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1.  View the label before you view the movie: A field experiment into the impact of Portion size and Guideline Daily Amounts labelling on soft drinks in cinemas 
BMC Public Health  2011;11:438.
Large soft drink sizes increase consumption, and thereby contribute to obesity. Portion size labelling may help consumers to select more appropriate food portions. This study aimed to assess the effectiveness of portion size and caloric Guidelines for Daily Amounts (GDA) labelling on consumers' portion size choices and consumption of regular soft drinks.
A field experiment that took place on two subsequent evenings in a Dutch cinema. Participants (n = 101) were asked to select one of five different portion sizes of a soft drink. Consumers were provided with either portion size and caloric GDA labelling (experimental condition) or with millilitre information (control condition).
Labelling neither stimulated participants to choose small portion sizes (OR = .75, p = .61, CI: .25 - 2.25), nor did labelling dissuade participants to choose large portion sizes (OR = .51, p = .36, CI: .12 - 2.15).
Portion size and caloric GDA labelling were found to have no effect on soft drink intake. Further research among a larger group of participants combined with pricing strategies is required. The results of this study are relevant for the current public health debate on food labelling.
PMCID: PMC3121640  PMID: 21645373
Portion sizes; Food labelling; Obesity prevention; Environmental interventions
Although the results we have recorded merely serve to indicate the possibilities of this interesting field of investigation, we have sufficient data to enable us to draw certain general conclusions. In the first place it is evident that the bloods of the more highly developed marine invertebrates, such as the active Crustacia and the Cephalopods, are specially adapted for the carriage of carbon dioxide. The quantity of carbon dioxide taken up by the blood of Maia, Palinurus, or Octopus at any given tension of the gas is, in general, about twice or three times as great as that which is taken up by sea water under the same conditions. On the other hand, the blood of a slow, creeping form, such as Aplysia, or of a sessile animal such as the ascidian Phallusia shows no more adaptation for the carriage of carbon dioxide than does sea water. But our estimations of the CO2 content of the blood as it circulates in the bodies of these more active invertebrates show that the conditions of transport of this gas differ considerably in some respects from those which obtain in mammals. For the invertebrate blood in the body contains only a relatively small quantity of carbon dioxide, averaging in the forms we examined from 3 to 10 cc. per 100 cc. of blood. This forms a marked contrast with the condition found in mammals where even the arterial blood contains about 50 cc. of CO2 per 100 cc. of blood. The invertebrate, therefore, works at a very low CO2 tension. There is a twofold significance in this circumstance. In the first place, it means that only the first portion of the carbon dioxide dissociation curve is in use in the respiratory mechanism. Now an inspection of our curves will show that at these low carbon dioxide tensions the dissociation curves tend to be steeper than at higher tensions. As we intend to show in a later paper it can be proved mathematically that, other things being equal, a blood with a carbon dissociation curve of moderate steepness, i.e. one in which the carbon dioxide content of the blood increases fairly rapidly with increase of carbon dioxide tension, is a more efficient carrier of the gas from the tissues to a respiratory surface than a blood in which the dissociation curve is either steeper or flatter. It would seem as if the active invertebrates avoid the use of too flat a part of their CO2 dissociation curves by working over the initial steeper portion. Furthermore, it is seen that over the range of this initial steep portion of the curves the changes of reaction produced by the uptake of carbon dioxide are much smaller than at higher tensions of the gas; for these initial portions of the curves are more nearly parallel to the lines of constant reaction calculated for a temperature of 15°C. according to Hasselbalch's method (10) on the assumption that the whole of the combined CO2 is in the form of sodium bicarbonate. It is evident also that on this assumption the hydrogen ion concentration of the blood of invertebrates (with the exception of the tunicates) would appear to be practically the same as that of the warm-blooded vertebrates—a conclusion confirmed by the direct measurements of Quagliariello (9). On the other hand, our measurements do not lend support to the idea put forward by Collip (4) that in order to maintain an appropriate faintly alkaline reaction an invertebrate needs to retain carbon dioxide in its blood at a comparatively high tension. This idea was based on the observation that at comparatively high CO2 tensions the blood of invertebrates contains considerably more sodium bicarbonate than does sea water. But our curves show that this is no longer true at the lower values of carbon dioxide tension, the amount of sodium bicarbonate falling off more rapidly in the blood than in the sea water with diminution of the carbon dioxide tension so that in order to maintain an appropriate reaction in the blood only a comparatively small tension of CO2 is required. The largest amount of carbon dioxide that we found present in the circulating blood of any of the types examined was 9.7 cc. per 100 cc. of blood in the case of Maia, and in most cases the amount was considerably less. But even this lowest value corresponds to a tension of CO2 of only about 3 mm., so that the tension gradient across the gill membrane must be even less than this. We would emphasize rather the circumstances that as the portion of the dissociation curve over which the reaction is approximately constant is of but small extent, it is necessary that in an active form like Octopus the carbon dioxide produced should be removed rapidly lest an accumulation of it should cause the limits of normal reaction to be exceeded; and this need is correlated with the extreme efficiency of the respiratory apparatus in this animal. It is interesting to notice that the mammal which, in order to obtain an appropriate reaction in the blood, has to work at relatively high carbon dioxide tensions where the dissociation curve is comparatively flat, secures a steeper physiological CO2 dissociation curve in the body, and with it a more efficient carriage of carbon dioxide and a more constant reaction in the circulating fluid, in virtue of the effect of oxygenation on the carbon dioxide-combining power of its blood (3, 6). Returning now to the consideration of the actual form of the dissociation curves we have obtained—it is a significant fact that it is in those forms such as Maia, Palinurus, and Octopus whose bloods are rich in proteins—particularly hemocyanine—that the initial steep portion of the curve is observed. This suggests that in these forms the blood proteins act as weak acids and expel carbon dioxide from the blood at the low tensions which include the physiological range, just as in vertebrates the hemoglobin similarly displaces carbonic acid from its combination with alkali metal. On the other hand the cœlomic fluid of Aplysia contains no pigment and only 0.00672 per cent of protein nitrogen (Bottazzi (11)) and shows no initial rapidly ascending portion of the CO2 dissociation curve. This is supported by the observation of Quagliariello (9) that the acid-neutralising power of the blood of an invertebrate is roughly proportional to its protein content. It seems as if the proteins of invertebrate blood like the blood proteins of vertebrates, exist in the form of sodium salts which are capable of giving up sodium for the transport of carbon dioxide as sodium bicarbonate. That this is so in the case of hemocyanine follows from the fact that the isoelectric point of this pigment occurs at a hydrogen ion concentration of 2.12 x 10–5 N, i.e. at a pH of 4.67 (Quagliariello (12)) so that in the alkaline blood of the invertebrates possessing it, hemocyanine will act as a weak acid. It is probable that the initial steep portion of the carbon dioxide dissociation curves which we have found to be of such importance in the respiration physiology of Octopus, Palinurus, and Maia is produced by the competition of this acid with carbonic acid for the available sodium of the blood.
PMCID: PMC2140628  PMID: 19872059
3.  Ebstein's Anomaly: Anatomo-echocardiographic correlation 
The aim of this investigation is to demonstrate that in Ebstein's Anomaly (EA) the right ventricle (RV) is affected in its three portions and to establish an anatomoechocardiographic correlation between the anatomic features and the equivalent echocardiographic images.
Thirty hearts with EA were studied. The alterations of each portions of the RV were described. Fifty adult patients with this anomaly were studied by echocardiography.
Anatomy: All hearts had atrial situs solitus, 27 had concordant atrioventricular connection and 3 discordant, of these 2 had transposition of the great arteries (TGA) and one double outlet right ventricle (DORV). The degree of tricuspid valve (TV) displacement showed a spectrum from I to III. The inlet of the RV was markedly thin in 27. The trabecular portion had multiples muscular bands in all. The outlet portion was dilated in 20 and stenotic in 5. In 25 atrial septal defects were found. Echocardiography: All patients had atrial situs solitus, 42 with concordant atrioventricular connection and 8 with discordant, of these last patients 5 had TGA and 3 DORV. The degree of TV displacement varied from I to III. The inlet of RV was markedly thin in 42. The trabecular portion had muscular bands in 45. The outlet portion was dilated in 31 and stenotic in 11. In 30 atrial septal defects were found.
The EA affects the whole RV and the anatomoechocardiographic correlation provides an appropriate understanding of echocardiographic images in terms of a precise diagnosis, therapeutic decisions and prognosis.
PMCID: PMC2217516  PMID: 18034907
4.  The Theory of Evolution - A Jewish Perspective 
All possible pro and con arguments regarding the theory of evolution have been discussed and debated in the vast literature—scientific, religious, and lay—in the past 150 years. There is usually great zealotry in all debating parties, with mutual intolerance of ideas and concepts, disrespect toward opposing opinions and positions, and usage of very harsh language. This prejudiced approach usually does not allow for a reasonable debate. It is important to look at the facts, assumptions, and beliefs of the theory of evolution in a more calm and humble way.
In this article a comparative analysis is offered between the scientific aspects of the theory of evolution and a Judaic approach to these aspects.
The two sets of human thought—religion and science—are fundamentally different in their aims and purposes, in their methods of operation, in their scope of interest and issues, and in their origin and ramifications. Whenever science surpasses its limits, or religion exceeds its boundaries, it actually is a form of an abuse of both. This has happened to the theory of evolution in a more powerful mode than any other interaction between science and religion.
The agenda of many scientists who promote the theory of evolution is to achieve the goal of understanding the existence of the universe as a random, purposeless, natural development, evolved slowly over billions of years from a common ancestor by way of natural selection, devoid of any supernatural metaphysical power.
Jewish faith perceives the development of the universe in a different way: God created the world, with a purpose known to Him; He established natural laws that govern the world; and He imposed a moral-religious set of requirements upon Man.
The discussion and comparative analysis in this article is based upon the current neo-Darwinian theory, although it seems almost certain that even the new and modern assumptions and speculations will continue to be challenged, changed, and revised as new scientific information will be discovered. The theory of evolution is based upon certain facts, many assumptions, speculations, and interpretations, and some fundamental non-evidence-based beliefs.
Judaism accepts all experimentally proven facts and observations of the theory of evolution. Judaism accepts some of the assumptions and interpretations embedded in the theory of evolution, but rejects other assumptions and speculations which contradict fundamental Jewish beliefs, and which are anyway not scientifically proven; to those Judaism offers different interpretations. Judaism strongly rejects all the extensions of the theory of evolution beyond natural sciences, which endorse the biological assumption of the “survival of the fittest” in commerce and human societies as a whole by justifying claims of social inequality, sexism, racism, Nazism, eugenics, and other moral-social deviations as “laws of nature”.
PMCID: PMC3721658  PMID: 23908780
evolution; Judaism; religion and science; fossils; random mutations; big bang
5.  Insights into secondary growth in perennial plants: its unequal spatial and temporal dynamics in the apple (Malus domestica) is driven by architectural position and fruit load 
Annals of Botany  2010;105(4):607-616.
Background and Aims
Secondary growth is a main physiological sink. However, the hierarchy between the processes which compete with secondary growth is still a matter of debate, especially on fruit trees where fruit weight dramatically increases with time. It was hypothesized that tree architecture, here mediated by branch age, is likely to have a major effect on the dynamics of secondary growth within a growing season.
Three variables were monitored on 6-year-old ‘Golden Delicious’ apple trees from flowering time to harvest: primary shoot growth, fruit volume, and cross-section area of branch portions of consecutive ages. Analyses were done through an ANOVA-type analysis in a linear mixed model framework.
Key Results
Secondary growth exhibited three consecutive phases characterized by unequal relative area increment over the season. The age of the branch had the strongest effect, with the highest and lowest relative area increment for the current-year shoots and the trunk, respectively. The growth phase had a lower effect, with a shift of secondary growth through the season from leafy shoots towards older branch portions. Eventually, fruit load had an effect on secondary growth mainly after primary growth had ceased.
The results support the idea that relationships between production of photosynthates and allocation depend on both primary growth and branch architectural position. Fruit load mainly interacted with secondary growth later in the season, especially on old branch portions.
PMCID: PMC2850790  PMID: 20228088
Branch age; fruit load; growth phase; Malus domestica (apple); primary growth; secondary growth; tree architecture
6.  Comparison of SpineJet™ XL and Conventional Instrumentation for Disk Space Preparation in Unilateral Transforaminal Lumbar Interbody Fusion 
Although unilateral transforaminal lumbar interbody fusion (TLIF) is widely used because of its benefits, it does have some technical limitations. Removal of disk material and endplate cartilage is difficult, but essential, for proper fusion in unilateral surgery, leading to debate regarding the surgery's limitations in removing the disk material on the contralateral side. Therefore, authors have conducted a randomized, comparative cadaver study in order to evaluate the efficiency of the surgery when using conventional instruments in the preparation of the disk space and when using the recently developed high-pressure water jet system, SpineJet™ XL.
Two spine surgeons performed diskectomies and disk preparations for TLIF in 20 lumbar disks. All cadaver/surgeon/level allocations for preparation using the SpineJet™ XL (HydroCision Inc., Boston, MA, USA) or conventional tools were randomized. All assessments were performed by an independent spine surgeon who was unaware of the randomizations. The authors measured the areas (cm2) and calculated the proportion (%) of the disk surfaces. The duration of the disk preparation and number of instrument insertions and withdrawals required to complete the disk preparation were recorded for all procedures.
The proportion of the area of removed disk tissue versus that of potentially removable disk tissue, the proportion of the area of removed endplate cartilage, and the area of removed disk tissue in the contralateral posterior portion showed 74.5 ± 17.2%, 18.5 ± 12.03%, and 67.55 ± 16.10%, respectively, when the SpineJet™ XL was used, and 52.6 ± 16.9%, 22.8 ± 17.84%, and 51.64 ± 19.63%, respectively, when conventional instrumentations were used. The results also showed that when the SpineJet™ XL was used, the proportion of the area of removed disk tissue versus that of potentially removable disk tissue and the area of removed disk tissue in the contralateral posterior portion were statistically significantly high (p < 0.001, p < 0.05, respectively). Also, compared to conventional instrumentations, the duration required to complete disk space preparation was shorter, and the frequency of instrument use and the numbers of insertions/withdrawals were lower when the SpineJet™ XL was used.
The present study demonstrates that hydrosurgery using the SpineJet™ XL unit allows for the preparation of a greater portion of disk space and that it is less traumatic and allows for more precise endplate preparation without damage to the bony endplate. Furthermore, the SpineJet™ XL appears to provide tangible benefits in terms of disk space preparation for graft placement, particularly when using the unilateral TLIF approach.
PMCID: PMC2883058  PMID: 20539797
Transforaminal lumbar interbody fusion; Diskectomy
7.  Beyond the Evidence of the New Hypertension Guidelines. Blood pressure measurement – is it good enough for accurate diagnosis of hypertension? Time might be in, for a paradigm shift (I) 
Despite widespread availability of a large body of evidence in the area of hypertension, the translation of that evidence into viable recommendations aimed at improving the quality of health care is very difficult, sometimes to the point of questionable acceptability and overall credibility of the guidelines advocating those recommendations.
The scientific community world-wide and especially professionals interested in the topic of hypertension are witnessing currently an unprecedented debate over the issue of appropriateness of using different drugs/drug classes for the treatment of hypertension. An endless supply of recent and less recent "drug-news", some in support of, others against the current guidelines, justifying the use of selected types of drug treatment or criticising other, are coming out in the scientific literature on an almost weekly basis. The latest of such debate (at the time of writing this paper) pertains the safety profile of ARBs vs ACE inhibitors.
To great extent, the factual situation has been fuelled by the new hypertension guidelines (different for USA, Europe, New Zeeland and UK) through, apparently small inconsistencies and conflicting messages, that might have generated substantial and perpetuating confusion among both prescribing physicians and their patients, regardless of their country of origin.
The overwhelming message conveyed by most guidelines and opinion leaders is the widespread use of diuretics as first-line agents in all patients with blood pressure above a certain cut-off level and the increasingly aggressive approach towards diagnosis and treatment of hypertension. This, apparently well-justified, logical and easily comprehensible message is unfortunately miss-obeyed by most physicians, on both parts of the Atlantic.
Amazingly, the message assumes a universal simplicity of both diagnosis and treatment of hypertension, while ignoring several hypertension-specific variables, commonly known to have high level of complexity, such as:
- accuracy of recorded blood pressure and the great inter-observer variability,
- diversity in the competency and training of diagnosing physician,
- individual patient/disease profile with highly subjective preferences,
- difficulty in reaching consensus among opinion leaders,
- pharmaceutical industry's influence, and, nonetheless,
- the large variability in the efficacy and safety of the antihypertensive drugs.
The present 2-series article attempts to identify and review possible causes that might have, at least in part, generated the current healthcare anachronism (I); to highlight the current trend to account for the uncertainties related to the fixed blood pressure cut-off point and the possible solutions to improve accuracy of diagnosis and treatment of hypertension (II).
PMCID: PMC1087862  PMID: 15813975
8.  Is there a north-south divide in social class inequalities in health in Great Britain? Cross sectional study using data from the 2001 census 
BMJ : British Medical Journal  2004;328(7447):1043-1045.
Objective To examine individual social class inequalities in self rated general health within and between the constituent countries of Great Britain and the regions of England.
Design Cross sectional study using data from the 2001 national census.
Setting Great Britain.
Participants Adults aged between 25 and 64 in Great Britain and enumerated in the 2001 population census (n = 25.6 million).
Main outcome measures European age standardised rates of self rated general health, for men and women classified by the government social class scheme.
Results In each of the seven social classes, Wales and the North East and North West regions of England had high rates of poor health. There were large social class inequalities in self rated health, with rates of poor health generally increasing from class 1 (higher professional occupations) to class 7 (routine occupations). The size of the health divide varied between regions: the largest rate ratios for routine versus higher professional classes were for Scotland (2.9 for men; 2.8 for women) and London (2.9 for men; 2.4 for women). Women had higher rates of poor health compared to men in the same social class, except in class 6 (semi-routine occupations).
Conclusions A northwest-southeast divide in social class inequalities existed in Great Britain at the start of the 21st century, with each of the seven social classes having higher rates of poor health in Wales, the North East and North West regions of England than elsewhere. The widest health gap between social classes, however, was in Scotland and London, adding another dimension to the policy debate on resource allocation and targets to tackle the health divide.
PMCID: PMC403842  PMID: 15117791
9.  The Family as a Social Unit 
Canadian Family Physician  1976;22:53-55.
Family medicine, in common with most other medical specialties, is passing through a period of lively debate concerning its course and development. This paper discusses that portion of the debate attempting to define the function of the family physician in overseeing the comprehensive and continuing health care of patients and their families. One consequence of such a definition is the need to understand thoroughly the family in its functional role as a social unit. This knowledge of the family unit will affect some aspects of the practice of family medicine. Some of our approaches to training practitioners in this challenging field are outlined.
PMCID: PMC2378397  PMID: 21304754
10.  Casting in Sport 
Journal of Athletic Training  1994;29(1):37-43.
Attempts by sports medicine professionals to return high school athletes with hand and wrist injuries to competition quickly and safely have been the source of confusion and debate on many playing fields around the country. In addition to the differing views regarding the appropriateness of playing cast usage in high school football, a debate exists among sports medicine professionals as to which material is best suited for playing cast construction. Materials used in playing cast construction should be hard enough to provide sufficient stabilization to the injured area and include adequate padding to absorb blunt impact forces. The purpose of the biomechanical portion of this investigation was to attempt to determine the most appropriate materials for use in constructing playing casts for the hand and wrist by assessing different materials for: 1) hardness using a Shore durometer, and 2) ability to absorb impact using a force platform. Results revealed that RTV11 and Scotchcast were the “least hard” of the underlying casting materials and that Temper Stick foam greatly increased the ability of RTV11 to absorb impact. Assessment of the mechanical properties of playing cast materials and review of current developments in high school football rules are used to aid practitioners in choosing the most appropriate materials for playing cast construction.
PMCID: PMC1317757  PMID: 16558257
11.  Shared Human-Chimpanzee Pattern of Perinatal Femoral Shaft Morphology and Its Implications for the Evolution of Hominin Locomotor Adaptations 
PLoS ONE  2012;7(7):e41980.
Acquisition of bipedality is a hallmark of human evolution. How bipedality evolved from great ape-like locomotor behaviors, however, is still highly debated. This is mainly because it is difficult to infer locomotor function, and even more so locomotor kinematics, from fossil hominin long bones. Structure-function relationships are complex, as long bone morphology reflects phyletic history, developmental programs, and loading history during an individual’s lifetime. Here we discriminate between these factors by investigating the morphology of long bones in fetal and neonate great apes and humans, before the onset of locomotion.
Methodology/Principal Findings
Comparative morphometric analysis of the femoral diaphysis indicates that its morphology reflects phyletic relationships between hominoid taxa to a greater extent than taxon-specific locomotor adaptations. Diaphyseal morphology in humans and chimpanzees exhibits several shared-derived features, despite substantial differences in locomotor adaptations. Orangutan and gorilla morphologies are largely similar, and likely represent the primitive hominoid state.
These findings are compatible with two possible evolutionary scenarios. Diaphyseal morphology may reflect retained adaptive traits of ancestral taxa, hence human-chimpanzee shared-derived features may be indicative of the locomotor behavior of our last common ancestor. Alternatively, diaphyseal morphology might reflect evolution by genetic drift (neutral evolution) rather than selection, and might thus be more informative about phyletic relationships between taxa than about locomotor adaptations. Both scenarios are consistent with the hypothesis that knuckle-walking in chimpanzees and gorillas resulted from convergent evolution, and that the evolution of human bipedality is unrelated to extant great ape locomotor specializations.
PMCID: PMC3405051  PMID: 22848680
12.  Endothelial Progenitors Exist within the Kidney and Lung Mesenchyme 
PLoS ONE  2013;8(6):e65993.
The renal endothelium has been debated as arising from resident hemangioblast precursors that transdifferentiate from the nephrogenic mesenchyme (vasculogenesis) and/or from invading vessels (angiogenesis). While the Foxd1-positive renal cortical stroma has been shown to differentiate into cells that support the vasculature in the kidney (including vascular smooth muscle and pericytes) it has not been considered as a source of endothelial cell progenitors. In addition, it is unclear if Foxd1-positive mesenchymal cells in other organs such as the lung have the potential to form endothelium. This study examines the potential for Foxd1-positive cells of the kidney and lung to give rise to endothelial progenitors. We utilized immunofluorescence (IF) and fluorescence-activated cell sorting (FACS) to co-label Foxd1-expressing cells (including permanently lineage-tagged cells) with endothelial markers in embryonic and postnatal mice. We also cultured FACsorted Foxd1-positive cells, performed in vitro endothelial cell tubulogenesis assays and examined for endocytosis of acetylated low-density lipoprotein (Ac-LDL), a functional assay for endothelial cells. Immunofluorescence and FACS revealed that a subset of Foxd1-positive cells from kidney and lung co-expressed endothelial cell markers throughout embryogenesis. In vitro, cultured embryonic Foxd1-positive cells were able to differentiate into tubular networks that expressed endothelial cell markers and were able to endocytose Ac-LDL. IF and FACS in both the kidney and lung revealed that lineage-tagged Foxd1-positive cells gave rise to a significant portion of the endothelium in postnatal mice. In the kidney, the stromal-derived cells gave rise to a portion of the peritubular capillary endothelium, but not of the glomerular or large vessel endothelium. These findings reveal the heterogeneity of endothelial cell lineages; moreover, Foxd1-positive mesenchymal cells of the developing kidney and lung are a source of endothelial progenitors that are likely critical to patterning the vasculature.
PMCID: PMC3688860  PMID: 23823180
13.  Long Head of the Biceps Tendon Allis Clamp Evaluation Technique 
Arthroscopy Techniques  2014;3(4):e491-e493.
Disorders of the long head of the biceps brachii are a common finding in conjunction with other causes of shoulder pathology. Nonoperative means as first-line treatment are often successful; however, surgery can be indicated for refractory tendinopathy. There is debate as to the best surgical treatment of the long head of the biceps tendon (LHBT) with different types of arthroscopic and open techniques. The decision on what treatment option to perform is often made at the time of surgery after arthroscopic evaluation of the LHBT. Certain examples of tendon disease are easily visible intra-articularly; however, a large portion of the tendon is not intra-articular and not readily viewed during routine arthroscopy. This study describes a simple arthroscopic technique for evaluation of an increased portion of the LHBT using an Allis clamp. The clamp is inserted through the anterior portal, placed around the LHBT, and rotated such that the tendon is wrapped around itself, bringing the distal tendon into the joint for arthroscopic viewing. This procedure is a routine part of our assessment of the LHBT during arthroscopy.
PMCID: PMC4175553  PMID: 25276608
14.  The orthology of HLA-E and H2-Qa1 is hidden by their concerted evolution with other MHC class I molecules 
Biology Direct  2006;1:2.
Whether MHC molecules undergo concerted evolution or not has been the subject of a long-standing debate.
By comparing sequences of eight functional homologues of HLA-E from primates and rodents with those of MHC class Ia molecules from the same eight species, we find that different portions of MHC class I molecules undergo different patterns of evolution. By focusing our analyses sequentially on these various portions, we have obtained clear evidence for concerted evolution of MHC class I molecules, suggesting the occurrence of extensive interallelic and intergenic exchanges. Intra-species homogenisation of sequences is particularly noticeable at the level of exon 4, which codes for the α3 domain, but our results suggest that homogenisation also concerns certain residues of the α1–α2 codomain that lie outside the antigen recognition site.
A model is presented in which Darwinian selective pressures due to pathogens could, at the same time, favour diversification of MHC class Ia molecules and promote concerted evolution of separate loci by spreading advantageous motifs arising by mutations in individual MHC molecules to other alleles and to other loci of the MHC region. This would also allow MHC molecules to co-evolve with the proteins with which they interact to fulfil their functions of antigen presentation and regulation of NK cell activity. One of the raisons d'être of the MHC may therefore be to favour at the same time both diversification of MHC class Ia molecules and homogenisation of the whole pool of MHC class I molecules (Ia and Ib) involved in antigen presentation.
This article was reviewed by Stephan Beck, Lutz Walter and Pierre Pontarotti.
PMCID: PMC1403747  PMID: 16542007
15.  A framework for comparing structural and functional measures of glaucomatous damage 
While it is often said that structural damage due to glaucoma precedes functional damage, it is not always clear what this statement means. This review has two purposes: first, to show that a simple linear relationship describes the data relating a particular functional test (standard automated perimetry (SAP)) to a particular structural test (optical coherence tomography (OCT)); and, second, to propose a general framework for relating structural and functional damage, and for evaluating if one precedes the other. The specific functional and structural tests employed are described in Section 2. To compare SAP sensitivity loss to loss of the retinal nerve fiber layer (RNFL) requires a map that relates local field regions to local regions of the optic disc as described in Section 3. When RNFL thickness in the superior and inferior arcuate sectors of the disc are plotted against SAP sensitivity loss (dB units) in the corresponding arcuate regions of the visual field, RNFL thickness becomes asymptotic for sensitivity losses greater than about 10 dB. These data are well described by a simple linear model presented in Section 4. The model assumes that the RNFL thickness measured with OCT has two components. One component is the axons of the retinal ganglion cells and the other, the residual, is everything else (e.g. glial cells, blood vessels). The axon portion is assumed to decrease in a linear fashion with losses in SAP sensitivity (in linear units); the residual portion is assumed to remain constant. Based upon severe SAP losses in anterior ischemic optic neuropathy (AION), the residual RNFL thickness in the arcuate regions is, on average, about one-third of the premorbid (normal) thickness of that region. The model also predicts that, to a first approximation, SAP sensitivity in control subjects does not depend upon RNFL thickness. The data (Section 6) are, in general, consistent with this prediction showing a very weak correlation between RNFL thickness and SAP sensitivity. In Section 7, the model is used to estimate the proportion of patients showing statistical abnormalities (worse than the 5th percentile) on the OCT RNFL test before they show abnormalities on the 24-2 SAP field test. Ignoring measurement error, the patients with a relatively thick RNFL, when healthy, will be more likely to show significant SAP sensitivity loss before statistically significant OCT RNFL loss, while the reverse will be true for those who start with an average or a relatively thin RNFL when healthy. Thus, it is important to understand the implications of the wide variation in RNFL thickness among control subjects. Section 8 describes two of the factors contributing to this variation, variations in the position of blood vessels and variations in the mapping of field regions to disc sectors. Finally, in Sections 7 and 9, the findings are related to the general debate in the literature about the relationship between structural and functional glaucomatous damage and a framework is proposed for understanding what is meant by the question, ‘Does structural damage precede functional damage in glaucoma?’ An emphasis is placed upon the need to distinguish between “statistical” and “relational” meanings of this question.
PMCID: PMC2110881  PMID: 17889587
16.  Phylogeography of Supralittoral Rocky Intertidal Ligia Isopods in the Pacific Region from Central California to Central Mexico 
PLoS ONE  2010;5(7):e11633.
Ligia isopods are widely distributed in the Pacific rocky intertidal shores from central California to central Mexico, including the Gulf of California. Yet, their biological characteristics restrict them to complete their life cycles in a very narrow range of the rocky intertidal supralittoral. Herein, we examine phylogeographic patterns of Ligia isopods from 122 localities between central California and central Mexico. We expect to find high levels of allopatric diversity. In addition, we expect the phylogeographic patterns to show signatures of past vicariant events that occurred in this geologically dynamic region.
Methodology/Principal Findings
We sequenced two mitochondrial genes (Cytochrome Oxidase I and 16S ribosomal DNA). We conducted Maximum Likelihood and Bayesian phylogenetic analyses. We found many divergent clades that, in general, group according to geography. Some of the most striking features of the Ligia phylogeographic pattern include: (1) deep mid-peninsular phylogeographic breaks on the Pacific and Gulf sides of Baja peninsula; (2) within the Gulf lineages, the northern peninsula is most closely related to the northern mainland, while the southern peninsula is most closely related to the central-southern mainland; and, (3) the southernmost portion of the peninsula (Cape Region) is most closely related to the southernmost portion of mainland.
Our results shed light on the phylogenetic relationships of Ligia populations in the study area. This study probably represents the finest-scale phylogeographic examination for any organism to date in this region. Presence of highly divergent lineages suggests multiple Ligia species exist in this region. The phylogeographic patterns of Ligia in the Gulf of California and Baja peninsula are incongruent with a widely accepted vicariant scenario among phylogeographers, but consistent with aspects of alternative geological hypotheses and phylo- and biogeographic patterns of several other taxa. Our findings contribute to the ongoing debate regarding the geological origin of this important biogeographic region.
PMCID: PMC2908127  PMID: 20657776
17.  Discrete Capacity Limits in Visual Working Memory 
Current opinion in neurobiology  2010;20(2):177-182.
The amount of information we can actively maintain “in mind” is very limited. This capacity limitation, as known as working memory capacity, has been of great interest due to its wide scope influence on the variety of intellectual abilities. Recently, there has been an ongoing debate about how this capacity should best be characterized. One viewpoint argues that working memory capacity is allocated in a discrete fashion with an upper limit of 3-4 representations. An alternative viewpoint argues that the capacity can be allocated in a continuous fashion with no upper limit in the number of representations. In this article, we will review recent neurobiological and behavioral evidence that has helped shape the debate regarding one of the more central mechanisms in cognitive neuroscience.
PMCID: PMC3019116  PMID: 20362427
18.  Should patents for antiretrovirals be waived in the developing world? Annual varsity medical debate - London, 21 January 2011 
The 2011 Varsity Medical Debate, between Oxford and Cambridge Universities, brought students and faculty together to discuss the waiving of patents for antiretroviral therapies in the developing world. With an estimated 29.5 million infected by Human Immunodeficiency Virus (HIV) in low- and middle-income countries and only 5.3 million of those being treated, the effective and equitable distribution of anti-retroviral therapy (ART) is an issue of great importance. The debate centred around three areas of contention. Firstly, there was disagreement about whether patents were the real barrier to the access of anti-retroviral therapy in the developing world. Secondly, there were differing views on the effectiveness of a patent pool. Thirdly, concerns were raised over the impact of waiving patents on research to produce new and better anti retro-viral drugs.
PMCID: PMC3160882  PMID: 21740573
19.  Donation after cardiocirculatory death: a call for a moratorium pending full public disclosure and fully informed consent 
Many believe that the ethical problems of donation after cardiocirculatory death (DCD) have been "worked out" and that it is unclear why DCD should be resisted. In this paper we will argue that DCD donors may not yet be dead, and therefore that organ donation during DCD may violate the dead donor rule. We first present a description of the process of DCD and the standard ethical rationale for the practice. We then present our concerns with DCD, including the following: irreversibility of absent circulation has not occurred and the many attempts to claim it has have all failed; conflicts of interest at all steps in the DCD process, including the decision to withdraw life support before DCD, are simply unavoidable; potentially harmful premortem interventions to preserve organ utility are not justifiable, even with the help of the principle of double effect; claims that DCD conforms with the intent of the law and current accepted medical standards are misleading and inaccurate; and consensus statements by respected medical groups do not change these arguments due to their low quality including being plagued by conflict of interest. Moreover, some arguments in favor of DCD, while likely true, are "straw-man arguments," such as the great benefit of organ donation. The truth is that honesty and trustworthiness require that we face these problems instead of avoiding them. We believe that DCD is not ethically allowable because it abandons the dead donor rule, has unavoidable conflicts of interests, and implements premortem interventions which can hasten death. These important points have not been, but need to be fully disclosed to the public and incorporated into fully informed consent. These are tall orders, and require open public debate. Until this debate occurs, we call for a moratorium on the practice of DCD.
PMCID: PMC3313846  PMID: 22206616
Dead donor rule; Death; Donation after cardiac death; Organ donation
20.  New Insight into the History of Domesticated Apple: Secondary Contribution of the European Wild Apple to the Genome of Cultivated Varieties 
PLoS Genetics  2012;8(5):e1002703.
The apple is the most common and culturally important fruit crop of temperate areas. The elucidation of its origin and domestication history is therefore of great interest. The wild Central Asian species Malus sieversii has previously been identified as the main contributor to the genome of the cultivated apple (Malus domestica), on the basis of morphological, molecular, and historical evidence. The possible contribution of other wild species present along the Silk Route running from Asia to Western Europe remains a matter of debate, particularly with respect to the contribution of the European wild apple. We used microsatellite markers and an unprecedented large sampling of five Malus species throughout Eurasia (839 accessions from China to Spain) to show that multiple species have contributed to the genetic makeup of domesticated apples. The wild European crabapple M. sylvestris, in particular, was a major secondary contributor. Bidirectional gene flow between the domesticated apple and the European crabapple resulted in the current M. domestica being genetically more closely related to this species than to its Central Asian progenitor, M. sieversii. We found no evidence of a domestication bottleneck or clonal population structure in apples, despite the use of vegetative propagation by grafting. We show that the evolution of domesticated apples occurred over a long time period and involved more than one wild species. Our results support the view that self-incompatibility, a long lifespan, and cultural practices such as selection from open-pollinated seeds have facilitated introgression from wild relatives and the maintenance of genetic variation during domestication. This combination of processes may account for the diversification of several long-lived perennial crops, yielding domestication patterns different from those observed for annual species.
Author Summary
The apple, one of the most ubiquitous and culturally important temperate fruit crops, provides us with a unique opportunity to study the process of domestication in trees. The number and identity of the progenitors of the domesticated apple and the erosion of genetic diversity associated with the domestication process remain debated. The Central Asian wild apple has been identified as the main progenitor, but other closely related species along the Silk Route running from Asia to Western Europe may have contributed to the genome of the domesticated crop. Using rapidly evolving genetic markers to make inferences about the recent evolutionary history of the domesticated apple, we found that the European crabapple has made an unexpectedly large contribution to the genome of the domesticated apple. Bidirectional gene flow between the domesticated apple and the European crabapple resulted in the domesticated apple being currently more similar genetically to this secondary genepool than to the ancestral progenitor, the Central Asian wild apple. We found that domesticated apples have evolved over long time scales, with contributions from at least two wild species in different geographic areas, with no significant erosion of genetic diversity. This process of domestication and diversification may be common to other fruit trees and contrasts with the models documented for annual crops.
PMCID: PMC3349737  PMID: 22589740
21.  Household and farm transitions in environmental context 
Population and environment  2011;32(4):287-317.
Recent debate in the literature on population, environment, and land use questions the applicability of theory that patterns of farm extensification and intensification correspond to the life course of farmers and to the life cycle of farm families. This paper extends the debate to the agricultural development of the United States Great Plains region, using unique data from 1875 to 1930 that link families to farms over time in 25 environmentally diverse Kansas townships. Results of multilevel statistical modeling indicate that farmer’s age, household size, and household structure are simultaneously related to both the extent of farm operations and the intensity of land use, taking into account local environmental conditions and time trends as Kansas was settled and developed. These findings validate farm- and life cycle theories and offer support for intergenerational motivations for farm development that include both daughters and sons. Environmental variation in aridity was a key driver of farm structure.
PMCID: PMC3105790  PMID: 21643468
Household; Life cycle; Land use; Agriculture; Semi-arid; Kansas
22.  Nucleosome Free Regions in Yeast Promoters Result from Competitive Binding of Transcription Factors That Interact with Chromatin Modifiers 
PLoS Computational Biology  2013;9(8):e1003181.
Because DNA packaging in nucleosomes modulates its accessibility to transcription factors (TFs), unraveling the causal determinants of nucleosome positioning is of great importance to understanding gene regulation. Although there is evidence that intrinsic sequence specificity contributes to nucleosome positioning, the extent to which other factors contribute to nucleosome positioning is currently highly debated. Here we obtained both in vivo and in vitro reference maps of positions that are either consistently covered or free of nucleosomes across multiple experimental data-sets in Saccharomyces cerevisiae. We then systematically quantified the contribution of TF binding to nucleosome positiong using a rigorous statistical mechanics model in which TFs compete with nucleosomes for binding DNA. Our results reconcile previous seemingly conflicting results on the determinants of nucleosome positioning and provide a quantitative explanation for the difference between in vivo and in vitro positioning. On a genome-wide scale, nucleosome positioning is dominated by the phasing of nucleosome arrays over gene bodies, and their positioning is mainly determined by the intrinsic sequence preferences of nucleosomes. In contrast, larger nucleosome free regions in promoters, which likely have a much more significant impact on gene expression, are determined mainly by TF binding. Interestingly, of the 158 yeast TFs included in our modeling, we find that only 10–20 significantly contribute to inducing nucleosome-free regions, and these TFs are highly enriched for having direct interations with chromatin remodelers. Together our results imply that nucleosome free regions in yeast promoters results from the binding of a specific class of TFs that recruit chromatin remodelers.
Author Summary
The DNA of all eukaryotic organisms is packaged into nucleosomes, which cover roughly of the genome. As nucleosome positioning profoundly affects DNA accessibility to other DNA binding proteins such as transcription factors (TFs), it plays an important role in transcription regulation. However, to what extent nucleosome positioning is guided by intrinsic DNA sequence preferences of nucleosomes, and to what extent other DNA binding factors play a role, is currently highly debated. Here we use a rigorous biophysical model to systematically study the relative contributions of intrinsic sequence preferences and competitive binding of TFs to nucleosome positioning in yeast. We find that, on the one hand, the phasing of the many small spacers within dense nucleosome arrays that cover gene bodies are mainly determined by intrinsic sequence preferences. On the other hand, larger nucleosome free regions (NFRs) in promoters are explained predominantly by TF binding. Strikingly, we find that only 10–20 TFs make a significant contribution to explaining NFRs, and these TFs are highly enriched for directly interacting with chromatin modifiers. Thus, the picture that emerges is that binding by a specific class of TFs recruits chromatin modifiers which mediate local nucleosome expulsion.
PMCID: PMC3749953  PMID: 23990766
23.  Preimplantation genetic diagnosis (PGD) according to medical ethics and medical law 
Assisted reproductive techniques not only nourish great and sometimes illusive hopes of couples who yearn for babies, but also spark new debates by reversing opinions, beliefs and values. Applications made to infertility clinics are increasing due to the influences such as broadcasts made by the media concerning assisted reproductive techniques and other infertility treatments, increase in the knowledge that people have about these problems, late marriages and postponement of childbearing age owing to sociological changes. Pre-implantation genetic diagnosis (PGD) is a technique applied to couples who are known to carry genetic diseases or who have children with genetic diseases. This technique is conducted by doctors in Turkey for its important contribution to decreasing the risk of genetic diseases and in order to raise healthy generations. In this paper, the general ethical debates and the legal situation in Turkey will be discussed.
PMCID: PMC3940112  PMID: 24627675
Preimplantation genetic diagnosis; artificial implantation; genetic diseases; medical ethics; medical law
24.  Navigation outside of the box: what the lab can learn from the field and what the field can learn from the lab 
Movement Ecology  2014;2(1):3.
Space is continuous. But the communities of researchers that study the cognitive map in non-humans are strangely divided, with debate over its existence found among behaviorists but not neuroscientists. To reconcile this and other debates within the field of navigation, we return to the concept of the parallel map theory, derived from data on hippocampal function in laboratory rodents. Here the cognitive map is redefined as the integrated map, which is a construction of dual mechanisms, one based on directional cues (bearing map) and the other on positional cues (sketch map). We propose that the dual navigational mechanisms of pigeons, the navigational map and the familiar area map, could be homologous to these mammalian parallel maps; this has implications for both research paradigms. Moreover, this has implications for the lab. To create a bearing map (and hence integrated map) from extended cues requires self-movement over a large enough space to sample and model these cues at a high resolution. Thus a navigator must be able to move freely to map extended cues; only then should the weighted hierarchy of available navigation mechanisms shift in favor of the integrated map. Because of the paucity of extended cues in the lab, the flexible solutions allowed by the integrated map should be rare, despite abundant neurophysiological evidence for the existence of the machinery needed to encode and map extended cues through voluntary movement. Not only do animals need to map extended cues but they must also have sufficient information processing capacity. This may require a specific ontogeny, in which the navigator’s nervous system is exposed to naturally complex spatial contingencies, a circumstance that occurs rarely, if ever, in the lab. For example, free-ranging, flying animals must process more extended cues than walking animals and for this reason alone, the integrated map strategy may be found more reliably in some species. By taking concepts from ethology and the parallel map theory, we propose a path to directly integrating the three great experimental paradigms of navigation: the honeybee, the homing pigeon and the laboratory rodent, towards the goal of a robust, unified theory of animal navigation.
PMCID: PMC4267593  PMID: 25520814
Cognitive map; Landmark; Geometry; Locomotion; Hippocampus; Parallel map theory
25.  Pro/con clinical debate: The use of prone positioning in the management of patients with acute respiratory distress syndrome 
Critical Care  2002;6(1):15-17.
Critical care medicine is a relatively new specialty and as such there is not a great deal of accumulated data to allow clinicians to practice 'evidence-based medicine' in all situations they encounter. When evidence does exist, intensivists may choose not to follow it based on 'gut feelings' or their own interpretation of how the data apply to their patient. It is perhaps not surprising that these latter events occur given that intensivists are often literally fighting for their patient's lives. Prone positioning evokes a large emotional response from many intensivists. Despite accumulating data there appears to be two camps of clinicians: those who strongly believe in the therapy, and those who want more data. The emotion and rationale for the mindset of the two camps is evident in this issue of Critical Care Forum. With compelling arguments on both sides of the fence, it is apparent that this debate is far from over. The authors of this pro/con debate, which is based on a clinical scenario, first describe their position and then respond to their opponent's position.
PMCID: PMC137391  PMID: 11940260
prone position; ventilation; ventilation–perfusion ratio

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