Tissue Matching and Early Rejection of Cadaveric-Donor Renal Allografts: The Importance of Unidentified Donor Antigens

Tissue typing has been reviewed in a series of 100 technically successful cadaveric-donor kidney grafts. The criterion of transplant failure was immunological rejection causing total loss of function within three months of operation.No significant correlation was observed between matching grade and graft failure due to early acute rejection. This is attributed to the failure to detect at least one “LA” or “4” antigen (as defined in our laboratory), representing a potential incompatibility, in 89% of the grafts, and in the remaining 11% to the lack of an available recipient with identical “LA” and “4” typing. Undetected antigens on the donor are usually incompatible, and probably these incompatibilities unfavourably influence early graft survival.If the results of cadaveric-donor renal transplantation are to equal those of transplantation from well-matched living related donors it will be necessary to type with sera which can recognize individually all HL-A antigens, including those not yet identified, and to create an international pool of over 1,000 potential recipients.     

Cooperating elephants mitigate competition until the stakes get too high

Cooperation is ubiquitous in the animal kingdom as it aims to maximize benefits through joint action. Selection, however, may also favor competitive behaviors that could violate cooperation. How animals mitigate competition is hotly debated, with particular interest in primates and little attention paid thus far to nonprimates. Using a loose-string pulling apparatus, we explored cooperative and competitive behavior, as well as mitigation of the latter, in semi-wild Asian elephants (Elephas maximus). Our results showed that elephants first maintained a very high cooperation rate (average = 80.8% across 45 sessions). Elephants applied “block,” “fight back,” “leave,” “move side,” and “submission” as mitigation strategies and adjusted these strategies according to their affiliation and rank difference with competition initiators. They usually applied a “fight back” mitigation strategy as a sanction when competition initiators were low ranking or when they had a close affiliation, but were submissive if the initiators were high ranking or when they were not closely affiliated. However, when the food reward was limited, the costly competitive behaviors (“monopoly” and “fight”) increased significantly, leading to a rapid breakdown in cooperation. The instability of elephant cooperation as a result of benefit reduction mirrors that of human society, suggesting that similar fundamental principles may underlie the evolution of cooperation across species.

This study shows that in a task requiring coordinated pulling, elephants compete for access to food but work to mitigate competition in order to maintain cooperation. If the cost of competition becomes too high, however, cooperation breaks down entirely. This behavior mirrors that seen in humans and other great apes, suggesting that certain cooperative mechanisms are not unique to primates.     

Genome Wide Association Study Identifies New Loci Associated with Undesired Coat Color Phenotypes in Saanen Goats

This paper reports a quantitative genetics and genomic analysis of undesirable coat color patterns in goats. Two undesirable coat colors have routinely been recorded for the past 15 years in French Saanen goats. One fifth of Saanen females have been phenotyped “pink” (8.0%) or “pink neck” (11.5%) and consequently have not been included in the breeding program as elite animals. Heritability of the binary “pink” and “pink neck” phenotype, estimated from 103,443 females was 0.26 for “pink” and 0.21 for “pink neck”. Genome wide association studies (using haplotypes or single SNPs) were implemented using a daughter design of 810 Saanen goats sired by 9 Artificial Insemination bucks genotyped with the goatSNP50 chip. A highly significant signal (-log10pvalue = 10.2) was associated with the “pink neck” phenotype on chromosome 11, suggesting the presence of a major gene. Highly significant signals for the “pink” phenotype were found on chromosomes 5 and 13 (-log10p values of 7.2 and, 7.7 respectively). The most significant SNP on chromosome 13 was in the ASIP gene region, well known for its association with coat color phenotypes. Nine significant signals were also found for both traits. The highest signal for each trait was detected by both single SNP and haplotype approaches, whereas the smaller signals were not consistently detected by the two methods. Altogether these results demonstrated a strong genetic control of the “pink” and “pink neck” phenotypes in French Saanen goats suggesting that SNP information could be used to identify and remove undesired colored animals from the breeding program.     

An Evolutionary Cascade Model for Sauropod Dinosaur Gigantism - Overview,Update and Tests

Sauropod dinosaurs are a group of herbivorous dinosaurs which exceeded all other terrestrial vertebrates in mean and maximal body size. Sauropod dinosaurs were also the most successful and long-lived herbivorous tetrapod clade, but no abiological factors such as global environmental parameters conducive to their gigantism can be identified. These facts justify major efforts by evolutionary biologists and paleontologists to understand sauropods as living animals and to explain their evolutionary success and uniquely gigantic body size. Contributions to this research program have come from many fields and can be synthesized into a biological evolutionary cascade model of sauropod dinosaur gigantism (sauropod gigantism ECM). This review focuses on the sauropod gigantism ECM, providing an updated version based on the contributions to the PLoS ONE sauropod gigantism collection and on other very recent published evidence. The model consist of five separate evolutionary cascades (“Reproduction”, “Feeding”, “Head and neck”, “Avian-style lung”, and “Metabolism”). Each cascade starts with observed or inferred basal traits that either may be plesiomorphic or derived at the level of Sauropoda. Each trait confers hypothetical selective advantages which permit the evolution of the next trait. Feedback loops in the ECM consist of selective advantages originating from traits higher in the cascades but affecting lower traits. All cascades end in the trait “Very high body mass”. Each cascade is linked to at least one other cascade. Important plesiomorphic traits of sauropod dinosaurs that entered the model were ovipary as well as no mastication of food. Important evolutionary innovations (derived traits) were an avian-style respiratory system and an elevated basal metabolic rate. Comparison with other tetrapod lineages identifies factors limiting body size.     

THE THORNY CHILD

Too many physicians—and parents—hide behind the overworked excuse that “Johnny is just going through a stage.” If the remark is inaccurate a great disservice can be done to both mother and child, and ultimately to society. The well oriented physician would no more permit a young mother to unwittingly feel “guilty” because her two-year-old “little stinker” behaves like a two-year-old little stinker than he would casually reassure when a ten-year-old behaves as though he were two.Actually much of the unpleasant behavior of children is quite normal. If physicians would help all young mothers to recognize this without dismissing abnormal behavior, it would do much to avert the overwhelming sense of inadequacy that so many modern young mothers feel—especially with their first baby. If they can be made comfortable with their first the others usually come easily. Many physicians who care for children are not trained in the rudiments of developmental behavior. By means of a simple outline and drawing of “the thorny child” even the least of the experts can better understand some of the chronologic variations in developmental behavior.     

Psychiatric assessment of patients with “20th-century disease” (“total allergy syndrome”)

“Twentieth-century disease”, or “total allergy syndrome”, is a condition attributed to hypersensitivity to the environment that may sometimes be seen as so serious that the patient is incapable of living in the modern world. Although the popular media frequently carry stories about it, there is little scientific literature. It is diagnosed by clinical ecologists, who maintain, among other theories, that susceptible individuals experience an overload in assaults by artificial materials in the environment. The patients usually have multiple ill defined symptoms for which no organic cause can be found, but they vigorously resist psychiatric referral, as they attribute their symptoms to allergy. A group of 18 patients who were purportedly suffering from 20th-century disease were referred to a university psychiatric consultation liaison service. They virtually all had a long history of visits to physicians, and their symptoms were characteristic of several well known psychiatric disorders. The case histories and management of three of them are presented. Although this group of patients may have been atypical in that they had more severe psychologic symptoms, the experience indicates that a psychiatric diagnosis ought to be considered. The symptoms of 20th-century disease have much in common with other conditions known to physicians for centuries.     

Horizontal Gene Transfer and the History of Life

Microbes acquire DNA from a variety of sources. The last decades, which have seen the development of genome sequencing, have revealed that horizontal gene transfer has been a major evolutionary force that has constantly reshaped genomes throughout evolution. However, because the history of life must ultimately be deduced from gene phylogenies, the lack of methods to account for horizontal gene transfer has thrown into confusion the very concept of the tree of life. As a result, many questions remain open, but emerging methodological developments promise to use information conveyed by horizontal gene transfer that remains unexploited today.The discovery of the existence of prokaryotic microbes dates back more than 300 years. Since then, our picture of our distant microscopic relatives has undergone several revolutions: from being the living “proofs” of the existence of spontaneous generation, they became later the “archaic” representatives of our distant ancestors, to finally be legitimately recognized as exceptionally diverse organisms, keystone to any ecosystem, including the most familiar and the most hostile environments on Earth. Similarly, although they were first seen as elementary and unbreakable bricks of life, they are now seen as genetically composite bodies, heavyweight champions of “gene robbery.” The most recent of these revolutions has indeed been the realization of their unparalleled ability to integrate genetic material coming from more or less evolutionarily distant organisms. This mechanism is called “horizontal gene transfer” as opposed to vertical transmission from mother to daughter cell.     

The Histological Components of the Phoniatrical Body-Cover Model in Minipigs of Different Ages

Pigs are models in human phoniatry. However, features of maturation and ageing have not been considered with regard to the so-called body-cover model in this species. Therefore, the glottis of “young” (2–3 months; n = 6) and “old” (4–7 years; n = 6) minipigs was investigated. Their cranial (CraF) and caudal (CauF) vocal folds were histomorphometrically and stratigraphically analysed with emphasis on their amounts of collagen structures and elastic fibres. A dense subepithelial layer (SEL) was a distinct feature of CraF and CauF of both age groups; it was spread upon the underlying loose, flexible “cover” like a fibro-elastic membrane. The “cover” was characterised by the so-called superficial layer (SL), which was distinctly loose in the “young” minipigs, but had a much denser texture in the “old” minipigs. Here, the SL was dominated by elastic fibres in the CraF, but was of mixed qualities (collagenous and elastic) in the CauF. The structural requirements for the SL’s function as a loose “cover” were thus met only in the “young” animals. A clearly demarcated intermediate layer (IL)—characterised by high amounts of elastic fibres (as in humans)—was only found in the CraF of the “young” animals. In the “old” animals, it had lost its demarcation. In the depth of the CraF of the “old” animals, many thick collagen fibre bundles were detected in a location equivalent to that of the vocal muscle in the CauF. The development of their large diameters was interpreted as part of the maturation process, thereby supporting the hypothesis of their functional importance as a component of the “body.” In the CauF, the amounts of collagen structures increased throughout the entire lamina propria, resulting in a loss of demarcated stratigraphical subdivisions in the “old” minipigs. This situation resembled that described in the vocal fold of geriatric humans.     

CHRONIC PROSTATITIS: A Psychosexual Approach

“Chronic prostatitis” unaccompanied by signs of active inflammatory disease is a psychosexual disturbance, not a bacteriological disease. Prostate massage, local therapy, and antibiotic therapy are usually of no therapeutic value; a careful history and evalution of the background and good social and psychiatric counseling are the only effective and rational means by which this so called “prostatitis” is controllable.     

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.     

Social Effects of Genetic Counselling

In a follow-up study of 104 subjects referred for genetic counselling between 1965 and 1969 all were at risk of having children with a variety of serious genetic disorders. Most subjects were in social classes III and IV, were married, in their late 20s, and already had an affected child. Sixty-three per cent. were referred by hospital consultants, 27% by their general practitioners, and 10% were self-referrals. All of those counselled appeared to have appreciated the genetic implications, although four overestimated the risks and 11 underestimated the risks.Of those at high risk (greater than 1 in 10) of having an affected child 10 out of 55 couples “planned” further pregnancies despite the risks. In two this was because they had been unable to adopt a child, in four because they had no living children and the disorders in question usually resulted in stillbirth or death in infancy so that the “burden” of an affected child would be of relatively short duration, and one mother had had antenatal diagnosis and selective abortion. Most of the couples in the low-risk group (less than 1 in 20) were reassured and planned further pregnancies.     

Intrinsic Motivations Drive Learning of Eye Movements: An Experiment with Human Adults

Intrinsic motivations drive the acquisition of knowledge and skills on the basis of novel or surprising stimuli or the pleasure to learn new skills. In so doing, they are different from extrinsic motivations that are mainly linked to drives that promote survival and reproduction. Intrinsic motivations have been implicitly exploited in several psychological experiments but, due to the lack of proper paradigms, they are rarely a direct subject of investigation. This article investigates how different intrinsic motivation mechanisms can support the learning of visual skills, such as “foveate a particular object in space”, using a gaze contingency paradigm. In the experiment participants could freely foveate objects shown in a computer screen. Foveating each of two “button” pictures caused different effects: one caused the appearance of a simple image (blue rectangle) in unexpected positions, while the other evoked the appearance of an always-novel picture (objects or animals). The experiment studied how two possible intrinsic motivation mechanisms might guide learning to foveate one or the other button picture. One mechanism is based on the sudden, surprising appearance of a familiar image at unpredicted locations, and a second one is based on the content novelty of the images. The results show the comparative effectiveness of the mechanism based on image novelty, whereas they do not support the operation of the mechanism based on the surprising location of the image appearance. Interestingly, these results were also obtained with participants that, according to a post experiment questionnaire, had not understood the functions of the different buttons suggesting that novelty-based intrinsic motivation mechanisms might operate even at an unconscious level.     

Some personal and historical notes on the utility of “deep-etch” electron microscopy for making cell structure/function correlations

This brief essay talks up the advantages of metal replicas for electron microscopy and explains why they are still the best way to image frozen cells in the electron microscope. Then it explains our approach to freezing, namely the Van Harreveld trick of “slamming” living cells onto a supercold block of metal sprayed with liquid helium at −269ºC, and further talks up this slamming over the alternative of high-pressure freezing, which is much trickier but enjoys greater favor at the moment. This leads me to bemoan the fact that there are not more young investigators today who want to get their hands on electron microscopes and use our approach to get the most “true to life” views of cells out of them with a minimum of hassle. Finally, it ends with a few perspectives on my own career and concludes that, personally, I''m permanently stuck with the view of the “founding fathers” that cell ultrastructure will ultimately display and explain all of cell function, or as Palade said in his Nobel lecture,electron micrographs are “irresistible and half transparent … their meaning buried under only a few years of work,” and “reasonable working hypotheses are already suggested by the ultrastructural organization itself.”     

Basis for Cumulative Cultural Evolution in Chimpanzees: Social Learning of a More Efficient Tool-Use Technique

Background

The evidence for culture in non-human animals has been growing incrementally over the past two decades. However, the ability for cumulative cultural evolution, with successive generations building on earlier achievements, in non-human animals remains debated. Faithful social learning of incremental improvements in technique is considered to be a defining feature of human culture, differentiating human from non-human cultures. This study presents the first experimental evidence for chimpanzees'' social transmission of a more efficient tool-use technique invented by a conspecific group member.

Methodology/Principal Findings

The chimpanzees were provided with a straw-tube, and spontaneously demonstrated two different techniques in obtaining juice through a small hole: “dipping” and “straw-sucking”. Both the “dipping” and “straw-sucking” techniques depended on the use of the same tool (straw-tube) for the same target (juice) accessible from exactly the same location (small hole 1 cm in diameter). Therefore the difference between “dipping” and “straw-sucking” was only in “technique”. Although the two techniques differed significantly in their efficiency, their cognitive and perceptuo-motor complexity were comparable. All five chimpanzees who initially performed the “dipping” technique switched to using the more efficient “straw-sucking” technique upon observing a conspecific or human demonstrate the more proficient alternate “straw-sucking” technique.

Conclusions/Significance

The social learning mechanism involved here was clearly not local or stimulus enhancement, but imitation or emulation of a tool-use technique. When there is no biologically relevant difference in cognitive or perceptuo-motor complexity between two techniques, and when chimpanzees are dissatisfied with their own technique, chimpanzees may socially learn an improved technique upon close observation of a proficient demonstrator. This study provides important insights into the cognitive basis for cumulative culture in chimpanzees, and also suggests possible conditions in which cumulative cultural evolution could arise even in non-human animals.     

Short Peptide Induces an “Uncultivable” Microorganism To Grow In Vitro

Microorganisms comprise the bulk of biodiversity, but only a small fraction of this diversity grows on artificial media. This phenomenon was noticed almost a century ago, repeatedly confirmed, and termed the “great plate count anomaly.” Advances in microbial cultivation improved microbial recovery but failed to explain why most microbial species do not grow in vitro. Here we show that at least some of such species can form domesticated variants capable of growth on artificial media. We also present evidence that small signaling molecules, such as short peptides, may be essential factors in initiating growth of nongrowing cells. We identified one 5-amino-acid peptide, LQPEV, that at 3.5 nM induces the otherwise “uncultivable” strain Psychrobacter sp. strain MSC33 to grow on standard media. This demonstrates that the restriction preventing microbial in vitro growth may be different from those offered to date to explain the “great plate count anomaly,” such as deficiencies in nutrient composition and concentrations in standard media, medium toxicity, and inappropriate incubation time. Growth induction of MSC33 illustrates that some microorganisms do not grow in vitro because they are removed from their native communities and the signals produced therein. “Uncultivable” species represent the largest source of unexplored biodiversity, and provide remarkable opportunities for both basic and applied research. Access to cultures of some of these species should be possible through identification of the signaling compounds necessary for growth, their addition to standard medium formulations, and eventual domestication.     

INITIAL CARE OF ACUTE BACK INJURIES

The mechanism of injury to the back should be obtained with the utmost accuracy and set down in the history as a separate paragraph under that heading. This is usually best obtained by questioning and requestioning the patient during the course of the examination. A history of any previous back affections should also be obtained at the first visit.The detailed examination of the back is not complete without a general physical examination.X-ray studies should be done immediately in all cases in which the injury has been caused by direct violence or forceful indirect violence (as in “jackknife” injury).Terms such as “disc disease,” “ruptured intervertebral disc” and various others that convey a similar meaning should not be used as the initial diagnosis and should be withheld until such a diagnosis is definitely established.The plan of treatment may include a period in hospital or of rest at home, or it may be carried out with the patient ambulatory. Corsets and braces should be prescribed only when they are to serve a definite function and the same can be said of physiotherapy.     

The Selection of Medical Students in Western Canada

The methods employed in the selection of medical students for the 1964-65 class of freshmen at the four Western medical schools are described and recommendations are made for improving the procedure. The structure and functions of the various selection committees varied from school to school but their prime purpose was the same—the selection of “good students” who would later become “good physicians”. Not surprisingly, academic achievement and confidence in estimating this ranked highest in importance, and while non-intellectual characteristics ranked almost as high, committee members had no confidence that they could evaluate these qualities.It is suggested that the ideal selection committee would be a “high-priority” committee consisting of six to eight members who would meet at least twice a year, have tenure of at least four years, be trained in interviewing applicants, consider Medical College Admission Test scores, review applications before each meeting, and establish research committees to investigate the students they choose.     

Endless forms most stupid,icky, and small: The preponderance of noncharismatic invertebrates as integral to a biologically sound view of life

Big, beautiful organisms are useful for biological education, increasing evolution literacy, and biodiversity conservation. But if educators gloss over the ubiquity of streamlined and miniaturized organisms, they unwittingly leave students and the public vulnerable to the idea that the primary evolutionary plot of every metazoan lineage is “progressive” and "favors" complexity. We show that simple, small, and intriguingly repulsive invertebrate animals provide a counterpoint to misconceptions about evolution. Our examples can be immediately deployed in biology courses and outreach. This context emphasizes that chordates are not the pinnacle of evolution. Rather, in the evolution of animals, miniaturization, trait loss, and lack of perfection are at least as frequent as their opposites. Teaching about invertebrate animals in a “tree thinking” context uproots evolution misconceptions (for students and the public alike), provides a mental scaffold for understanding all animals, and helps to cultivate future ambassadors and experts on these little‐known, weird, and fascinating taxa.     

Dogs (Canis familiaris) Evaluate Humans on the Basis of Direct Experiences Only

Reputation formation is a key component in the social interactions of many animal species. An evaluation of reputation is drawn from two principal sources: direct experience of an individual and indirect experience from observing that individual interacting with a third party. In the current study we investigated whether dogs use direct and/or indirect experience to choose between two human interactants. In the first experiment, subjects had direct interaction either with a “nice” human (who played with, talked to and stroked the dog) or with an “ignoring” experimenter who ignored the dog completely. Results showed that the dogs stayed longer close to the “nice” human. In a second experiment the dogs observed a “nice” or “ignoring” human interacting with another dog. This indirect experience, however, did not lead to a preference between the two humans. These results suggest that the dogs in our study evaluated humans solely on the basis of direct experience.