amino-2-deoxy-β-D-arabinofuranosyl)adenine

Abstract

The synthesis of modified oligodeoxyribonucleotides# This publication is dedicated to Professor Tsujiaki Hata, who made a valuable contribution to the chemistry of nucleosides and nucleotides. containing 2′-amino-2′-deoxyarabinoadenosine residues (aAⁿ) was carried out by means of the standard phosphoramidite chemistry. A high reactivity of such compounds to electrophilic reagents was shown. The cross-link formation between 2′-amino group of aAⁿ and carboxyl function introduced into complementary strands occurs with 55% yield. The aAⁿ residues was shown to induce the increased resistance of modified oligomers towards the enzymatic cleavage and provide the insignificant destabilization of DNA duplexes.

     

Factors predicting patient use of the emergency department: a retrospective cohort study

Background:

Many studies have shown the tendency for people without a regular care provider or primary physician to make greater use of emergency departments. We sought to determine the effects of three aspects of care provided by primary physicians (physician specialty, continuity of care and comprehensiveness of care) on their patients’ use of the emergency department.

Methods:

Using provincial administrative databases, we created a cohort of 367 315 adults aged 18 years and older. Participants were residents of urban areas of Quebec. Affiliation with a primary physician, the specialty of this physician (i.e., family physician v. specialist), continuity of care (as measured using the Usual Provider Continuity index) and comprehensiveness of care (i.e., number of complete annual examinations) were measured among participants (n = 311 701) who had visited a physician three or more times during a two-year baseline period. We used multivariable negative binomial regression to investigate the relationships between measures of care and the number of visits to emergency departments during a 12-month follow-up period.

Results:

Among participants under 65 years of age, emergency department use was higher for those not affiliated than for those affiliated with a family physician (incidence rate ratio [IRR] 1.11, 95% confidence interval [CI] 1.05–1.16) or a specialist (IRR 1.10, 95% CI 1.04–1.17). Among patients aged 65 years and older, having a specialist primary physician, as opposed to a family physician, predicted increased use of the emergency department (IRR 1.13, 95% CI 1.09–1.17). Greater continuity of care with a family physician predicted less use of the emergency department only among participants who made 25 or more visits to a physician during the baseline period. Greater continuity of care with a specialist predicted less use of the emergency department overall, particularly among participants with intermediate numbers of multimorbidities and admissions to hospital. Greater comprehensiveness of care by family physicians predicted less use of the emergency department.

Interpretation:

Efforts to increase the proportion of adults affiliated with a family physician should target older adults, people who visit physicians more frequently and people with multiple comorbidities and admissions to hospital.Reforming primary care in Canada has been stimulated in part by increased crowding of emergency departments and evidence that their use, particularly for nonurgent care, may be related to inadequate primary care in the community.^1,2 Restructuring efforts, such as encouraging family physicians to work in multidisciplinary group practices with 24-hour access, are challenged by a relative shortage of family physicians.³ These issues are of particular importance in Quebec; despite relatively high numbers of family physicians per capita, in comparison with other provinces, residents of Quebec have the lowest rates of affiliation with a family physician and have one of the highest rates of seeing specialists.^4,5 In addition, residents of Quebec have among the highest rates of visits to emergency departments in international comparative studies.^6–8Research is needed into the effect that affiliation with a specialist rather than a family physician has on patients’ use of the emergency department, as is research into the continuity and comprehensiveness of care provided by the primary physician, regardless of specialty.Many studies have shown the tendency for people without a regular care provider to use the emergency department more often than people who have a primary physician.^1,9,10 Greater continuity of care with a primary physician has also been associated with fewer visits to the emergency department, but much of this research is cross-sectional, making causal interpretation difficult.¹¹ Furthermore, the distinction between continuity with a family physician versus a specialist primary physician has not been made, although one American study reported that having a specialist primary physician was associated with increased use of emergency departments.⁹We sought to determine whether certain factors predicted patients’ subsequent use of emergency departments, such as the specialty of their primary physician, the continuity of care with that physician and the comprehensiveness of care provided by that physician. To determine whether certain subgroups of the population may derive greater benefit from a particular type of care, we examined the potentially modifying effects of demographic factors, health status and previous use of health services. We restricted our study to residents of urban areas of Quebec for three reasons: rural residents visit the emergency department for primary care more often than residents of urban areas;¹² most specialist care is provided in urban areas; and primary care services in rural areas are more likely to be provided by salaried physicians, whose information is not available in the billing database.     

The process of reversible phosphorylation: the work of Edmond H. Fischer

Edmond H. Fischer was awarded the 1992 Nobel Prize in Physiology or Medicine for his joint research with Edwin G. Krebs on reversible protein phosphorylation. The two Classics reprinted here relate some of Fischer and Krebs'' early discoveries in their phosphorylase researchPhosphorylase Activity of Skeletal Muscle Extracts (Krebs, E. G., and Fischer, E. H. (1955) J. Biol. Chem. 216, 113–120)Conversion of Phosphorylase b to Phosphorylase a in Muscle Extracts (Fischer, E. H., and Krebs, E. G. (1955) J. Biol. Chem. 216, 121–132)Edmond H. Fischer was born in Shanghai, China in 1920. He was sent to boarding school in Switzerland at age 7, and in 1935, he entered Geneva''s Collège de Calvin. There, he became friends with his classmate Wilfried Haudenschild, and together, they decided that one of them should go into the sciences and the other into medicine so they could cure the world of all ills. Fischer chose science.Open in a separate windowEdmond H. FischerJust before the start of World War II, Fischer completed high school and entered the School of Chemistry at the University of Geneva. He earned two Licences ès Sciences, one in biology, the other in chemistry, and 2 years later, he was awarded a Diploma of “Ingénieur Chimiste.” For his thesis, he worked with Kurt H. Meyer on the purification of amylase from hog and human pancreas, as well as saliva and several strains of bacteria.In 1950, Fischer went to the United States to do a postdoctoral fellowship with Paul Karrer at CalTech. However, when he arrived in Pasadena he received a letter from Journal of Biological Chemistry (JBC) Classic author Hans Neurath (1), chairman of the department of biochemistry at the University of Washington, offering him an assistant professorship in his department. Fischer visited Seattle and accepted the offer, in part because the surrounding mountains, forests, and lakes reminded him of his native Switzerland.Within 6 months of his arrival, Fischer started working on glycogen phosphorylase with Edwin G. Krebs, who was featured in a previous JBC Classic (2). Krebs had trained with JBC Classic authors Carl and Gerty Cori who had discovered that muscle phosphorylase exists in two forms, phosphorylase a, which was easily crystallized and was active without the addition of AMP, and phosphorylase b, a more soluble protein, which was inactive without AMP (3). They believed that AMP served some kind of co-factor function for the enzyme, facilitating its transition between the two forms.However, in Geneva, Fischer had purified potato phosphorylase, which had no AMP requirement. Because it seemed unlikely that muscle phosphorylase but not potato phosphorylase would require AMP as a co-factor, Fischer and Krebs decided to try to elucidate the role of AMP in the phosphorylase reaction. They never discovered what the nucleotide was doing (this problem was solved several years later when Jacques Monod proposed his allosteric model for the regulation of enzymes), but they did discover that muscle phosphorylase was regulated by an enzyme-catalyzed phosphorylation-dephosphorylation reaction.The two JBC Classics reprinted here relate some of Fischer and Krebs'' early discoveries in their phosphorylase research. In the first Classic, the pair performed experiments to determine whether environmental temperature affects the phosphorylase content of skeletal muscle. They were unable to detect any temperature effects, but they did make the surprising discovery that the muscle extracts contained mainly phosphorylase b rather than phosphorylase a. The pair concluded that “If resting muscle contains mainly phosphorylase b… then pronounced activation of the phosphorylase reaction under various conditions is possible.”The second JBC Classic was printed back-to-back with the first. In it, Krebs and Fischer examine the requirements for the phosphorylase conversion and present evidence that the conversion of phosphorylase b to a in cell-free muscle extracts requires a nucleotide containing high energy phosphate and a divalent metal ion. However, they state that “whether this implies that during conversion there is a direct phosphorylation of the enzyme or the formation of an ‘active’ intermediate cannot be stated at this time. It is also possible that the function of ATP is concerned with the synthesis of a prosthetic group.”Similar work was being carried out on liver phosphorylase at approximately the same time by Earl Sutherland. As discussed in a previous JBC Classic (4), Sutherland discovered the second messenger cyclic AMP (cAMP), which he showed promoted the phosphorylation and activation of phosphorylase. The way in which cAMP promoted phosphorylase activation was eventually elucidated when Krebs and Fischer discovered phosphorylase kinase, which was responsible for phosphorylating phosphorylase. Phosphorylase kinase itself existed in a highly activated phosphorylated form and a less active nonphosphorylated form.As a result of the significance of their studies, Krebs and Fischer were awarded the 1992 Nobel Prize in Physiology or Medicine “for their discoveries concerning reversible protein phosphorylation as a biological regulatory mechanism.”In addition to the Nobel Prize, Fischer has received many awards and honors in recognition of his contributions to science. These include the Werner Medal from the Swiss Chemical Society, the Lederle Medical Faculty Award, the Prix Jaubert from the University of Geneva, and jointly with Krebs, the Senior Passano Award and the Steven C. Beering Award from Indiana University. Fischer was elected to the American Academy of Arts and Sciences in 1972 and to the National Academy of Sciences in 1973.¹