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.     

The transformative promise of aging science

Adapted from a whitepaper written for the Healthspan Campaign, sponsored by the Alliance for Aging Research.The economic peril posed by burgeoning federal debt has inspired fierce political wrangling in recent years. But the elephant in the room when the issue comes up is apolitical: the graying of baby boomers will relentlessly increase federal entitlement costs in coming years, especially those for healthcare, threatening ever larger budget deficits and federal debt. Indeed, annual deficits, largely due to healthcare spending, have put us on a path of unsustainable debt growth that could lead to “financial Armageddon,” according a recent analysis.¹While the population’s rising median age is a key driver of healthcare costs, the way we buy time during our later years is arguably as important as aging itself. We’re living in an era of minor miracles with major costs, such as $10,000-per-dose cancer drugs that extend average survival by a few months. Barring drastic healthcare rationing, the use of such palliatives will continue to grow in tandem with the elderly population.But a much more efficient alternative is on the horizon: leaders in gerontology have concluded that anti-aging drugs capable of delaying all diseases of aging by about seven years are now technically feasible.² Such drugs would be very broadly effective preventive medicines, staving off dementia, cancer, heart failure, frailty—and a myriad other old-age ills—in much the same way that drugs that lower blood pressure help postpone or avert heart disease.Unlike palliatives applied late in the course of diseases, the envisioned drugs would increase life expectancy by expanding the period of good health before the onset of disabling illness.³ A 2005 RAND Corp. study of the economic implications of 10 future medical advances that may benefit the elderly concluded that such anti-aging medicines would be by far the most cost-effective means of adding healthy life years among the analyzed technologies.⁴Interventions that slow aging in mammals have been known since the 1930s, when very low-calorie diets were found to extend rats’ lifespans. In 2009, researchers showed that rapamycin, a drug used to prevent rejection of transplanted organs, significantly extended lifespan in mice in a way reminiscent of calorie restriction.⁵ Intriguingly, this effect was observed in mice first put on the drug late in life, at 20 months of age, roughly equivalent to 60 years in humans; the life expectancy of the aged male rodents after initiation of the drug rose by 28% compared with controls, and that of the aged females by 38%. Many forms of age-dependent change occur more slowly in rapamycin-treated mice than in controls, suggesting that the drug has an authentic anti-aging effect.⁶Mutations, diets and drugs that slow aging in animals delay late-life morbidity, effectively increasing healthspan along with lifespan—they don’t extend the period of late-life decline, as feared by skeptics unfamiliar with the gerontology literature. For instance, mutations that delay aging in mice make them resistant to multiple diseases of aging, and the animals retain cognitive function later in life than do normal mice.⁷ A sizable fraction of human centenarians, who likely possess genetic loci that effectively slow aging, remain in remarkably good health nearly all their lives.⁸ The world’s longest-lived human population, natives of Japan’s Okinawa prefecture, suffer about 40% fewer hip fractures than U.S. peers.⁹ Remarkably, they also experience only half the rate of dementia, between 85 and 90, than their American peers do.¹⁰Increasing healthy life years with anti-aging drugs would slow projected increases in medical spending and deliver large, ongoing benefits across many sectors of the economy, helping to offset the costs of population aging, reduce future budget deficits and contain the federal debt. Healthier, longer-living people can stay in the workforce longer, preserving human capital that might otherwise be lost to disability. Healthier workers are physically and mentally more robust, making them more productive and less likely to lose workdays from illness. They’re motivated to make larger personal investments in developing their skills, because they expect to reap the benefits of such investments for longer periods. They save more for retirement, boosting capital formation that fuels economic growth. They pose lighter burdens on federal entitlement programs for seniors and contribute more in federal and state tax revenues. The combined effect of such factors is thought to explain why per-capita incomes of nations around the world have long risen in tandem with their populations’ life expectancies.¹¹Unfortunately, there''s still a wide gap between research and development in gerontology. Realizing the promise of advances in aging science, for example, will likely require the identification of well-grounded biomarkers of aging to help assess purported anti-aging interventions’ efficacy in relatively short clinical trials¹²—human lifespan studies are untenable. Such research will require a major increase in funding for biogerontology studies.Basic research on aging has perennially garnered less than 1% of the NIH’s overall annual budget. Still, there have been some signs of growing support for stepping up such work. Recently, nearly 70 prominent scientists, including four Nobel laureates, endorsed a “healthspan campaign” to push for more research on aging as the common denominator of major diseases. Spearheaded by the Alliance for Aging Research, a nonprofit group in Washington, D.C., the campaign represents a significant preliminary step toward work that could pave the way for development of validated anti-aging drugs. Many more steps will be needed. But few, if any, areas for investing research dollars offer greater potential returns.     

2009 Society for Medical Anthropology Conference: Training,Communication, and Competence: The Making of Health Care Professionals

The role of medical anthropology in tackling the problems and challenges at the intersections of public health, medicine, and technology was addressed during the 2009 Society for Medical Anthropology Conference at Yale University in an interdisciplinary panel session entitled Training, Communication, and Competence: The Making of Health Care Professionals.The discipline of medical anthropology is not very formalized in the health setting. Although medical anthropologists work across a number of health organizations, including schools of public health, at the Centers for Disease Control (CDC), and at non-governmental organizations (NGOs), there is an emerging demand for an influential applied medical anthropology that contributes both pragmatically and theoretically to the health care field.The role of anthropology at the intersections of public health, medicine, and technology was addressed during the 2009 Society for Medical Anthropology Conference at Yale University in September. In a conference session entitled Training, Communication, and Competence: The Making of Health Care Professionals, health professional career issues, including training and education, medical entrepreneurship, and the maintenance of clinical relationships with patients were examined. The presentations encompassed macro approaches to institutional reform in training, education, and health care delivery, as well as micro studies of practitioner-patient interaction. Seemingly disparate methodological, disciplinary, and theoretical orientations were united to assess the increasing relevance of medically oriented anthropology in addressing the challenges of health care delivery, health education, and training.Margaret Bentley, a professor of public health at the University of North Carolina, Chapel Hill, spoke about the increasing “epidemic of global health” in universities, noting a doubling of global health majors within the past three years. Despite this expansion of the field, a common discipline of global health continues to be developed. In September, the Association of Schools of Public Health (ASPH) and the University of Minnesota hosted a Global Health Core Competency Development Consensus Conference with the initiative to explore “workforce needs, practice settings, and to identify core constructs, competency domains, and a preliminary global health competency model”¹. Given the current variability in training, Bentley believes medical anthropology is uniquely suited to inform training in global health because of its offerings in the way of interdisciplinary methods and team-based applied field experience.Anthropologists Carl Kendall of Tulane University and Laetitia Atlani of Université de Paris X Nanterre have seen medical anthropologists examine models of health strictly within a clinical experience. Understanding of the social determinants of epidemiology, methodological issues of population health, and survey research is crucial. However, training individuals through a more formalized program (currently in development in Europe) will allow anthropologists to better understand context, explain complex models, humanize aggregate statistics, and articulate methods of the multidimensional “social field” of health outside of the clinical experience.The social field of health, however, as Robert Like of the University of Medicine and Dentistry of New Jersey explained, shares an uncomfortable interface with clinical medicine. Recent efforts by the New Jersey Board of Examiners to incorporate cultural competency legislation have been robustly criticized. Evaluations of six-hour training sessions on cultural competency training have revealed health professionals’ frustration with the health care system’s inability to deal with “culturally different” individuals. In fact, the majority of health professionals who were required to complete the training believe cultural competency to be an area of study that is a “waste of time.”This opposition to cross-cultural education and the value of “cultural competence” training also has been a topic of great debate among anthropologists and health researchers. Despite the ubiquitous use of the term among research and health professionals, cultural competency is a term that cannot be defined precisely enough to operationalize.In “Anthropology in the Clinic: The Problem of Cultural Competency and How to Fix It,” Arthur Kleinman and Peter Benson asserted that the static notion of culture in the medical field “suggests that a culture can be reduced to a technical skill for which clinicians can be trained to develop expertise” [1]. T.S. Harvey, a linguistic and medical anthropologist at the University of California, Riverside, expounded on Kleinman’s opposition to competence as an acquired “technical skill” [1] and suggested reconceptualizing the approach to competence as communication. Although Kleinman’s explanatory models approach [2] provides a health care professional with what to ask the patient, Harvey pulls from Dell Hymes’ communicative competence [3] to understand how to ask it. Harvey recommended viewing competence as a “sociolinguistic acquisition … like a foreign language” where competencies are rule-governed and communication and speech events are formulaic.Harvey also noted that the “onus of cultural competency” is too often placed on the practitioner. Inevitably, there is an asymmetry in every clinical encounter, whereby the “would-be patient” is perpetually considered the “passive receptor.” Patients also share a stake in their health and, as such, should be taught communicative competence as well.Harvey also noted that the “onus of cultural competency” is too often placed on the practitioner. Inevitably, there is an asymmetry in every clinical encounter, whereby the “would-be patient” is perpetually considered the “passive receptor.” Patients also share a stake in their health and, as such, should be taught communicative competence as well.The role of the patient is made ever more complex by the power relationship that exists in the patient-provider context. Through ethnographic research, Sylvie Fainzang, director of research in the Inserm (Cermes), examines how doctors and patients lie. She argues that lying, in the context of secrecy, is an indication of a power relationship [4]. Fainzaing’s further research on the relationship between doctors and patients has yielded additional information on how patients learn about their diagnoses and how they will react to these diagnoses. Though a clinical encounter between a doctor and patient is expected to be one of informed consent, doctors often judge patients upon their ability to “intellectually understand” [4] and assess who is “psychologically ready” [4] to bear the information. This leads to manipulated, misinformed, and “resigned consent” [4]. This sort of social training of obligation of a subject to medical authority provides the patient with the choice either to conform or overthrow the rules as defined by society.Collectively, this interdisciplinary panel worked to inform the discussion on how medical anthropology can address training, communication, and competence at the intersections of medicine, public health, and education. By reviewing health professionals’ growing interest in public health, training in health education and competence, and the patient-provider relationship, medical anthropology can be seen as both relevant and necessary to addressing the challenges faced by the medical and health community today.     

Gain weight by “going diet?” Artificial sweeteners and the neurobiology of sugar cravings: Neuroscience 2010

America’s obesity epidemic has gathered much media attention recently. A rise in the percent of the population who are obese coincides with an increase in the widespread use of non-caloric artificial sweeteners, such as aspartame (e.g., Diet Coke) and sucralose (e.g., Pepsi One), in food products (Figure 1). Both forward and reverse causalities have been proposed [1,2]. While people often choose “diet” or “light” products to lose weight, research studies suggest that artificial sweeteners may contribute to weight gain. In this mini-review, inspired by a discussion with Dr. Dana Small at Yale’s Neuroscience 2010 conference in April, I first examine the development of artificial sweeteners in a historic context. I then summarize the epidemiological and experimental evidence concerning their effects on weight. Finally, I attempt to explain those effects in light of the neurobiology of food reward.Open in a separate windowFigure 1Time line of artificial sweetener use and obesity trends in the United States. Blue line: changes in the percentage of the population who are obese (BMI >30) from 1961 to 2006. Source: National Health and Nutrition Examination Survey [57]. Orange line: changes in the percentage of the population who are regular artificial sweetener users from 1965 to 2004. Source: National Household Survey [2]. Purple line: changes in the number of new artificial sweetener containing food products introduced to the American market from 1999 to 2004. Source: Mintel Market Analysis [14]. Bars below the time axis indicates the type and availability of artificial sweeteners in the United States over time. Source: Kroger et al [9].     

KSR Int'l Co. v. Teleflex, Inc.: no obvious changes for the biotechnology market

With the advent of molecular biology, genomics, and proteomics, the intersection between science and law has become increasingly significant. In addition to the ethical and legal concerns surrounding the collection, storage, and use of genomic data, patent disputes for new biotechnologies are quickly becoming part of mainstream business discussions. Under current patent law, new technologies cannot be patented if they are “obvious” changes to an existing patent. The definition of “obvious,” therefore, has a huge impact on determining whether a patent is granted. For example, are modifications to microarray protocols, popular in diagnostic medicine, considered “obvious” improvements of previous products? Also, inventions that are readily apparent now may not have been obvious when discovered. Polymerase chain reaction, or PCR, is now a common component of every biologist’s toolbox and seems like an obvious invention, though it clearly was not in 1983. Thus, there is also a temporal component that complicates the interpretation of an invention’s obviousness. The following article discusses how a recent Supreme Court decision has altered the definition of “obviousness” in patent disputes. By examining how the obviousness standard has changed, the article illuminates how legal definitions that seem wholly unrelated to biology or medicine could still potentially have enormous effects on these fieldsJust what is obvious or not is a question that has provoked substantial litigation in the Federal Circuit, the appellate court with special jurisdiction over patent law disputes. Under U.S. patent law, an inventor may not obtain a patent, which protects his invention from infringement by others, if the differences between the subject matter sought to be patented and the prior art are such that “the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill” in the patent’s subject matter area [1]. However, what was “obvious” at the time of invention to a person of ordinary skill is hardly clear and is, in effect, a legal fiction designed to approximate objectivity. As illustrated by Chief Justice John Roberts of the Supreme Court in a moment of levity, “Who do you get to ... tell you something’s not obvious … the least insightful person you can find?” [2] Despite the apparent objectivity provided by a “person of ordinary skill” obviousness standard, the difficulty lies in that such a standard is still susceptible to multiple interpretations, depending on the point of view and knowledge ascribed to the “ordinary person.” As such, how obviousness is defined and interpreted by the courts will have important implications on biotechnology patents and the biotechnology business.The issue of obviousness arose in April 2007 when the Supreme Court handed down its decision in KSR Int’l Co. v. Teleflex, Inc. [3] The facts of the case were anything but glamorous; in the suit, Teleflex, a manufacturer of adjustable pedal systems for automobiles, sued KSR, its rival, for infringement of its patent, which “describe[d] a mechanism for combining an electronic sensor with an adjustable automobile pedal so that the pedal’s position can be transmitted to a computer that controls the throttle in the vehicle’s engine.” [4] Teleflex believed that KSR’s new pedal design was too similar to its own patented design and therefore infringed upon it [5]. In defense, KSR argued that Teleflex’s patent was merely the obvious combination of two pre-existing elements and, thus, the patent, upon which Teleflex’s infringement claim was based, was invalid.Patent law relies on the concept of obviousness to distinguish whether new inventions are worthy of being protected by a patent. If a new invention is too obvious, it is not granted a patent and is therefore not a legally protected property interest. However, if an invention is deemed not obvious and has met the other patentability requirements, a patent will be granted, thereby conferring exclusive use of the invention to the patent holder. This exclusive right prohibits others from making, using, selling, offering to sell, or importing into the United States the patented invention [6]. Essentially, the definition of obviousness sets the balance between rewarding new inventions with exclusive property rights and respecting old inventions by not treating minor variations of existing patents as new patents. In this manner, the law seeks to provide economic incentives for the creation of new inventions by ensuring that the property right conferred by the patent will be protected against insignificant variations. The importance of where the line for obviousness is drawn and how clearly it is drawn is especially important in the biotechnology industry. Studies have shown that the development of a new pharmaceutical therapy can take up to 14 years with costs exceeding $800 million [7]. Such an enormous investment of time and money would not be practical if it did not predictably result in a legally enforceable property right.The standard for what constitutes a patentable discovery has evolved over the last 150 years. In 1851, the Supreme Court held in Hotchkiss v. Greenwood that a patentable discovery required a level of ingenuity above that possessed by an ordinary person [8]. Lower courts treated the Hotchkiss standard as a subjective standard, whereby courts sought to determine “what constitute[d] an invention” [9] and a “flash of creative genius” [10]. However, the attempts at imposing the Hotchkiss standard proved unworkable, and in 1952, Congress overrode the case law with the Patent Act, “mandat[ing] that patentability be governed by an objective nonobviousness standard.” [11] This new statutory standard moved the courts away from subjective determinations and toward a more workable, objective obviousness standard.While the Patent Act laid the foundation for the current obviousness standard, the Supreme Court in Graham v. John Deere Co. interpreted the statutory language in an attempt to provide greater clarity as to what exactly “obvious” meant [12]. The Supreme Court determined that the objective analysis would require “the scope and content of the prior art ... to be determined; differences between the prior art and the claims at issue ... to be ascertained; and the level of ordinary skill in the pertinent art resolved.” [13] In addition to analysis under this three-part framework, the Supreme Court called for several secondary considerations to be weighed, including “commercial success, long felt but unresolved needs, [and the] failure of others [to solve the problem addressed].” [13]Unsurprisingly, lower courts were unsatisfied with the Supreme Court’s attempts to clarify the obviousness standard and sought to provide “more uniformity and consistency” to their evaluation of obviousness than the Supreme Court’s jumble of factors provided [14]. In search of consistency, the Federal Circuit created the “teaching, suggestion, or motivation” test (TSM test) “under which a patent is only proved obvious if ‘some motivation or suggestion to combine prior art teachings’ can be found in the prior art, the nature of the problem, or the knowledge of a person having ordinary skill in the art.” [14] Through implementation of the TSM test, the Federal Circuit sought to maintain the flexibility envisioned by the Supreme Court in Graham, while at the same time providing more certainty and predictability to obviousness determinations.The issue before the Supreme Court in KSR Int’l Co. v. Teleflex, Inc. was whether the Federal Circuit’s elaboration on the statutory language of the Patent Act, the TSM test, was consistent with the terms of the Patent Act itself and the Supreme Court’s own analysis in Graham. The Supreme Court determined that while the TSM test was, on its terms, consistent with the framework set out in Graham, the rigid manner in which the Federal Circuit had taken to applying that standard was inconsistent with the flexible approach established by Graham [15]. More generally, it appears the Supreme Court was mainly interested in restoring a more rounded, thorough inquiry to the evaluation of obviousness: “Graham set forth a broad inquiry and invited courts, where appropriate, to look at any secondary considerations that would prove instructive.” [16] As stated by the Supreme Court, “[r]igid preventative rules that deny factfinders recourse to common sense, however, are neither necessary under our case law nor consistent with it.” [17] As such, the Supreme Court reversed the findings of the Federal Circuit, which had found the Teleflex patent valid, and remanded the case back to the lower court with directions to analyze, without rigid adherence to the TSM test, whether the Teleflex patent was obvious [18].The Supreme Court’s ruling in KSR Int’l Co. v. Teleflex, Inc. that the Federal Circuit apply its TSM test less rigidly may have implications for those seeking biotechnology patents in the future. As discussed above, the large investments necessary to develop a marketable biotechnology product demand that entrepreneurs making those investments be reasonably assured that they can predict any future legal hurdles in patenting their invention and in ultimately protecting their patent. As explained by the Biotechnology Industry Organization in its amicus curiae brief in KSR Int’l Co. v. Teleflex, Inc., “[i]nvestment thus is predicated on an expected return on investment in the form of products or services that are protected by patents whose validity can be fairly determined.” [19] Therefore, the Supreme Court’s insistence that the Federal Circuit no longer rigidly rely on the TSM test could increase uncertainty in the grant of future patents. However, the Supreme Court’s refusal to completely dismiss the TSM test, while in fact endorsing its continued use, albeit on a less rigid basis, has to be viewed as a profound victory for an industry with a significant stake in maintaining the status quo. Moreover, it is unclear how much the Supreme Court’s holding in KSR Int’l Co. v. Teleflex, Inc. will truly change the legal analysis of the lower courts, given the evidence that lower courts already were independently shifting away from rigid adherence to the TSM test before the Supreme Court’s ruling [20].More importantly, several aspects of the Supreme Court’s reasoning in KSR Int’l Co. v. Teleflex, Inc. seem to directly address relevant concerns of the biotechnology market in favorable ways. First, the Supreme Court made clear that though a product is the result of a combination of elements that were “obvious to try,” it is not necessarily “obvious” under the Patent Act. Retaining the possibility that “obvious to try” inventions still may be patentable is extremely important to the biotechnology industry in particular because “many patentable inventions in biotechnology spring from known components and methodologies found in [the] prior art.” [21] Rather than foreclosing all “obvious to try” inventions as being obvious, and therefore not patentable, the Supreme Court instead explained that where there is “a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions,” it is more likely that a person of ordinary skill would find it obvious to pursue “known options.” [22] Thus, the proper inquiry, as stated by the Supreme Court, is “whether the improvement is more than the predictable use of prior art elements according to their established functions.” [23] While this reasoning may prevent some “obvious to try” inventions from being patented, it is unlikely to have a substantial effect on inventions in the biotechnology market because “most advances in biotechnology are only won through great effort and expense, and with only a low probability of success in achieving the claimed invention at the outset.” [24] In other words, it would be hard to characterize the use of prior art in the biotechnology context as predictable based on the inherent unpredictability of obtaining favorable results. As such, most biotechnology inventions would presumably fall outside the Supreme Court’s “obvious to try” reasoning due to the very nature of the industry, meaning they would remain patentable under the Supreme Court’s KSR Int’l Co. v. Teleflex, Inc. decision.Second, the Supreme Court recognized the “distortion caused by hindsight bias” and the importance of avoiding “arguments reliant upon ex post reasoning,” though it lessened the Federal Circuit’s rigid protection against hindsight bias [24]. Hindsight bias requires that obviousness be viewed at the time the invention was made, because what may seem revolutionary at the time of invention may, upon the passage of time, seem “obvious.” Cognizance of hindsight bias is crucial for biotechnology patents because “there often is a long ‘passage of time between patent application filing and litigation with biotechnology inventions [that] can exacerbate the problem’ of hindsight bias.” [25] The problem is further exacerbated by the “significantly longer durations of commercial utility” biotechnology inventions enjoy as compared to those in other fields [25]. The more time between the filing of a patent and the subsequent litigation over its validity, the greater the risk that “reliable accounts of [the] context” in which the discovery is made will no longer exist [26]. As such, inventions that were not obvious when they were created will be inescapably colored by the passage of time and by new knowledge and discoveries; the likelihood of this occurrence is higher the further removed the litigation is from the patent filing date. Once again, however, it seems clear that despite the Supreme Court’s abandonment of the TSM test’s rigidity, strong protections against hindsight bias still were emphasized in the Supreme Court’s KSR Int’l Co. v. Teleflex, Inc. decision. In fact, lower courts applying KSR Int’l Co. v. Teleflex, Inc. acknowledge they are “cautious” to avoid “using hindsight” in biotechnology obviousness determinations [27].Finally, the Supreme Court seems to believe that the imposition of a more flexible approach will be more likely to benefit markets not directly at issue in KSR Int’l Co. v. Teleflex, Inc. The Supreme Court asserted, “[t]he diversity of inventive pursuits and of modern technology counsels against limiting the analysis” to the rigid TSM test of the Federal Circuit [28]. This language suggests that the Supreme Court expects lower courts to take into consideration the special considerations facing unique markets, such as the biotechnology market. As such, the specific concerns of the biotechnology market discussed above may receive more attention under the flexible framework asserted by the Supreme Court in KSR Int’l Co. v. Teleflex, Inc.Leading up to the oral argument in KSR Int’l Co. v. Teleflex, Inc., there was widespread speculation that the case could result in a watershed moment, significantly altering the definition of obviousness in patent law. For many, including those in the biotechnology industry, there was ample reason to be concerned. Any change in the definition of obviousness would effectively shift property rights from new patent holders to old, or vice versa. However, the Supreme Court acted with restraint. While the decision purports to make substantial changes by doing away with the Federal Circuit’s TSM test, the opinion seems more like a mild-mannered rebuke of lower courts that had become too complacent in the implementation of their beloved test. If anything, the Supreme Court’s insistence on a more flexible formula is simply a call for lower courts to employ common sense, in addition to considering the factors from Graham and the TSM test. Accordingly, the Supreme Court’s opinion in KSR Int’l Co. v. Teleflex, Inc. is unlikely to have a pronounced effect on the biotechnology market, despite the widespread concern generated before the actual decision was handed down.     

2009 Society for Medical Anthropology Conference: The Intersection of Anthropology and Medicine as Portrayed in Paul Farmer’s Photo Album

Paul Farmer, physician, anthropologist, and author, spoke at the 2009 Society for Medical Anthropology Conference at Yale University in September.Medical anthropology is a very young field, only approximately 50 years old. The underpinnings of medical anthropology have been around for some time, but as a discipline, the burden to ensure that it continues to flourish and grow belongs to future generations of students and scholars. However, future generations of medical anthropologists cannot carry the field forward unless they examine the teachings of previous teachers and scholars. By narrating his own story, just as he so frequently narrates the intricacies of Haiti [1], Paul Farmer, physician, anthropologist, and author of Pathologies of Power: Health, Human Rights, and the New War on the Poor [2], displayed a parallel between the stories of his own past with that of medical anthropology.At the 2009 Society for Medical Anthropology Conference at Yale University in September, Farmer began his aptly titled presentation, Photo Album, with a discussion of his introduction to medical anthropology while an undergraduate at Duke. He stumbled upon medical anthropology quite by chance as an ambitious pre-med who was interested in taking every course that had the word “medical” in its title. He credited many people, including Patricia Pessar, Arthur Kleinman, and Linda Garro with aiding the development of his ideas and perception of the world and teaching him to use medical anthropology not only in passive observation, but in the active practice of medicine. You “don’t have to be a faculty member to teach,” stressed Farmer. Some of the most important lessons to learn come from the poor, to whom few listen.Farmer believes that listening can form the work we do. He honed his listening skills, which are used in anthropology in an ethnographic context, after his first night in an emergency room, when he saw that many minor cases were brought in solely because individuals had no other outlet for treatment. Being a good listener allowed Farmer to understand the full impact of a 1981 slavery case involving migrant workers in Florida. It was this skill of listening that enabled Farmer to understand and tell Haiti’s story, as well as understand the intricate web that exists between privilege and privation. Just as the line between medical anthropology and primary care is often blurred, the “bracing connection between privilege and privation” becomes even more apparent the longer one spends studying both extremes.This is a vantage point Farmer was particularly susceptible to, given his trips from Haiti to Harvard and back again. Listening to his patients in Haiti and the United States would allow Farmer to draw parallels of inequality and injustice that exist for the impoverished in both places. The only difference between the United States and Haiti is that eventually many impoverished individuals in the United States will wind up in somewhat adequate medical facilities. In the story of global economics, Farmer said, “Good things get stuck in customs and bad things get traded freely.” A practicing physician may easily note that inequalities between the rich and poor are not unique to the United States or to Haiti, but what, Farmer asks, can anthropologists say about this division?The cursory glance through Farmer’s photo album ended with a picture of friends whom he fondly termed “the structural violence mafia” and anthropological ideas regarding unequal access to health care. While at first, the portion of anthropology that dissects the structures of violence seems isolated from medical anthropology, those structures of violence institute the vast inequalities that cause medicine to seem inaccessible. Farmer also stressed that “how we think about social theory influences global health.” Work in Haiti taught Farmer firsthand about the phenomenon of blaming the victim [3]. To understand this entrenched system of structural violence fully, an intensive bio-social analysis must be undertaken. Structural violence results in a system in which the victims are blamed, empowering those who suppress the victim while inhibiting the victim’s access to health care. Pointing fingers at the vulnerable is illustrated by the fact that Haiti is often blamed for the introduction of AIDS into North America [4,5]. Farmer stressed not only the inherent trauma of structural violence, but Carolyn Nordstrom’s ideas on violence having a distinct tomorrow [6]. The perpetual cycle of structural violence enables this concept of violence having a clear future with the inherent cultural systems that allow for violence remaining stagnant while the individuals entrapped within the system change.Beyond this concept of structural violence is that of structural healing [3]. Though structural healing is a new phenomenon being examined by anthropologists, it provides a balance to structural violence with the idea being that there are certain societal standards that are either in place or can be introduced that allow for an alleviation of the suffering caused by structural violence. While Farmer’s discussion of the path that led him to his current position was inspirational in itself, the sharing of his story is of even more importance because he has been a teacher to so many. His story reinforces the idea that even though structural violence has a definite past and future, so do medical anthropology and the idea of structural healing. Thankfully, medical anthropology may be used as a relatively new force to combat structural violence. Farmer’s speech may have been unexpected in its autobiographical content, but perhaps the main point is that the intersection between medicine and anthropology can be seen not as a single point but a line that runs the full length of each of these disciplines. We all have a distinct responsibility to not only hear but to listen and learn, not to just passively observe, but actively understand. It is with this listening and acting, that future medical anthropologists can bridge the gap between social sciences and practical medicine.     

Plant Neurobiology as a Paradigm Shift Not Only in the Plant Sciences

Plants are complex living beings, extremely sensitive to environmental factors, continuously adapting to the ever changing environment. Emerging research document that plants sense, memorize, and process experiences and use this information for their adaptive behavior and evolution. As any other living and evolving systems, plants act as knowledge accumulating systems. Neuronal informational systems are behind this concept of organisms as knowledge accumulating systems because they allow the most rapid and efficient adaptive responses to changes in environment. Therefore, it should not be surprising that neuronal computation is not limited to animal brains but is used also by bacteria and plants. The journal, Plant Signaling & Behavior, was launched as a platform for exchanging information and fostering research on plant neurobiology in order to allow our understanding of plants in their whole integrated, communicative, and behavioral complexity.

I always go by official statistics because they are very carefully compounded and, even if they are false, we have no others …∼ Jaroslav Hašek, 1911

Key Words: plant neurobiology, sensory biology, behavior, biological complexity, evolution, signal integrationThis quotation of writer and mystificator Jaroslav Hašek is from his electorial speech aimed to get a seat in the Austro-Hungarian parliament for his imaginary political party ‘Moderate Progress within the Limits of the Law’ in 1911. It indicates how statistics can be misused for manipulation of public opinion, sometimes allegedly for general good. This quotation is partially relevant also for recent biology which is passing through a critical cross-road from reductionist-mechanistic concepts and methodologies towards the post-genomic, holistic, systems-based analysis of integrated and communicative hierarchic networks known as life processes.There is a message hidden in this Hašek''s aphorism. All those mathematical models, scientific theories and concepts, however appealing, harmonious and long-standing … but which do not correspond to reality …; inevitably will be ‘killed by ugly’ facts generated by scientific progress, and finally replaced by new models, theories, and concepts.¹Despite the indisputable success of the reductionistic approach in providing many discoveries regarding single cells and their components, it is increasingly clear that promises of ‘mechanistic’ genocentric biology were just chimeras and that living organisms are much more complex than the sum of their constituents. Ernst Mayr, in his final opus, almost a testament published at his age of 100, strongly opposed the belief that the reductionism at the molecular level could help to explain the complexity of life. He stressed that the concept of biological “emergence”, which deals with the occurrence of unexpected features in complex living systems, is not fully accessible using only physical and chemical approaches.²Themes of hierarchy, continuity, and order dominated biology before the turn of the century, but these have in many cases been replaced by images of the workshop. Examples include such terms as ‘machineries’, ‘mechanistic understanding’, ‘mechanistic explanation’, ‘motors’, ‘machines’, ‘clocks’ etc. This shift may well reflect the characteristic style of our age. These concepts, although useful for mining of details, do not reveal the true complexity of life and can be misleading. Even a one-celled organism is made up of ‘millions’ of subcellular parts. Concerning the great complexity of unicellular creatures Ilya Prigogine (1973) wrote: “… but let us have no illusions, our research would still leave us quite unable to grasp the extreme complexity of the simplest of organism.”³ Moreover, eukaryotic cell proved to be, in fact, ‘cells within cell’,^4–8 while there are numerous supracellular situations, the most dramatic one is represented by plants when all cells are interconnected via plasmodesmata into supracellular organism.⁶ All this collectively indicate that the currently valid ‘Cell Theory’ dogma is approaching its replacement with a new updated concept of a basic unit of eukaryotic life.^6–8All those mathematical models, scientific theories and concepts, however appealing, harmonious and long-standing … but which do not correspond to reality …; inevitably will be ‘killed by ugly’ facts generated by scientific progress, and finally replaced by new models, theories, and concepts.Furthermore, genomes are much more complex and dynamic as we ever anticipated.^9,10 They often have as much as 99% of non-coding DNA sequences,¹¹ which is not ‘junk DNA’ but rather DNA which is part of multitask networks integrating coding DNA.¹² In genomes exposed to stress (like mutations), changes are scored preferentially in non-coding sequences which regain a new balance by complex changes in genome composition and activity.^9,10,13,14 There are several definitions regarding what is gene¹¹ and molecular biologists and genetics are learning to be careful not to make strong conclusions from under-expression, knocking-out, or overexpression of any particular gene. It is increasingly clear that mutations in single genes are accompanied with altered expressions of other genes and non-coding DNA sequences too, and even subtle re-arrangements of chromatin structure and genome architecture are possible. The dynamic genome actively regains the lost balance, also via extensive re-shufflings of non-coding DNA.After complete sequencing of numerous genomes, it is clear that our understanding of what constitutes life and what distinguishes living biological systems from non-living chemical - biochemical systems is not much better than our understanding before the start of the genomics era some 60 years ago. Yet, it is also obvious that living systems, whether single cells or whole complex organisms like animals and plants, are not machines and automata which respond to external signals via a limited set of predefined responses and automatic reflexes. While humans and other animals, even insects, are already out of this ‘mechanistic’ trap^15,16 which can be traced back to Descartes,¹⁷ plants are still considered to act only in predetermined automatic fashions, as mechanical devices devoid of any possibility for choice and planning of their activities. In contrast to machines, life systems are based on wet chemistry, being systems of hierarchical and dynamic integration, communication and emergence.^1,18Recently, a critical mass of data has accumulated demanding reconsideration of this mechanistic view of plants.^19,20 Plants are complex living beings, extremely sensitive to environmental factors and continuously adapting to the ever changing environment.²¹ In addition, plants respond to environmental stimuli as integrated organisms. Often, plants make important decisions, such as onset or breakage of dormancy and onset of flowering, which implicate some central or decentralized command center. Moreover, roots and shoots act in an integrated manner allowing dynamic balance of above-ground and below-ground organs. The journal, Plant Signaling & Behavior, was launched as a platform for exchange of information about the integration of discrete processes, including subcellular signalling integrated with higher-level processes. Signal integration and communication results in adaptive behavior of whole supracellular organisms, encompassing also complex, and still elusive, plant-plant, plant-insect, and plant-animal communications. Coordinated behavior based on sensory perception is inherent for neurobiological systems.²² Therefore, plants can be considered for neuronal individuals. Moreover, plants are also able to share knowledge perceived from environment with other plants, communicating both private and public messages.^23,24 This implicates social learning and behavioral inheritance in plants too.After complete sequencing of numerous genomes, it is clear that our understanding of what constitutes life and what distinguishes living biological systems from non-living chemical - biochemical systems is not much better than our understanding before the start of genomics era some 60 years ago.

Behavior

1. An activity of a defined organism: observable activity when measurable in terms of quantitative effects of the environment whether arising from internal or external stimuli.
2. Anything that an organism does that involves action and response to stimulation.

(Webster Third New International Dictionary 1961).Neuronal informational systems allow the most rapid and efficient adaptive responses. Therefore, it should not be surprising that neuronal computation is not limited to animal brains but is used also by bacteria and plants.Some of our colleagues assert that plants do not exhibit any integrated neuronal principles.²⁵ They maintain that plants do not show complex experience- or learning-based behavior. Plants, they aver, act rather as machines manifesting predefined reflexes. Yet recent studies indicate that even prokaryotic bacteria exhibit cognitive behavior^26,27 and posses linguistic communication and rudimentary intelligence.^28–30 Therefore, it should not be too surprising that plants also show features of communication and even plant-specific cognition.^{19,20,31,32–35} As any other living systems, plants act as ‘knowledge accumulating systems’.¹ In fact, in order to adapt, all organisms continuously generate hypotheses about their environment via well formulated ‘questions’ which are solved by an increasing set of possible ‘answers’ in order to adapt.¹ Neuronal informational systems are behind this concept of organisms as ‘knowledge accumulating systems’ because they allow the most rapid and efficient adaptive responses.²² As a consequence, neuronal computation is not limited to animal brains but is used also by bacteria and plants.Reductionistic approaches will continue to “atomize” biological systems. Nevertheless, the avalanche of new data will be in need of functional integration, winning adherents to the idea that plants have integrated signaling and communicative systems that endowed them with complex and adaptive behavior. We trust that Plant Signaling & Behavior, will become an important platform for exchange of these ideas. With progress of sciences, plants show more and more similarities to animals despite obviously plant-specific evolutionary origins, cellular basis, and multicellularity. We can just mention sexuality and sex organs, embryos, stem cells, immunity, circadian rhythms, hormonal and peptide signaling, sensory perception and bioelectricity including action potentials, communication and neurobiological aspects of signal integration. The whole picture strongly suggest that convergent evolution is much more important^36,37 than currently envisioned in evolutionary theories.Reductionistic approaches will continue to “atomize” biological systems. Nevertheless, the avalanche of new data will be in need of functional integration, winning adherents to the idea that plants have integrated signaling and communicative systems that endowed them with complex and adaptive behavior.We have started with Jaroslav Hašek and we close with him as well. His quotation from 1911 is also a warning for future that we should stay open-minded. We should not slip into dogmatic ‘traps’ which have been so characteristic for the mechanistic and genocentric biology. Mathematics and computational biology are important tools, and surely will play decisive role in systems biology in the future. But they can be easily misinterpreted, and even misused. Plant systems biology, and the whole biology in general, must overcome dogmas of mechanistic genocentric biology. We hope that characterizing plants in their whole behavioral and communicative complexity will allow us to better understand what is life and how it emerged from chemical and biochemical complex systems.     

Patient Satisfaction with Methadone Maintenance Treatment in Vietnam: A Comparison of Different Integrative-Service Delivery Models

Background

Patient satisfaction is an important component of quality in healthcare delivery. To inform the expansion of Methadone Maintenance Treatment (MMT) services in Vietnam, we examined the satisfaction of patients with regards to different services delivery models and identified its associated factors.

Methods

We interviewed 1,016 MMT patients at 5 clinics in Hanoi and Nam Dinh province. The modified SATIS instrument, a 10-item scale, was used to measure three dimensions: “Services quality and convenience”, “Health workers’ capacity and responsiveness” and “Inter-professional care”.

Results

The average score was high across three SATIS dimensions. However, only one third of patients completely satisfied with general health services and treatment outcomes. Older age, higher education, having any problem in self-care and anxiety/depression were negatively associated with patient’s satisfaction. Meanwhile, patients receiving MMT at clinics, where more comprehensive HIV and general health care services were available, were more likely to report a complete satisfaction.

Conclusion

Patients were highly satisfied with MMT services in Vietnam. However, treatment for drug users should go beyond methadone maintenance to address complicated health demands of drug users. Integrating MMT with comprehensive HIV and general health services together with improving the capacity of health workers and efficiency of services organisation to provide interconnected health care for drug users are critical for improving the outcomes of the MMT program.     

Selection of Treatment Strategies among Patients with Type 2 Diabetes Mellitus in Malaysia: A Grounded Theory Approach

Background

Diabetes Mellitus is a multifaceted chronic illness and its life-long treatment process requires patients to continuously engage with the healthcare system. The understanding of how patients manoeuvre through the healthcare system for treatment is crucial in assisting them to optimise their disease management. This study aims to explore issues determining patients’ treatment strategies and the process of patients manoeuvring through the current healthcare system in selecting their choice of treatment for T2DM.

Methods

The Grounded Theory methodology was used. Twelve patients with Type 2 Diabetes Mellitus, nine family members and five healthcare providers from the primary care clinics were interviewed using a semi-structured interview guide. Three focus group discussions were conducted among thirteen healthcare providers from public primary care clinics. Both purposive and theoretical samplings were used for data collection. The interviews were audio-taped and transcribed verbatim, followed by line-by-line coding and constant comparison to identify the categories and core category.

Results

The concept of “experimentation” was observed in patients’ help-seeking behaviour. The “experimentation” process required triggers, followed by information seeking related to treatment characteristics from trusted family members, friends and healthcare providers to enable decisions to be made on the choice of treatment modalities. The whole process was dynamic and iterative through interaction with the healthcare system. The decision-making process in choosing the types of treatment was complex with an element of trial-and-error. The anchor of this process was the desire to fulfil the patient’s expected outcome.

Conclusion

Patients with Type 2 Diabetes Mellitus continuously used “experimentation” in their treatment strategies and help-seeking process. The “experimentation” process was experiential, with continuous evaluation, information seeking and decision-making tinged with the element of trial-and-error. The theoretical model generated from this study is abstract, is believed to have a broad applicability to other diseases, may be applied at varying stages of disease development and is non-context specific.     

2009 Society for Medical Anthropology Conference: Global Public Health through the Eyes of Medical Anthropologist Didier Fassin

At the 2009 Society for Medical Anthropology Conference at Yale University, anthropologist Didier Fassin discussed social inequality and the politicization of health in the context of global public health.U.S. Rep. Joe Wilson shouted, “You lie!” during President Obama’s denial that the proposed health care reform bill would cover illegal immigrants, and anthropologist Didier Fassin used that antagonistic stance toward what the 1978 Declaration of Alma-Ata [1] had called a fundamental human right to best illustrate the issues of social inequality and the politicization of health.Global public health was one focus of the 2009 Society for Medical Anthropology Conference at Yale University in September. Since its inception in 1948, the World Health Organization (WHO) has striven to provide health assistance to the world population, especially those in developing countries. But Fassin, professor of social science at the Institute for Advanced Study at Princeton, professor of sociology at the Université de Paris, Nord, and director of studies in political and moral anthropology at the Ecole des Hautes Études en Sciences Sociales, argued that the concept of global health, albeit well-meaning, is problematic. Its utopian nature is clearly apparent in the rhetoric of politicians, he said, adding that health as a gift of nature, a common good, and the core of the WHO, quickly becomes an object of politics and the coverage in times of sickness of a select few is akin to entitlement and privilege.The present age of globalization certainly makes health threats such as epidemics a threat to all, and nations are in it together to take preventive measures or put up a concerted fight. However, threats like bioterrorism or predicted consequences of global warming such as population migration may be viewed, particularly by Western countries, as security issues that menace national interests and state sovereignties. The consequence being that new policies are implemented that may directly or indirectly affect the rest of the world population.And then there is the issue of humanitarian intervention, which Fassin refers to as “politics of life” [2]. How can we view humanitarianism with the eye of a cynic when it is, in essence, the effort to demonstrate the very best of our nature? Yet the transformation of some humanitarian interventions into military operations and the decision to intervene (Iraq, Kosovo, Bosnia) or not (Rwanda, Ethiopia, Cambodia), politicize this notion. Additionally, Fassin believes that the key nation-states integrate their own cultural and political biases during interventions in troubled regions.Nowhere is this subjectivity more apparent than in the image of suffering as depicted by psychologists and psychiatrists working for non-government organizations (NGOs). NGOs compile testimonies of traumatized people in war and conflict zones, but their subjective narratives enmeshed in the diagnosis reports are increasingly supplanting faithful witness accounts. Fassin sees this trauma as “political expression of the world” [3]. The experts, in trying to raise awareness on issues that need immediate attention, may dramatize certain situations or get emotionally involved during their missions and take sides. They become the new voice of the conflict and their efforts may throw the victims into a state of confusion.It’s no surprise then that some nations view with distrust Western practices and their portrayal of aggressors and victims [4]. In 2000, Thabo Mbeki, then president of South Africa, convened an advisory panel that aimed to collect scientific data to prove that HIV does not cause AIDS. In return, he received the Durban Declaration with the signatures of more than 5,000 scientists and doctors who unilaterally declared the opposite to be scientifically true.Fassin brings up the abovementioned issues in order to shift attention to the difficulties that face our common efforts for better health services. It is truly challenging for Western leaders to mend the rift between their political agendas and accessible health for all, and as long as that continues to be the case, health care will elude millions.     

Creative destruction of the microtubule array

Comment on: Mukherjee S, et al. Cell Cycle 2012; 11:2359-66.Typical cells contain a dense array of microtubules that serves as a structural backbone and also provides a substrate against which molecular motor proteins generate force. Cells transitioning through the cell cycle or undergoing significant morphological changes must be able to tear apart the microtubule array and reconstruct it into new configurations, either partially or completely. The microtubule field was revolutionized in the 1980s with the introduction of the dynamic instability model,¹ now broadly recognized as a fundamental mechanism by which microtubule populations are reconfigured.² Dynamic instability involves the catastrophic disassembly of microtubules, generally from their plus ends, as well as the rapid reassembly of microtubules and selective stabilization of particular ones. Microtubules can be stabilized along their length by binding to various proteins and can be attached at their minus ends to structures such as the centrosome and “captured” at their plus ends by proteins in the cell’s cortex.² Given the contribution of these stabilizing and anchoring factors, additional mechanisms beyond dynamic instability are required to tear down previous microtubule structures so that new ones can be constructed. Borrowing from the field of economics, we refer to this as creative destruction.Various proteins such as stathmin³ and kinesin-13⁴ contribute to creative destruction by promoting loss of tubulin subunits from the ends of the microtubules. We find especially interesting a category of AAA enzymes called microtubule-severing proteins that use the energy of ATP hydrolysis to yank at tubulin subunits within the microtubule, thereby causing the lattice to break.⁵ If this occurs along the length of the microtubule, the microtubule will be severed into pieces. If this occurs at either of the two ends of the microtubule, the microtubule will lose subunits from that end. The first discovered and best-studied microtubule-severing proteins are katanin and spastin.Thanks to David Sharp and his colleagues at Albert Einstein College of Medicine, as well as other workers in the field, we now know that cells express at least five other AAA proteins with potential microtubule-severing properties, on the basis of sequence similarity to katanin and spastin in the AAA region.⁵ Two of these, called katanin-like-1 and katanin-like-2, are very similar to katanin. The three others are similar to one another, collectively termed fidgetins (fidgetin, fidgetin-like-1 and fidgetin-like-2). One possibility is that all seven of the microtubule-severing proteins are regulated similarly and are functionally redundant with one another. A more compelling possibility is that, while there is some functional redundancy, there is also a division of labor, with each severing protein displaying distinct properties and carrying out its own duties. Thus far, Sharp’s studies on mitosis support the latter scenario, with katanin, fidgetin and spastin having characteristic distributions within the spindle, resulting in unique phenotypes when depleted.⁶In a new article, Sharp’s group has confirmed that fidgetin has microtubule-severing properties. Interestingly, fidgetin depolymerizes microtubules preferentially from the minus end.⁷ In addition, the new work shows that in human U2OS cells, fidgetin targets to the centrosome, where most minus ends of microtubules are clustered, suggesting a scenario by which fidgetin suppresses microtubule growth from the centrosome as well as attachment to it. Consistent with this scenario, the authors show that experimental depletion of fidgetin reduces that speed of poleward tubulin flux as well as the speed of anaphase A chromatid-to-pole motion and also results in an increase in both the number and length of astral microtubules. Notably, this contrasts with katanin, which favors the plus ends of microtubules, for example, at the chromosome during cell division⁶ and at the leading edge of motile cells.⁸The authors close their article by pointing out that microtubule-severing is important beyond mitosis, for example, in the restructuring of the microtubule array in neurons and migrating cells, and we would point to plants as well.⁹ We previously described a mechanism called “cut and run,” wherein the severing of microtubules is important for motility within the microtubule array, as short microtubules are more mobile than long ones.⁹ Now, inspired by the work of Sharp and colleagues, we envision “creative destruction” as another way of understanding the crucial roles played by a diversity of microtubule-severing proteins in cells.     

Arbuscular Mycorrhiza: Studies on the Geosiphon Symbiosis Lead to the Characterization of the First Glomeromycotan Sugar Transporter

The intimate arbuscular mycorrhiza (AM) association between roots and obligate symbiotic Glomeromycota (‘AM fungi’) ‘feeds’ about 80% of land plants. AM forming fungi supply land plants with inorganic nutrients and have an enormous impact on terrestrial ecosystems. In return, AM fungi obtain up to 20% of the plant-fixed CO₂, putatively as monosaccharides. In a recent work we have reported the characterization of the first glomeromycotan monosaccharide transporter, GpMST1, and its gene sequence. We discuss that AM fungi might take up sugars deriving from plant cell-wall material. The GpMST1 sequence delivers valuable data for the isolation of orthologues from other AM fungi and may eventually lead to the understanding of C-flows in the AM.Key Words: arbuscular mycorrhiza, Geosiphon symbiosis, monosaccharide transporter, hexosesThe arbuscular mycorrhiza (AM) as an outstanding terrestrial plant symbiosis directly and indirectly is a driver of most terrestrial ecosystems. It is formed by ∼80% of land plants and by obligate symbiotic fungi of the phylum Glomeromycota.¹ The glomeromycotan fungi usually are called ‘arbuscular mycorrhizal (AM) fungi’, or ‘AMF’, and obviously play an enormous ecological (and economical) role. Most land plants and glomeromycotan fungi are ‘joint systems’, forming the intimate AM.² By this fact, statements like that of the BEG (European Bank of Glomeromycota) committee (1993): “The study of plants without their mycorrhizas is the study of artefacts; the majority of plants, strictly speaking, do not have roots—they have mycorrhizas” were provoked. AM fungi supply the vast majority of land plants with inorganic nutrients, mainly phosphorous, but also nitrogen, trace elements, and water. In return, they obtain up to >20% of the photosynthetically fixed CO₂ as carbohydrates from the plants.³ It was calculated that, each year, 5 billion tons of carbon are transferred from plants to fungi (and therefore partly get deposited in the soil) via the AM symbiosis. AM fungi therefore represent a large sink for atmospheric CO₂ on our planet and play a role in C-deposition in the soil.     

ATG7 contributes to plant basal immunity towards fungal infection

Autophagy has an important function in cellular homeostasis. In recent years autophagy has been implicated in plant basal immunity and assigned negative (“anti-death”) and positive (“pro-death”) regulatory functions in controlling cell death programs that establish sufficient immunity to microbial infection. We recently showed that Arabidopsis mutants lacking the autophagy-associated (ATG) genes ATG5, ATG10 and ATG18a are compromised in their resistance towards infection with necrotrophic fungal pathogens but display an enhanced resistance towards biotrophic bacterial invaders. Thus, the function of autophagy as either being pro-death or anti-death depends critically on the lifestyle and infection strategy of invading microbes. Here we show that ATG7 contributes to resistance to fungal pathogens. Genetic inactivation of ATG7 results in elevated susceptibility towards the necrotrophic fungal pathogen, Alternaria brassicicola, with atg7 mutants developing spreading necrosis accompanied by production of reactive oxygen intermediates. Likewise, treatment with the fungal toxin fumonisin B1 causes spreading lesion formation in the atg7 mutant. We conclude that ATG7-dependent autophagy constitutes an “anti-death” (“pro-survival”) plant mechanism to control the containment of cell death and immunity to necrophic fungal infection.Key words: autophagy, ATG7, basal immunity, fungal resistance, arabidopsisPlants have evolved a bipartite plant immune system to cope with microbial infections. The first layer of defense relies on the recognition of pathogen-associated molecular patterns (PAMP) by pattern-recognition receptors (PAMP-triggered immunity, PTI).^1,2 To overcome this defense strategy, successful pathogens deliver so-called effector proteins into plant cells to modify host cellular processes and to suppress immune responses to enhance virulence. The presence or activities of these microbial effectors is sensed by plant resistance proteins and triggers the second layer of defense, the effector-triggered immunity (ETI).^1,2 In contrast to PTI, ETI is most often accompanied by programmed host cell death (PCD) at the site of attempted microbial invasion; however the molecular basis of this apoptosis-like hypersensitive response (HR) is largely unknown.In recent years evidence accumulated that a non-apoptotic form of cell death called autophagy is not only involved in animal PCD and innate immunity³ but is also an important component in the plant basal immune response.⁴ Generally, autophagy (auto, meaning “self” and phagy, “to eat”) is a cytoplasmic bulk degradation process in which cellular components are targeted to lysosomal or vacuolar degradation. This process is ubiquitous in eukaryotic organisms and is considered to aid cellular survival, differentiation, development and homeostasis by nutrient recycling or removal of damaged or toxic materials.^5–7     

Challenges in the Care of Clients with Established Cardiovascular Disease: Lessons Learned from Australian Community Pharmacists

Background

As primary healthcare professionals, community pharmacists have both opportunity and potential to contribute to the prevention and progression of chronic diseases. Using cardiovascular disease (CVD) as a case study, we explored factors that influence community pharmacists’ everyday practice in this area. We also propose a model to best illustrate relationships between influencing factors and the scope of community pharmacy practice in the care of clients with established CVD.

Methods

In-depth, semi-structured interviews were conducted with 21 community pharmacists in New South Wales, Australia. All interviews were audio-recorded, transcribed ad verbatim, and analysed using a “grounded-theory” approach.

Results

Our model shows that community pharmacists work within a complex system and their practice is influenced by interactions between three main domains: the “people” factors, including their own attitudes and beliefs as well as those of clients and doctors; the “environment” within and beyond the control of community pharmacy; and outcomes of their professional care. Despite the complexity of factors and interactions, our findings shed some light on the interrelationships between these various influences. The overarching obstacle to maximizing the community pharmacists’ contribution is the lack of integration within health systems. However, achieving better integration of community pharmacists in primary care is a challenge since the systems of remuneration for healthcare professional services do not currently support this integration.

Conclusion

Tackling chronic diseases such as CVD requires mobilization of all sources of support in the community through innovative policies which facilitate inter-professional collaboration and team care to achieve the best possible healthcare outcomes for society.     

Trichomes as sensors: Detecting activity on the leaf surface

The dramatic movements of some carnivorous plants species are triggered by sensory structures derived from trichomes. While unusual plant species such as the Venus fly trap and sundews may be expected to have elaborate sensors to capture their insect prey, more modest plant species might not be expected to have similar sensory capabilities. Our recent work, however, has revealed that glandular trichomes on tomato (Solanum lycopersicum) appear to have a function similar to trigger hairs of carnivorous species, acting as “early warning” sensors. Using a combination of behavioral, molecular, and biochemical techniques, we determined that caterpillars, moths and mechanical disruption upregulate signaling molecules and defensive genes found in glandular trichomes. Importantly, we discovered that plants whose trichomes have been broken respond more vigorously when their defenses were induced. Taken together, our results suggest that glandular trichomes can act as sensors that detect activity on the leaf surface, and ready plants for herbivore attack.Key words: glandular trichome, induced responses, jasmonic acid, plant-insect interactions, sensor, Solanum lycopersicum, tomatoCertain plant species are renowned for their ability to respond to contact. The Venus fly trap (Dionaea muscipula) and sundew (Drosera) species come to mind quickly as obviously thigmotropic species. When an insect lands on these carnivorous plant species, dramatic movements ensue once the prey is detected. Some Drosera species respond to contact by bending their “tentacles” toward their trapped prey to further ensnare the victim and begin the process of digestion. These dramatic plant species have captured the attention of many scientists, including Darwin, who remarked on the “extraordinary sensitiveness of [their] glands to slight pressure” and surmised that the tentacles of sundew plants “existed primordially as glandular hairs.”¹ As is often the case, Darwin appears to have been quite right. Indeed, morphological and molecular work supports the notion that sundew tentacles and the trigger hairs of the Venus fly trap are homologous sensory structures likely derived from trichomes.^2,3Given Darwin’s appreciation of these trichome-derived sensory organs, he perhaps would not have been surprised by mounting evidence that suggests that trichomes may play even a broader sensory role for plants. We have recently found evidence that glandular trichomes can act as early detection sensors for some plant species.⁴ These trichomes can be disrupted by the footsteps of walking moths and caterpillars (and other forms of light touching), and this apparently minor plant damage leads to a state of defensive readiness that allows plants to respond to herbivory more quickly than undamaged plants. While this level of trichome-mediated detection does not result in the conspicuous responses of some carnivorous plant species, it still results in significant physiological changes that prepare plants for attack.In our recent effort, we worked with tomato (Solanum lycopersicum), using a combination of behavioral, molecular, and biochemical techniques to understand the role of trichomes in detecting activity on the leaf surface.⁴ Defense signaling has been well studied in tomato and there exists a variety of mutants whose defensive responses have been compromised. Moreover, it has been known that tomatoes have a variety of trichome types, including two types of glandular trichomes that burst upon contact with insects, releasing their cellular contents and physically impeding insects (Fig. 1).^5,6Open in a separate windowFigure 1Surface of a tomato leaf showing (A) intact rounded heads of glandular trichomes (black arrows) and (B) trichomes disrupted with a gloved hand (absence of rounded heads except for a few in the upper left corner [black arrows]). Images were captured at 36x magnification and were taken from different parts of the same leaf.To determine if plant defense pathways were induced by insect contact, we allowed three species of caterpillar (Manduca sexta, Heliothis virescens and Helicoverpa zea) and one species of moth (H. zea) to crawl over tomato leaves for ten minutes. As a positive control, we also lightly rubbed leaves with a gloved hand or a metal rod. Within time frames ranging from three to twenty-four hours all treatments, insect and otherwise, significantly induced defensive genes as measured by qRT-PCR. Using a combination of RT-PCR and in situ hybridization, we confirmed that JA-signaling and defensive genes are expressed in trichomes. A GC-MS-based technique then confirmed that JA was present in trichomes of undamaged plants and DAB staining, in combination with catalase treatment, provided evidence that hydrogren peroxide and JA are key signals mediating defensegene induction. These conclusions were further reinforced by experiments with def1 mutants, a line of tomato impaired in JA signaling, and accession LA3610, a tomato variety with reduced numbers of trichomes. Lastly, we conducted a factorial experiment both disrupting trichomes and treating tomato plants with methyl jasmonate (MeJA), which induces plant defenses and increases densities of trichomes.⁷ Results of this final experiment indicated that plants that received both treatments (i.e., MeJA and disruption) had greater defensive gene induction than plants that were only treated with MeJA or plants whose trichomes remained intact, suggesting that increases in trichomes may contribute to greater sensitivity to touch-induced responses.Taken together, our results are highly suggestive that trichomes can act as “early warning” detectors for plants. Moths seeking to lay eggs on tomato are likely to break trichomes as they explore leaves, upregulating plant defenses in anticipation of egg hatch and feeding by neonate caterpillars. Similarly, herbivores colonizing a new host plant and breaking trichomes on their way across a leaf also appear to “tip the plant off” to impending attack. Considering the drastic response of carnivorous plants to touch, perhaps it should not be surprising that trichomes can function more broadly as sensors. In an evolutionary context, it seems logical that trichomes took on this role. For many plant species, “hairy” varieties receive less herbivory,⁸ so within a population there could have been a fitness advantage in having more trichomes. Once established, this hairy phenotype could then have been refined via mutation and selection for trichome varieties that had functions adaptive for the plant, perhaps driving the evolution of glandular trichomes and their role as sensors.Granted, the generalized nature of our results would appear to indicate that plants could be “primed” by nearly any arthropod species that crosses one of their leaves. This would, of course, include natural enemies, which are capable of decreasing herbivore pressure and improving plant fitness.^9,10 However, it has been hypothesized that priming evolved due to high fitness costs associated with defensive induction following threats of only minor severity.¹¹ Priming provides an advantage by settling plants into an intermediate “ready” state that allows them to deploy strong defense responses more quickly and the fitness cost associated with being “primed” are lower than full defensive induction.¹² Presumably, fitness costs following priming due to natural enemyinduced trichome disruption would also be less than the cost incurred from a bout of unanticipated herbivory and, over the life of the plant, it would be worth the effort to prepare for attack even if the perceived risk is from a natural enemy and not a foe.Our results build on previously reported priming mechanisms that prepare plants for attack.^13,14 And they reveal an additional level of sophistication in the sensory capabilities of plants, which have already been shown to be able to detect nearby threats of herbivory and increase their defenses in response.^15,16 It seems that trichomes may have played a much wider role in shaping the nature of plant-animal interaction than previously recognized and we look forward to further work elaborating their function.     

In search of decoy/guardee to R genes: Deciphering the role of sugars in defense against Fusarium wilt in chickpea

Plant responses are coordinately controlled by both external and internal signals. Apt perception of pathogen attack and its appropriate conversion to internal signals ultimately determine the outcome of innate immunity. The present review predicts the involvement of unconventional ‘guard/decoy model’ in chickpea-Fusarium encounter. Rapid alkalinization factor is predicted to act as initial ‘Gatekeeper decoy’ counteracting fungal entry. Phospholipases and cystatins probably function as ‘Guardees’ being shielded by R gene(s). Serine Threonine Kinases decodes external pathogenic signals to in planta defense alarms. 14.3.3 provides clues to the wilt mechanism. The versatile sugars serve as signal generators and transmitters maintaining intra and inter cellular connectivity during stress.Key words: R gene, decoy, guardee, RALF, ROS, STK, 14.3.3, sugar, defense‘Survival for existence’ is the dictum followed by the entire living world. Similarly ‘survival of the fittest’ is nature''s preference. Owing to the extensive surveillance system of higher organisms resistance becomes the natural rule while susceptibility the exception.¹ All living entities are being exposed to a plethora of interactions ranging from mutualism to antagonism.² However the adaptive strategies opted by the plants are unique, versatile and still grossly unknown which have attracted the researchers since decades towards looking into the varied responses and diversification of plant adaptation.Plants are hosts to a large number of organisms such as symbiotic/pathogenic bacteria, phytopathogenic fungi, harmful viruses and nematodes. All have their own stratagem to gain over their host.³ However only the plant-fungal interaction with Chickpea-Fusarium case study in particular, shall be the focal area of the present review. Fungi are classified as necrotrophic and biotrophic according to their nutritional requirements.⁴ Necrotrophs apply ‘brute force’ by killing host cells and thriving on their dead remains while biotrophs prefer subtler ‘modus operandi’—the stealth mechanism used to derive nutrients from live host cells.⁵ Irrespective of the pathogen type and their mode of nutrition procurement, perception of attack lies central to effective induction of innate immunity in plants.