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1.  THE FATE OF THE GIANT CELLS IN HEALING TUBERCULOUS TISSUE, AS OBSERVED IN A CASE OF HEALING TUBERCULOUS MENINGITIS 
From the foregoing description of the histological changes in the leptomeninx it is quite evident that we are dealing with a chronic, stationary, healing form of tuberculous inflammation. This statement is substantiated, in the first place, by the clinical history. The only reasonable interpretation of the symptoms would establish the duration of the process as four months. The imaginable contingency that there existed first a meningeal syphilitic lesion that was dispersed by the iodide of potassium only to be followed by a tuberculous infection is so remote and unlikely that it need not be discussed. At all events the tuberculous leptomeningitis, which presented a typical distribution, began insidiously, existed at times in a latent condition, and pursued a very anomalous course, marked by a relative mildness of all the symptoms, and thus it came about that when an apparent or real improvement followed the administration of iodide of potassium able observers were induced to make an erroneous diagnosis. Death occurred as a result of an intercurrent infection. The long duration of the process is also shown, anatomically, by the thick layer of firm, translucent and gelatinous material that matted together the structures at the base, and also by the evident adhesions between the pia and the brain. The histological examination furnishes proof positive of the correctness of the conclusion in regard to the peculiar character of this process because it shows: (1) That the tuberculous proliferation is uniform in development and has reached nearly the same stage of evolution throughout the entire extent of the leptomeninx involved; it is not a process that has advanced by exacerbations and irregular extensions; the lesions are, generally speaking, of nearly the same age everywhere and must have begun at about the same time. (2) That only a very limited degree of caseous degeneration is present, pointing to an early arrest of the activity of the tubercle bacillus or to a very decided diminution or attenuation of its virulence. (3) That the subendothelial intimal proliferations of epithelioid cells, so generally found in acute tuberculous leptomeningitis,* have in this case become more or less completely changed into distinct fibrous tissue in which but very slight, if any, direct evidence of its tuberculous origin can be found. It is only by recognizing that the chronic endarteritis is most marked in correspondence with the most advanced adventitial tuberculous changes, and by finding an imperfect, much altered giant cell in one district of intimal thickening, that we were able to establish the direct kinship of the endovascular changes with those of the pia in general. (4) That acute inflammatory changes, in the form of emigration of polymorphonuclear leucocytes and of fibrinous exudation, are entirely absent in all parts of the district involved. The presence of a turbid serous fluid is of course not at all inconsistent with the view that the anatomical changes are of long duration. (5) That the granulation tissue present is, in general, undergoing fibrillation and contains a rich supply of enabryonal capillary vessels as well as of larger blood-vessels of evidently new formation. The absence of any considerable extent of polymorphonuclear leucocytic infiltration in this tissue has already been referred to. The cells in the granulation tissue correspond to the cells of embryonal or formative connective tissue. Vacuolation is rarely present. (6) That the unusually large number of giant cells present are remarkably free from evidences of necrosis and degeneration of the character ordinarily observed in tuberculous proliferations, that they do not contain in demonstrable form tubercle bacilli, and that the majority of the giant cells seem to be separating into individual cells and smaller masses often with, but sometimes also without, evidences of nuclear disintegration. The possibility that these phenomena may signify fusion instead of the sundering of cells will be discussed below. For these reasons there can be no doubt that the general claim that we are dealing with an instance of chronic, healing tuberculous meningitis must be regarded as established beyond dispute. The growth of tubercle bacilli in the glycerine-agar tubes, inoculated with the fluid from the pial meshes, and the demonstration of tubercle bacilli, though in very small numbers, between the cells of the embryonal tissue, furnish the positive evidence that we are actually dealing with a tuberculous process due to living and not to dead bacilli. The degree of virulence of the cultures of tubercle bacilli was, unfortunately perhaps, not studied. The presence of living tubercle bacilli in a tissue free from active and acute changes characteristic of tuberculosis demonstrates that, whatever the actual degree of virulence of the bacilli may have been, the tissue in which they were found was at this time relatively immune from their action. The manner in which this immunity was produced, and in which the process of healing was initiated, need not be discussed at this time any further than to again direct attention to the fact that the bacilli lost their virulency as regards the cells in this leptomeninx before these cells underwent any marked degree of degeneration. The cells of the tuberculous proliferations survived the further action of the bacilli whose original effect it was to initiate cell accumulation or proliferation; the cells also retained sufficient vitality to develop, in some instances at any rate, into formative cells according as their origin would dictate, e. g. into fibroblasts. That fibroblasts are formed only by embryonal connective tissue cells, and not by wandering cells, such as the large mononuclear leucocytes, we are well aware, is possibly still a disputable assumption, and we do not consider it pertinent to discuss the question any further in connection with this study, but would only emphasize the point that some of the cells of tuberculous proliferations may, under favorable circumstances, become formative cells, and, furthermore, that the amount of formative tissue produced may be far in excess of what is actually needed for purposes of repair only. Surely the appearances here noted indicate that the bacillus of tuberculosis has the power to stimulate fixed cells to multiply, unless one assumes that all, or almost all, the formative cells here seen are derived from wandering cells attracted by the presence of the bacillus and its products. As to the ultimate fate of the formative and other cells in this healing tuberculous tissue no final statements can be made. It must be remembered that it is only one stage in the process of healing that is dealt with. The well marked evidences of fibrillation, the quite extensive formation of new vessels, the absence of evidences of degenerative changes in the uninuclear cells, all point to the production of new fibrous tissue as sure to occur, but it seems quite probable that occasional epithelioid cells may undergo or have undergone dropsical or other forms of degeneration, although it is certainly apparent that so far as the small cells are concerned the involution of the tuberculous tissue is not occurring through disintegration. Perhaps the most interesting feature in this case is the opportunity it affords to study the changes in the giant cells of healing, non-degenerated tuberculous tissue. In the first place, the large number of giant cells is quite remarkable. The general characters of the tissue in which they are found recall the fact that giant cells are regarded as quite constant elements in chronic mild tuberculosis; often the giant cells are the only cells that contain bacilli (Koch). In this instance the giant cells do not contain bacilli that are demonstrable by the usual methods; neither do they contain bodies that can be definitely interpreted as degenerate forms of bacilli such as those found by Metchnikoff, Stchastny, Weicker, and others, in the giant cells of Spermophilus guttatus, in avian and in human tuberculosis. Metchnikoff states, however, that he knows of the occurrence of such degenerate forms only in the Spermophilus guttatus under the circumstances mentioned, and in the rabbit and guinea-pig in mammalian tuberculosis, but not in man; consequently, the manner in which the giant cells rid themselves of the bacilli undoubtedly present in their interior at some time during their existence, must as yet remain without any explanation. In the description of the histological changes the various appearances presented by the giant cells are described somewhat minutely. The essential observations made concern, in my opinion, the further fate of giant cells which are still found to persist in healing nondegenerated tuberculous tissue. It was, I believe, quite conclusively shown that the consecutive changes appear to consist in the breaking up of the nuclei, the removal of the detritus by phagocytes, and the formation of a few apparently viable uninuclear cells in the case of more degenerated, exhausted giant cells, while other, and, as it would seem, better preserved or younger giant cells, separate into a number of individual, uninuclear cells with but little or no nuclear disintegration. Objection might be raised to this interpretation of the appearances in the giant cells. While no one could very well dispute the view that part of the giant cells are undergoing retrogressive and absorptive changes with the production of some viable cells, a question might well be raised concerning the nature of the process taking place in those giant cells that have been spoken of as splitting up or dividing into uninuclear cells and smaller multinucleated masses without much evidence of nuclear disintegration. It might be claimed that the process is one of fusion of many cells to form giant cells, and not one of division of fully formed giant cells into small cells. But a broad view of the processes described speaks against fusion. In the first place we are not dealing with a stage of tuberculous proliferation (Baumgarten), or cell accumulation (Metchnikoff), in which one would look for the production of giant cells, no matter which view concerning the histogenesis of tubercle be assumed as the correct one, because it has been demonstrated that, from whichever point of view the lesions are examined, the same positive conclusion that they are in the process of healing is reached; there is, therefore, no occasion for the formation of new giant cells in such wide-spread degree throughout the district involved. It might he claimed that the cells became arrested and, as it were, fixed in the act of fusion which was taking place in the early stage of the meningitis, but it would be difficult to understand the nature of the stimulus that could hold the cells together in such a peculiar manner for such a long time. It must be remembered that bacilli or bacillary detritus could not be found among the incomplete or in the complete giant cells. In the second place the difference between the cells that are undergoing disintegration and those regarded as dividing is essentially, to a certain extent at any rate, one of degree, because in the first instance there is not much, if any, doubt but that viable smaller cells are also formed, and in the second instance some, though often very slight, evidence of nuclear fragmentation is nearly always present; it would also be correct to infer that in advanced subdivision of a giant cell much, and perhaps all, of the nuclear detritus produced might have been removed up to the last trace; finally, the two extremes of these changes in the giant cells are connected by transition stages passing by gradation from the one to the other. Hence it is justifiable to conclude, for the time being, that in healing non-degenerated tuberculous tissue, the multinucleated giant cells may in part disintegrate and undergo absorption, in part form viable small cells; that both these changes may, and usually do, affect the same cell, but that in one class of cells—presumably the older or the more exhausted—the retrogressive process is predominant, while in a second class of cells—presumably the young and vigorous—the progressive changes are the more marked. In this connection it may be pointed out that while there cannot very well be any question but that we are dealing only with dividing and not coalescing cells, yet if this conclusion should be disputed and found incorrect, then the only remaining alternative would be to infer that this tissue furnished a unique and striking example of the formation of plasmodial masses by fusion in human tuberculosis, a conclusion to which many pathologists would refuse to subscribe, if for no other reason than because it is not in accordance with the almost universally accepted teachings of Baumgarten and Weigert in regard to the mode of formation of the giant cells in tuberculosis. Believing as I do that the giant cells under consideration are in the act of division and not at all of fusion, there remain to be discussed some of the histological and other features presented by the dividing cells. Many of the giant cells, perhaps the majority, contain larger and smaller vacuoles in the protoplasm. The exact significance of this vacuolation is not always clear. When the vacuolation accompanies an evident solution of the nucleus (karyolysis), there cannot be any doubt but that we are in the presence of a distinctly retrogressive process. Vacuoles are also most numerous in the giant cells that present other evidences of degeneration, such as coarseness of the granules in the protoplasm and extensive nuclear disintegration, but they occur as well around nuclei that stain deeply, around cells that seem to be separating from the giant cell, and even about nuclei that present mitoses. The formation of vacuoles seems to be responsible, to a certain extent at any rate, for the diminution in the volume of disintegrating and dividing giant cells, as shown by the clear spaces that form about them; these spaces are too large and occur too uniformly to be attributed solely to artificial shrinking produced by the hardening in alcohol. Further undoubted evidence of retrogression in certain giant cells is the occurrence of nuclear disintegration, or karyorhexis, which sets free larger and smaller chromatin masses that are recognized in the giant cell as well as in the interior of the phagocytes usually found around such cells. Almost all the polymorphonuclear leucocytes found in this tissue are met with around giant cells with broken-up nuclei. In many nuclei of disintegrating giant cells can be noted appearances that correspond well to certain stages in the complicated karyorhexis observed in anæmic necrosis by Schmaus and Albrecht; some of the nuclei with budding processes correspond particularly well with those in certain of their drawings; the interior of giant cells of tuberculous tissue may, it would seem, present conditions favorable to the development of this series of postnecrotic nuclear change. Vacuolation, karyolysis and karyorhexis are the essential steps that lead to destruction of the whole or parts of some of the giant cells; associated with these processes there is usually observed a splitting up of the body of the giant cell into irregular fragments with as well as without nuclei; and, as described, more or less phagocytosis of the resulting remnants of various kinds is seen. But evident degenerative and necrotic processes in a giant cell may be associated with progressive changes. While some nuclei undergo vacuolation or break up, others seem to become richer in chromatin and to stain more deeply at the same time that they seem to acquire cell bodies quite distinct from the protoplasm of the giant cells: this hyperchromatosis does not, therefore, seem to be a stage in karyorhexis. A very few but undoubted karyokinetic figures were found, together with evidences of division of the cell body formed in the giant cell protoplasm. Precisely similar changes are described by Klebs in healing pulmonary tuberculosis of the guinea-pig; the nuclei of the giant cells became rich in chromatin and karyokinetic figures occurred. Krückmann among others has found occasional mitoses in giant cells around foreign bodies, as well as elsewhere, but it would seem that such mitoses have always been interpreted as indicating the probable mode of formation of the giant cells rather than of their involution. The question of mitosis in existing multinucleated cells has recently been studied by Krompecher, who concludes that the individual nuclei of such cells may undoubtedly divide by mitosis, either simultaneously or at separate times. Division by amitosis can also occur, but mitosis is the only progressive form of division, amitosis being a retrogressive, disintegrating process that must be looked upon as an evidence of degeneration of the nucleus. Ziegler states that in division of giant cells whose nuclei have multiplied by mitosis it may happen that the separating cell remains enclosed in the protoplasm of the mother cell. A singular phase in the involution of the giant cells in this pia is to be found in the existence of progressive changes side by side with nuclear necrosis and with degeneration; this finding indicates that giant cells may contain many independent elements which, though apparently fused into one large cell, may preserve their individuality so that while some nuclei die, others proliferate and perhaps feed on the remnants of their dead brethren and form new, viable small cells. The nuclei in giant cells may be looked upon as representing independent centres, capable at times of existing even though the cell protoplasm is disintegrated. Many of the giant cells separate into individual cells, unaccompanied or unassociated with much evidence of necrosis. These cells may be regarded as the more vigorous forms. Here also are observed occasional mitoses—but on the whole extremely few—and very constantly an evident increase in the amount of chromatin in the nuclei of the new cells as compared with the amount ordinarily found in the nuclei of giant cells. These deductions concerning the persistence of the vitality of some of the nuclei, even in the presence of molecular and morphological changes in the cytoplasm and in other nuclei of the giant cell that lead to disintegration, are not entirely without the support of previous observations on cells, which, although made under different conditions, are nevertheless, it would seem, applicable to cells in general. Thus the brilliant investigations of Loeb upon the effects of various unfavorable surroundings, such as absence of oxygen or reduction of the amount of water, upon the cleavage of eggs of many kinds, show that the conditions which arrest development are qualitatively alike for nucleus and protoplasm, but quantitatively less for the protoplasm; when the irritability of the protoplasm is suspended the nucleus may segment without segmentation of the protoplasm, but upon re-establishment of favorable conditions the protoplasm may divide into about as many spheres as there are nuclei preformed—the nucleus persists, preserves the irritability of the cell and stimulates the protoplasm to segmentation. From the appearances of the giant cells here described it would seem, then, that some nuclei are able to maintain their vitality longer than others in the same cell, and under certain conditions to stimulate parts of the protoplasm to segment; in other cells all the nuclei have, as a rule, preserved their irritability. The groups of cells formed by the dividing of the giant cells can be traced by studying the process at the different stages in the different parts of the tissue. They assume an oval or spindle-shaped form, becoming more and more like the formative and endothelioid cells of young connective tissue, but their ultimate fate cannot be determined because it concerns essentially only one limited period in the involution of the tissue. It may be said with reasonable certainty, however, that the new cells do not form blood-vessels, but as regards their forming lymph-vessels nothing definite can be concluded. It would not be safe to draw any definite conclusions, from the appearances described, with regard to the origin and the mode of formation of the giant cells. The resulting small cells in general resemble very much endothelial and formative cells, but some of them are, at certain stages at any rate, not unlike large mononuclear leucocytes; their final fully developed or mature condition being unknown, no positive inference can be drawn as to their pre-giant-cell origin. The evidence points to the fact that the most probable origin of the giant cells, as indicated by their form and the apparent future career of their descendants, would be the fixed mesoblastic cells of the pia. In regard to the mode of formation of the giant cells it is quite clear that it must involve some process which is not incompatible with the viability of the small cells which may spring from the giant cells. Whether this would speak more in favor of formation by fusion than by karyokinesis of a single cell without division of the cell body cannot be well determined, and as long as authors are not agreed upon the question of the production of living, procreative cells by amitosis (direct segmentation, direct and indirect fragmentation) it would not be profitable to discuss the compatibility or incompatibility of the views of those investigators who trace the origin of giant cells to amitotic division, with the progressive changes that giant cells have been shown to be capable of. The fact that giant cells in tuberculous tissue, under certain conditions, undergo progressive changes and separate into small, living cells proves that they are not, as claimed by Baumgarten, Weigert and others, necrobiotic elements that are doomed to destruction from their very inception. On the other hand it lends more strength, if that were necessary, to the teleological view urged by Metchnikoff that they are living, defensive cells (whatever their origin may be), formed for the distinct purpose, like plasmodial masses in general, of isolating and removing foreign, harmful bodies, in this case the tubercle bacillus, and, having accomplished their object without being destroyed or exhausted, or the cause of their formation being removed or neutralized in some way, they, or their nuclei, may retain enough irritability to form a larger or smaller number of living, small, uninuclear cells.
PMCID: PMC2117963  PMID: 19866866
2.  Association of Medical Students' Reports of Interactions with the Pharmaceutical and Medical Device Industries and Medical School Policies and Characteristics: A Cross-Sectional Study 
PLoS Medicine  2014;11(10):e1001743.
Aaron Kesselheim and colleagues compared US medical students' survey responses regarding pharmaceutical company interactions with the schools' AMSA PharmFree scorecard and Institute on Medicine as a Profession's (IMAP) scores.
Please see later in the article for the Editors' Summary
Background
Professional societies use metrics to evaluate medical schools' policies regarding interactions of students and faculty with the pharmaceutical and medical device industries. We compared these metrics and determined which US medical schools' industry interaction policies were associated with student behaviors.
Methods and Findings
Using survey responses from a national sample of 1,610 US medical students, we compared their reported industry interactions with their schools' American Medical Student Association (AMSA) PharmFree Scorecard and average Institute on Medicine as a Profession (IMAP) Conflicts of Interest Policy Database score. We used hierarchical logistic regression models to determine the association between policies and students' gift acceptance, interactions with marketing representatives, and perceived adequacy of faculty–industry separation. We adjusted for year in training, medical school size, and level of US National Institutes of Health (NIH) funding. We used LASSO regression models to identify specific policies associated with the outcomes. We found that IMAP and AMSA scores had similar median values (1.75 [interquartile range 1.50–2.00] versus 1.77 [1.50–2.18], adjusted to compare scores on the same scale). Scores on AMSA and IMAP shared policy dimensions were not closely correlated (gift policies, r = 0.28, 95% CI 0.11–0.44; marketing representative access policies, r = 0.51, 95% CI 0.36–0.63). Students from schools with the most stringent industry interaction policies were less likely to report receiving gifts (AMSA score, odds ratio [OR]: 0.37, 95% CI 0.19–0.72; IMAP score, OR 0.45, 95% CI 0.19–1.04) and less likely to interact with marketing representatives (AMSA score, OR 0.33, 95% CI 0.15–0.69; IMAP score, OR 0.37, 95% CI 0.14–0.95) than students from schools with the lowest ranked policy scores. The association became nonsignificant when fully adjusted for NIH funding level, whereas adjusting for year of education, size of school, and publicly versus privately funded school did not alter the association. Policies limiting gifts, meals, and speaking bureaus were associated with students reporting having not received gifts and having not interacted with marketing representatives. Policy dimensions reflecting the regulation of industry involvement in educational activities (e.g., continuing medical education, travel compensation, and scholarships) were associated with perceived separation between faculty and industry. The study is limited by potential for recall bias and the cross-sectional nature of the survey, as school curricula and industry interaction policies may have changed since the time of the survey administration and study analysis.
Conclusions
As medical schools review policies regulating medical students' industry interactions, limitations on receipt of gifts and meals and participation of faculty in speaking bureaus should be emphasized, and policy makers should pay greater attention to less research-intensive institutions.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Making and selling prescription drugs and medical devices is big business. To promote their products, pharmaceutical and medical device companies build relationships with physicians by providing information on new drugs, by organizing educational meetings and sponsored events, and by giving gifts. Financial relationships begin early in physicians' careers, with companies providing textbooks and other gifts to first-year medical students. In medical school settings, manufacturers may help to inform trainees and physicians about developments in health care, but they also create the potential for harm to patients and health care systems. These interactions may, for example, reduce trainees' and trained physicians' skepticism about potentially misleading promotional claims and may encourage physicians to prescribe new medications, which are often more expensive than similar unbranded (generic) drugs and more likely to be recalled for safety reasons than older drugs. To address these and other concerns about the potential career-long effects of interactions between medical trainees and industry, many teaching hospitals and medical schools have introduced policies to limit such interactions. The development of these policies has been supported by expert professional groups and medical societies, some of which have created scales to evaluate the strength of the implemented industry interaction policies.
Why Was This Study Done?
The impact of policies designed to limit interactions between students and industry on student behavior is unclear, and it is not known which aspects of the policies are most predictive of student behavior. This information is needed to ensure that the policies are working and to identify ways to improve them. Here, the researchers investigate which medical school characteristics and which aspects of industry interaction policies are most predictive of students' reported behaviors and beliefs by comparing information collected in a national survey of US medical students with the strength of their schools' industry interaction policies measured on two scales—the American Medical Student Association (AMSA) PharmFree Scorecard and the Institute on Medicine as a Profession (IMAP) Conflicts of Interest Policy Database.
What Did the Researchers Do and Find?
The researchers compared information about reported gift acceptance, interactions with marketing representatives, and the perceived adequacy of faculty–industry separation collected from 1,610 medical students at 121 US medical schools with AMSA and IMAP scores for the schools evaluated a year earlier. Students at schools with the highest ranked interaction policies based on the AMSA score were 63% less likely to accept gifts as students at the lowest ranked schools. Students at the highest ranked schools based on the IMAP score were about half as likely to accept gifts as students at the lowest ranked schools, although this finding was not statistically significant (it could be a chance finding). Similarly, students at the highest ranked schools were 70% less likely to interact with sales representatives as students at the lowest ranked schools. These associations became statistically nonsignificant after controlling for the amount of research funding each school received from the US National Institutes of Health (NIH). Policies limiting gifts, meals, and being a part of speaking bureaus (where companies pay speakers to present information about the drugs for dinners and other events) were associated with students' reports of receiving no gifts and of non-interaction with sales representatives. Finally, policies regulating industry involvement in educational activities were associated with the perceived separation between faculty and industry, which was regarded as adequate by most of the students at schools with such policies.
What Do These Findings Mean?
These findings suggest that policies designed to limit industry interactions with medical students need to address multiple aspects of these interactions to achieve changes in the behavior and attitudes of trainees, but that policies limiting gifts, meals, and speaking bureaus may be particularly important. These findings also suggest that the level of NIH funding plays an important role in students' self-reported behaviors and their perceptions of industry, possibly because institutions with greater NIH funding have the resources needed to implement effective policies. The accuracy of these findings may be limited by recall bias (students may have reported their experiences inaccurately), and by the possibility that industry interaction policies may have changed in the year that elapsed between policy grading and the student survey. Nevertheless, these findings suggest that limitations on gifts should be emphasized when academic medical centers refine their policies on interactions between medical students and industry and that particular attention should be paid to the design and implementation of policies that regulate industry interactions in institutions with lower levels of NIH funding.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001743.
The UK General Medical Council provides guidance on financial and commercial arrangements and conflicts of interest as part of its good medical practice document, which describes what is required of all registered doctors in the UK
Information about the American Medical Student Association (AMSA) Just Medicine campaign (formerly the PharmFree campaign) and about the AMSA Scorecard is available
Information about the Institute on Medicine as a Profession (IMAP) and about its Conflicts of Interest Policy Database is also available
“Understanding and Responding to Pharmaceutical Promotion: A Practical Guide” is a manual prepared by Health Action International and the World Health Organization that medical schools can use to train students how to recognize and respond to pharmaceutical promotion
The US Institute of Medicine's report “Conflict of Interest in Medical Research, Education, and Practice” recommends steps to identify, limit, and manage conflicts of interest
The ALOSA Foundation provides evidence-based, non-industry-funded education about treating common conditions and using prescription drugs
doi:10.1371/journal.pmed.1001743
PMCID: PMC4196737  PMID: 25314155
3.  Revisiting Gaussian Process Regression Modeling for Localization in Wireless Sensor Networks 
Sensors (Basel, Switzerland)  2015;15(9):22587-22615.
Signal strength-based positioning in wireless sensor networks is a key technology for seamless, ubiquitous localization, especially in areas where Global Navigation Satellite System (GNSS) signals propagate poorly. To enable wireless local area network (WLAN) location fingerprinting in larger areas while maintaining accuracy, methods to reduce the effort of radio map creation must be consolidated and automatized. Gaussian process regression has been applied to overcome this issue, also with auspicious results, but the fit of the model was never thoroughly assessed. Instead, most studies trained a readily available model, relying on the zero mean and squared exponential covariance function, without further scrutinization. This paper studies the Gaussian process regression model selection for WLAN fingerprinting in indoor and outdoor environments. We train several models for indoor/outdoor- and combined areas; we evaluate them quantitatively and compare them by means of adequate model measures, hence assessing the fit of these models directly. To illuminate the quality of the model fit, the residuals of the proposed model are investigated, as well. Comparative experiments on the positioning performance verify and conclude the model selection. In this way, we show that the standard model is not the most appropriate, discuss alternatives and present our best candidate.
doi:10.3390/s150922587
PMCID: PMC4610506  PMID: 26370996
sensor modeling; WLAN received signal strength; Gaussian process regression; machine learning; location fingerprinting
4.  An Ethnographic Study of the Social Context of Migrant Health in the United States 
PLoS Medicine  2006;3(10):e448.
Background
Migrant workers in the United States have extremely poor health. This paper aims to identify ways in which the social context of migrant farm workers affects their health and health care.
Methods and Findings
This qualitative study employs participant observation and interviews on farms and in clinics throughout 15 months of migration with a group of indigenous Triqui Mexicans in the western US and Mexico. Study participants include more than 130 farm workers and 30 clinicians. Data are analyzed utilizing grounded theory, accompanied by theories of structural violence, symbolic violence, and the clinical gaze. The study reveals that farm working and housing conditions are organized according to ethnicity and citizenship. This hierarchy determines health disparities, with undocumented indigenous Mexicans having the worst health. Yet, each group is understood to deserve its place in the hierarchy, migrant farm workers often being blamed for their own sicknesses.
Conclusions
Structural racism and anti-immigrant practices determine the poor working conditions, living conditions, and health of migrant workers. Subtle racism serves to reduce awareness of this social context for all involved, including clinicians. The paper concludes with strategies toward improving migrant health in four areas: health disparities research, clinical interactions with migrant laborers, medical education, and policy making.
A qualitative study of migrant Triqui Mexicans in the western US and Mexico shows that structural racism and anti-immigrant practices lead to poor working and living conditions, and poor health.
Editors' Summary
Background.
For centuries, recent immigrants have experienced poorer living and working conditions than more established inhabitants, which in turn means that the health of immigrants is often worse. Immigrants often take on the very lowest-paid jobs. One might suppose that in more recent years the increasing prosperity of countries such as the United States and those of western Europe would have reversed this trend. But as recently as 2005 the New York–based Human Rights Watch published a report entitled “Blood, Sweat and Fear,” which documented appalling conditions for the mostly immigrant workers in the US meat and poultry industry. In the UK also, legislation has recently been introduced to try to regulate the activity of “gang masters” who control large groups of immigrant workers. This legislation was triggered by public horror about the deaths in 2004 of 21 immigrant cockle pickers who drowned in Morecambe Bay in Lancashire. A group of workers at particular risk of poor conditions because of the seasonal and uncertain patterns of work are those who work as farm laborers.
Why Was This Study Done?
There are relatively few studies that have looked in detail at the pattern of health problems among migrant farm workers in the US. Understanding the working conditions of these workers would be of help in understanding more about their health problems and, in particular, how to prevent them. One problem is that few of these workers are seen in the usual health-care settings; few of them have health insurance.
What Did the Researchers Do and Find?
The paper's author spent 15 months with a group of indigenous Triqui Mexicans as they migrated around the western US and Mexico working on farms. He used a type of research called qualitative research, which involved observing and interviewing more than 130 farm workers and 30 health workers on farms and in clinics. He found that working and housing conditions were organized according to ethnicity and citizenship, and that there was an unofficial hierarchy, with undocumented indigenous Mexicans having the worst health. Even worse, migrant farm workers were often blamed for their sicknesses by those in charge of them or those from whom they sought help.
What Do These Findings Mean?
The author concludes that “structural racism and anti-immigrant practices determine the poor working conditions, living conditions, and health of migrant workers.” Furthermore, it seems that “subtle” racism among all involved, including clinicians, reduces awareness and perhaps even allows tacit acceptance of these patterns of health. It seems that targets for specific health interventions for these workers will need to be closely integrated with a broader approach to improving migrant health including medical education and policymaking.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030448.
Migration Dialogue regularly consolidates news related to immigration around the world
Global Exchange has information related to fair trade, CAFTA, and other related current events
United Farm Workers has information related to working conditions of migrant laborers
PCUN has information related to migrant laborers in the Pacific Northwest
The Border Action Network has information related to the US-Mexico border
Border Links provides education and experiential learning related to the US-Mexico Border
Tierra Nueva and the Peoples Seminary provide social services for migrant laborers in the Pacific Northwest and education related to the lives of migrant workers
The Pesticide Action Network of North America provides information related to pesticides and health
The Pesticide Education Center provides detailed lists of the contents of pesticides and their health effects
The Center for Comparative Immigration Studies conducts research and education projects related to international migration
Human Rights Watch publishes and campaigns on many issues, including conditions for workers, such as that on the US meat-packing industry
European Research Centre on Migration and Ethnic Relations has a range of information concerning migrants
doi:10.1371/journal.pmed.0030448
PMCID: PMC1621098  PMID: 17076567
5.  Interventions to reduce corruption in the health sector 
Background
Corruption is the abuse or complicity in abuse, of public or private position, power or authority to benefit oneself, a group, an organisation or others close to oneself; where the benefits may be financial, material or non-material. It is wide-spread in the health sector and represents a major problem.
Objectives
Our primary objective was to systematically summarise empirical evidence of the effects of strategies to reduce corruption in the health sector. Our secondary objective was to describe the range of strategies that have been tried and to guide future evaluations of promising strategies for which there is insufficient evidence.
Search methods
We searched 14 electronic databases up to January 2014, including: CENTRAL; MEDLINE; EMBASE; sociological, economic, political and other health databases; Human Resources Abstracts up to November 2010; Euroethics up to August 2015; and PubMed alerts from January 2014 to June 2016. We searched another 23 websites and online databases for grey literature up to August 2015, including the World Bank, the International Monetary Fund, the U4 Anti-Corruption Resource Centre, Transparency International, healthcare anti-fraud association websites and trial registries. We conducted citation searches in Science Citation Index and Google Scholar, and searched PubMed for related articles up to August 2015. We contacted corruption researchers in December 2015, and screened reference lists of articles up to May 2016.
Selection criteria
For the primary analysis, we included randomised trials, non-randomised trials, interrupted time series studies and controlled before-after studies that evaluated the effects of an intervention to reduce corruption in the health sector. For the secondary analysis, we included case studies that clearly described an intervention to reduce corruption in the health sector, addressed either our primary or secondary objective, and stated the methods that the study authors used to collect and analyse data.
Data collection and analysis
One review author extracted data from the included studies and a second review author checked the extracted data against the reports of the included studies. We undertook a structured synthesis of the findings. We constructed a results table and 'Summaries of findings' tables. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the certainty of the evidence.
Main results
No studies met the inclusion criteria of the primary analysis. We included nine studies that met the inclusion criteria for the secondary analysis.
One study found that a package of interventions coordinated by the US Department of Health and Human Services and Department of Justice recovered a large amount of money and resulted in hundreds of new cases and convictions each year (high certainty of the evidence). Another study from the USA found that establishment of an independent agency to investigate and enforce efforts against overbilling might lead to a small reduction in overbilling, but the certainty of this evidence was very low. A third study from India suggested that the impacts of coordinated efforts to reduce corruption through increased detection and enforcement are dependent on continued political support and that they can be limited by a dysfunctional judicial system (very low certainty of the evidence).
One study in South Korea and two in the USA evaluated increased efforts to investigate and punish corruption in clinics and hospitals without establishing an independent agency to coordinate these efforts. It is unclear whether these were effective because the evidence is of very low certainty.
One study from Kyrgyzstan suggested that increased transparency and accountability for co-payments together with reduction of incentives for demanding informal payments may reduce informal payments (low certainty of the evidence).
One study from Germany suggested that guidelines that prohibit hospital doctors from accepting any form of benefits from the pharmaceutical industry may improve doctors' attitudes about the influence of pharmaceutical companies on their choice of medicines (low certainty of the evidence).
A study in the USA, evaluated the effects of introducing a law that required pharmaceutical companies to report the gifts they gave to healthcare workers. Another study in the USA evaluated the effects of a variety of internal control mechanisms used by community health centres to stop corruption. The effects of these strategies is unclear because the evidence was of very low certainty.
Authors' conclusions
There is a paucity of evidence regarding how best to reduce corruption. Promising interventions include improvements in the detection and punishment of corruption, especially efforts that are coordinated by an independent agency. Other promising interventions include guidelines that prohibit doctors from accepting benefits from the pharmaceutical industry, internal control practices in community health centres, and increased transparency and accountability for co-payments combined with reduced incentives for informal payments. The extent to which increased transparency alone reduces corruption is uncertain. There is a need to monitor and evaluate the impacts of all interventions to reduce corruption, including their potential adverse effects.
Interventions to reduce corruption in the health sector
What is the aim of this review?
The aim of this Cochrane review is to assess the effectiveness of strategies to reduce corruption in the health sector. Cochrane researchers searched for all potentially relevant studies, and found nine studies that met their criteria.
Key messages
The review suggests that some strategies to fight corruption in the health sector can have an effect on corruption. These strategies include the use of independent agencies to investigate and punish corruption, telling healthcare workers that they are not allowed to accept payments from pharmaceutical companies, ensuring that information about healthcare prices is clear and accessible to the public together with increasing healthcare worker salaries. However, the certainty of this evidence varies. We need more high-quality studies that assess the effects of these and other strategies.
What was studied in the review?
Corruption can occur in any area of the health sector, and happens when people abuse their own position to benefit themselves, their organisation, or other people close to them. It can take many forms, including bribes, theft, or giving incorrect or inaccurate information deliberately.
Healthcare officials, for instance, may steal healthcare funds, hospital administrators may change patient records to increase hospital payments, doctors may accept bribes from pharmaceutical companies in exchange for using their products, and patients may try to bribe hospital staff to avoid treatment queues.
Corruption affects the health sector in many ways. It can take money away from healthcare, lead to poorer quality care and make access to healthcare unfair, and often affects poor people the hardest.
What are the main results of the review?
The review authors included nine relevant studies that used different strategies to stop corruption.
• In a study from the USA, efforts to investigate and punish corruption in the health sector were also increased. An independent agency at the national level coordinated these efforts, which led to convictions and the recovery of large amounts of money (high certainty evidence). These efforts may also have led to substantial savings to the government (low certainty evidence). In another study from the USA establishment of an independent agency to investigate and enforce efforts against overbilling was established, but the effects of these efforts are unclear because the evidence was of very low certainty. In India, there were efforts to stop corruption through the appointment of an ombudsman in one state. However, the effect of this strategy is unclear because the evidence was of very low certainty.
• In one study in South Korea and two in the USA, efforts to investigate and punish corruption in clinics and hospitals were increased, without establishing an independent agency. However, it is unclear whether these were effective because the evidence is of very low certainty.
• In a study in Kyrgyzstan, the government carried out a number of strategies, including giving patients and the public information about how much they should be paying, and increasing healthcare workers' salaries. This study shows that these strategies may have led to fewer patients giving their doctors informal payments (low certainty evidence).
• In a study in Germany, hospital doctors were given guidelines telling them that they were not allowed to accept money or gifts from pharmaceutical companies. The study suggests that this may have changed doctors' attitudes about the influence of pharmaceutical companies on their choice of medicines (low certainty evidence).
• In one study in the USA, the authorities introduced a law that required pharmaceutical companies to report the gifts they gave to healthcare workers. In another USA-based study, community health centres attempted to stop corruption using a variety of internal control mechanisms. However, the effect of these strategies is unclear because the evidence was of very low certainty.
We don't know what the effects of these strategies have on healthcare or people's health, or if these strategies had any harmful effects. This is because the studies only assessed the effects of the strategies on corruption and the use of resources, or because the evidence was of very low certainty.
How up to date is this review?
The review authors searched for studies that had been published up to 06 June 2016.
doi:10.1002/14651858.CD008856.pub2
PMCID: PMC5014759  PMID: 27528494
6.  GIFtS: annotation landscape analysis with GeneCards 
BMC Bioinformatics  2009;10:348.
Background
Gene annotation is a pivotal component in computational genomics, encompassing prediction of gene function, expression analysis, and sequence scrutiny. Hence, quantitative measures of the annotation landscape constitute a pertinent bioinformatics tool. GeneCards® is a gene-centric compendium of rich annotative information for over 50,000 human gene entries, building upon 68 data sources, including Gene Ontology (GO), pathways, interactions, phenotypes, publications and many more.
Results
We present the GeneCards Inferred Functionality Score (GIFtS) which allows a quantitative assessment of a gene's annotation status, by exploiting the unique wealth and diversity of GeneCards information. The GIFtS tool, linked from the GeneCards home page, facilitates browsing the human genome by searching for the annotation level of a specified gene, retrieving a list of genes within a specified range of GIFtS value, obtaining random genes with a specific GIFtS value, and experimenting with the GIFtS weighting algorithm for a variety of annotation categories. The bimodal shape of the GIFtS distribution suggests a division of the human gene repertoire into two main groups: the high-GIFtS peak consists almost entirely of protein-coding genes; the low-GIFtS peak consists of genes from all of the categories. Cluster analysis of GIFtS annotation vectors provides the classification of gene groups by detailed positioning in the annotation arena. GIFtS also provide measures which enable the evaluation of the databases that serve as GeneCards sources. An inverse correlation is found (for GIFtS>25) between the number of genes annotated by each source, and the average GIFtS value of genes associated with that source. Three typical source prototypes are revealed by their GIFtS distribution: genome-wide sources, sources comprising mainly highly annotated genes, and sources comprising mainly poorly annotated genes. The degree of accumulated knowledge for a given gene measured by GIFtS was correlated (for GIFtS>30) with the number of publications for a gene, and with the seniority of this entry in the HGNC database.
Conclusion
GIFtS can be a valuable tool for computational procedures which analyze lists of large set of genes resulting from wet-lab or computational research. GIFtS may also assist the scientific community with identification of groups of uncharacterized genes for diverse applications, such as delineation of novel functions and charting unexplored areas of the human genome.
doi:10.1186/1471-2105-10-348
PMCID: PMC2774327  PMID: 19852797
7.  STUDIES ON THE TUBERCULIN REACTION AND ON SPECIFIC HYPERSENSITIVENESS IN BACTERIAL INFECTION 
The work reported in the preceding sections justifies, we think, a number of definite conclusions. In addition to this, some of the experiments indicate a line of thought which may lead to considerable alteration in our conceptions, both of phenomena of bacterial hypersensitiveness and of infection. 1. In guinea pigs two fundamentally different types of intradermal reactions may be observed. One of these is the immediate, transitory reaction which develops in animals sensitized against proteins (horse serum, etc.) and may be regarded as one of the manifestations of general protein hypersensitiveness, or anaphylaxis; the other is the tuberculin type of skin reaction which develops more slowly, leads to a more profound injury of the tissues and is independent of anaphylaxis as ordinarily conceived. 2. The tuberculin type of hypersensitiveness (as well as probably the typhoidin, mallein, abortin reactions, etc.) does not develop at all in guinea pigs sensitized with proteins, like horse serum, etc. While this form of hypersensitiveness may eventually be induced with materials not bacterial in origin, it has been observed up to date only as a reaction of bacterial infection. 3. Methods of treatment with protein material from bacterial cultures which sensitize guinea pigs to anaphylactic reactions with the bacterial extracts, do not sensitize them to the tuberculin type of reaction. Such sensitization is easily accomplished only by infecting the animals with living organisms. No reliable method of sensitizing guinea pigs to such reactions with dead bacterial material has as yet been worked out, though a few hopeful experiments have been obtained with massive injections of large amounts of the acid-precipitable substances (nucleoproteins?) from bacterial extracts. 4. In animals made hypersensitive to the tuberculin type of reaction by infection with living bacteria, the reaction may be elicited by intradermal injections of bacterial extracts from which all coagulable proteins, nucleoproteins, and Bence-Jones proteins have been removed, as well as this can be done by boiling with acid, etc. This proteose residue alone suffices to elicit such reactions. The exact chemical nature of the so called proteose residue must be further studied and analyzed when we have had opportunity to produce bacterial extracts in large quantity. These points seem incontrovertible on the basis of our own experiments, as well as those of other workers. There thus seem to develop two definite forms of hypersensitiveness in guinea pigs infected with bacteria, typical anaphylaxis in which the protein material of the bacterial cells is concerned, which develops late and which can be induced by repeated injections of dead bacterial material, and a hypersensitiveness to non-protein constituents which differs from the former, both in the laws that govern sensitization and in the manifestations which follow injections into the sensitized animals. While there is virtual agreement among immunologists concerning the essential mechanism of protein anaphylaxis, its dependence upon an antigen-antibody reaction, and the dominating rôle played by the sessile antibodies, the mechanism of hypersensitiveness to tuberculin and similar bacterial substances is still a problem of much uncertainty. The most striking difference between the two phenomena lies, as we have seen, in the criteria of sensitization, in that hypersensitiveness to the tuberculin type of reaction can hardly ever be induced by any of the ordinary methods of preparation with the constituents of dead bacteria, but develops promptly (7 to 10 days) in the course of actual infection with living organisms. The considerable specificity of such reactions forces the conclusion that the sensitizing substance must, in some way, be derived from the infecting microorganisms. The idea that the failure of sensitization with dead culture materials is perhaps due to the elaboration in the body of infected animals of bacterial products not represented in extracts of test-tube cultures is rendered unlikely by the fact that in the tuberculin-sensitive, infected animals, we can produce the reactions by the application of such dead extracts. It is neither logical nor in keeping with biological experience to assume that one substance will sensitize to reaction with another. This mistake was made early in the study of anaphylaxis in another connection and caused considerable delay of progress. Krause has shown that tuberculin sensitiveness may be blunted in infected animals by massive, but sublethal injections of tuberculin, and we have obtained some indications of the same thing. Moreover, others as well as ourselves have seen tuberculin reactivity decline in guinea pigs and in man in the stages of very severe infection. These facts would eliminate any assumption of mere cumulative injury as explaining this type of reaction, and stamp it as a mechanism at least analogous to ordinary anaphylaxis. The only remaining possibility to explain the difference between infected animals and those treated with dead bacterial constituents would be to assume that the difference must lie in the manner in which the sensitizing substance is administered to the animals, and that sensitization with the proteose residue materials depends upon criteria of sensitization differing in regard to the time and quantity factors from those governing protein sensitization. If one considers the relatively simpler chemical structure and perhaps physically greater diffusibility of the materials concerned in this reaction, one might readily expect such differences in the methods needed for sensitization. In keeping with such a line of reasoning our experiments have shown that the tuberculin active materials are constantly and rapidly being diffused out into the culture fluid from growing organisms, in quantities greater than can be extracted from similar amounts of the dead bacteria. It seems reasonable to assume from this that the same thing may happen in the animal body harboring a growing focus. And it would seem quite likely that the association of the tuberculin type of reaction with actual infection may depend upon the fact that sensitization to these non-protein substances depends upon a constant steady absorption of large amounts of the material. Moreover, the only hopeful experiments on the artificial production of tuberculin sensitiveness in guinea pigs obtained by us were those in which massive doses of the nucleoprotein material injected into guinea pigs gave rise to a moderate skin sensitiveness. Does the so called proteose residue form antibodies, and, if so, are substances analogous to antibodies involved in the tuberculin type of hypersensitiveness? The failure to transfer passively this form of hypersensitiveness to normal animals with the blood and tissues of tuberculin-sensitive ones would suggest that no antibodies are involved. But this is not conclusive on the basis of available experimental facts. We are inclined to believe that antibodies of a sort are involved, for the following reasons: (a) In our experiments with the uteri of highly sensitive extract-treated guinea pigs and of tuberculous guinea pigs, we have occasionally had positive reactions when the proteose residue alone was used. (b) We believe that these proteose substances are entirely analogous to the substances studied by Avery and Dochez (22) in the urine and blood of typhoid and pneumonia patients. They obtained precipitin reactions against homologous immune sera with the urine of infected cases concentrated by evaporation after boiling with acetic acid to remove coagulable proteins. (c) Petroff, with whom we discussed this proteose residue early in our work, has produced it, and tells us that he has obtained precipitin reactions with it by titrating it against the serum of a sheep treated for a long time with tubercle bacillus products. In suggesting an antibody response to a non-protein antigen we are aware that we are opposing what has been regarded as a well established doctrine in immunity; this is justified, or at least mitigated, we believe, by the consideration that reactions of the antigen-antibody type are the only explanation of specificity; and tuberculin, mallein, and typhoidin reactions are to a considerable degree specific. If such reaction bodies cannot be produced by precisely the same methods of administration as to time and quantity which are successful in calling forth protein antibodies, this should not astonish us, since, after all, the substances that we are dealing with are simpler in chemical structure than are the proteins, and physically are probably of relatively greater diffusibility. It may be that the greater diffusibility of the proteose-like substances transfers much of the actual reaction phenomena to an intracellular location, and that this to some extent influences the presence of circulating antibodies. It may also be that these more diffusible non-protein antigens are more rapidly eliminated from the animal body than are the proteins. Indeed, the above mentioned observations of Avery and Dochez, and the recent work of Wildbolz (23), Lanz (24), Imhof (25), and Gibson and Carroll (26), who demonstrated tuberculin active antigens in the urine of active cases, would corroborate such a view. The evidence available at the present time, however, concerning antibody formation to these non-protein substances is, we recognize, largely indirect, at least as far as our own work is concerned, and we present it in the present connection purely as a working hypothesis. Finally, perhaps the most important theoretical consideration indicated by our experiments is the following. We have in the tuberculin reaction a form of hypersensitiveness which seems to be (in guinea pigs, at least) analogous entirely to the typhoidin reaction, the mallein reaction, and the abortin reaction. Whenever reactions of this type have been carefully studied, whatever the bacteria involved, they have been associated with infection as in tuberculosis, and have been followed by analogous clinical manifestations. It would seem perhaps that we are dealing with a law applicable to bacterial infection in general. It would appear that certain non-coagulable substances of uncertain chemical constitution are being constantly elaborated in the course of bacterial growth, and passed into the circulation of infected animals. As a result of this, infected animals become sensitized to these heat-and acid-resistant materials, in tuberculosis in the course of I to 2 weeks, in the case of more rapidly growing bacteria perhaps sooner. Early in the course of infection, the animal becomes sensitized and subsequently the further elaboration and distribution of these materials from the bacterial focus plays a fundamental part in the injury of the animal. These proteose-like substances, like tuberculin, possessing but slight toxicity for the normal animal, become highly toxic to the sensitized one. Thus, these substances, while not being true exotoxins in the ordinary sense, would still represent a highly toxic bacterial product comparable in its injurious effect to toxins when produced in the body of an animal thus sensitized. If there is any value in these deductions the attention of bacteriologists should be turned to the non-protein constituents of bacterial cells in their further immunological studies, as well as to the protein materials. It is obvious that the next step in our investigations must consist in producing the non-coagulable material from bacterial extracts in considerable quantity, to determine their antibody-forming properties in detail, and elucidate, if possible, the laws which govern sensitization with them. This work has been begun, but it has seemed advisable to publish this as far as we have gone because it will take a long time before it can be completed.
PMCID: PMC2128693  PMID: 19868574
8.  Brain ‘imaging’ in the Renaissance 
During the Renaissance, a period of ‘rebirth’ for humanities and science, new knowledge and speculation began to emerge about the function of the human body, replacing ancient religious and philosophical dogma. The brain must have been a fascinating mystery to a Renaissance artist, but some speculation existed at that time on the function of its parts. Here we show how revived interest in anatomy and life sciences may have influenced the figurative work of Italian and Flemish masters, such as Rafael, Michelangelo and David. We present a historical perspective on the artists and the period in which they lived, their fascination for human anatomy and its symbolic use in their art.
Prior to the 16th century, knowledge of the brain was limited and influenced in a dogmatic way by the teachings of Galen1 who, as we now know, conducted his anatomical studies not on humans but on animals.2 Nemesus, Bishop of Emesa, in around the year 400 was one of the first to attribute mental faculties to the brain, specifically to the ventricles. He identified two anterior (lateral) ventricles, to which he assigned perception, a middle ventricle responsible for cognition and a posterior ventricle for memory.2,3 After a long period of stasis in the Middle Ages, Renaissance scholars realized the importance of making direct observations on dissected cadavers. Between 1504 and 1507, Leonardo da Vinci conducted experiments to reveal the anatomy of the ventricular system in the brain. He injected hot wax through a tube thrust into the ventricular cavities of an ox and then scraped the overlying brain off, thus obtaining, in a simple but ingenious way, an accurate cast of the ventricles.2,4 Leonardo shared the belief promoted by scholarly Christians that the ventricles were the abode of rational soul.
We have several examples of hidden symbolism in Renaissance paintings, but the influence of phrenology and this rudimentary knowledge of neuroanatomy on artists of that period is under-recognized. In the absence of documentary or scientific evidence as to the real intentions of these painters, the notion of such commixture of sacred and profane remains speculative and probably controversial, but at the same time fascinating and provocative. Here we present three examples of Renaissance masterpieces where such symbolism may have been used, although probably many more exist. Conducting an artistic, philosophical and anatomical analysis of the paintings can be an intriguing exercise, but the interpretation will inevitably be conjectural.
PMCID: PMC2121627  PMID: 18065703
9.  Factors influencing the decision that women make on their mode of delivery: the Health Belief Model 
Background
Childbirth is regarded as an important life event for women, and growing numbers of them are making the choice to give birth by Caesarean Delivery. The aim of this study was to identify the factors influencing the decision that women make on their mode of delivery, underpinned by the Health Belief Model.
Methods
This was a cross-sectional study. Hong Kong Chinese women aged 18–45, who were pregnant or had given birth within the last three years were recruited. The participants were asked to complete a structured self-administered questionnaire consisting of 62 questions.
Results
A total of 319 women were recruited, of whom 73 (22.9%) preferred to have a cesarean section delivery (CD). The results showed that women preferred CD because they were concerned about being pregnant at an advanced age, were worried about labor pain and perineum tearing, wanted to have a better plan for maternity leave, had chosen an auspicious date to deliver, and perceived that CD is a more convenience way to deliver. The perceived benefits and severity of a vaginal birth (VB), and the perceived benefits, severity, and cues to action of CD, affected the decision to undergo either a VB or CD.
Conclusions
The data indicated that the constructs of the Health Belief Model – perceived benefits, perceived severity, and cues to action – affect the decision that women make on their mode of delivery. This research indicates that there is value in designing educational programs for pregnant women to educate them on the benefits, risks, and severity of the two different modes of birth based on the constructs of HBM. This will enable women to be active participants in choosing the mode of birth that they believe is right for them.
doi:10.1186/s12913-015-0931-z
PMCID: PMC4506759  PMID: 26188472
Mode of delivery decisions; Cesarean section; Vaginal birth; Health Belief Model
10.  Use and trade of bitumen in antiquity and prehistory: molecular archaeology reveals secrets of past civilizations 
Natural asphalt (or bitumen) deposits, oil seepage and liquid oil shows are widespread in the Middle East, especially in the Zagros mountains of Iran. Ancient people from northern Iraq, south-west Iran and the Dead Sea area extensively used this ubiquitous natural resource until the Neolithic period (7000 to 6000 BC). Evidence of earlier use has been recently documented in the Syrian desert near El Kown, where bitumen-coated flint implements, dated to 40,000 BC (Mousterian period), have been unearthed. This discovery at least proves that bitumen was used by Neanderthal populations as hafting material to fix handles to their flint tools. Numerous testimonies, proving the importance of this petroleum-based material in Ancient civilizations, were brought to light by the excavations conducted in the Near East as of the beginning of the century. Bitumen remains show a wide range of uses that can be classified under several headings. First of all, bitumen was largely used in Mesopotamia and Elam as mortar in the construction of palaces (e.g. the Darius Palace in Susa), temples, ziggurats (e.g. the so-called 'Tower of Babel' in Babylon), terraces (e.g. the famous 'Hanging Gardens of Babylon') and exceptionally for roadway coating (e.g. the processional way of Babylon). Since the Neolithic, bitumen served to waterproof containers (baskets, earthenware jars, storage pits), wooden posts, palace grounds (e.g. in Mari and Haradum), reserves of lustral waters, bathrooms, palm roofs, etc. Mats, sarcophagi, coffins and jars, used for funeral practices, were often covered and sealed with bitumen. Reed and wood boats were also caulked with bitumen. Abundant lumps of bituminous mixtures used for that particular purpose have been found in storage rooms of houses at Ra's al-Junayz in Oman. Bitumen was also a widespread adhesive in antiquity and served to repair broken ceramics, fix eyes and horns on statues (e.g. at Tell al-Ubaid around 2500 BC). Beautiful decorations with stones, shells, mother of pearl, on palm trees, cups, ostrich eggs, musical instruments (e.g. the Queen's lyre) and other items, such as rings, jewellery and games, have been excavated from the Royal tombs in Ur. They are on view in the British Museum. With a special enigmatic material, commonly referred to as 'bitumen mastic', the inhabitants of Susa sculpted masterpieces of art which are today exhibited in the Louvre Museum in Paris. This unique collection is presented in a book by Connan and Deschesne (1996). Last, bitumen was also considered as a powerful remedy in medical practice, especially as a disinfectant and insecticide, and was used by the ancient Egyptians to prepare mixtures to embalm the corpses of their dead. Modern analytical techniques, currently applied in the field of petroleum geochemistry, have been adapted to the study of numerous archaeological bituminous mixtures found in excavations. More than 700 bituminous samples have been analysed during the last decade, using gas chromatography alone and gas chromatography coupled with mass spectrometry and isotopic chemistry (carbon and hydrogen mainly). These powerful tools, focused on the detailed analysis of biomarkers in hydrocarbon fractions, were calibrated on various well-known natural sources of bitumen in Iraq, Syria, Iran, Bahrain and Kuwait. These reference studies have made it possible to establish the origins of bitumen from numerous archaeological sites and to document the bitumen trade routes in the Middle East and the Arabo-Persian Gulf. Using a well-documented case history, Tell el 'Oueili (5800 to 3500 BC) in South Mesopotamia, we will illustrate in this paper how these new molecular and isotopic tools can help us to recognize different sources of bitumen and to trace the ancient trade routes through time. These import routes were found to vary with major cultural and political changes in the area under study. A second example, referring to the prehistoric period, describes bitumen traces on flint implements, dated from Mousterian times. This discovery, from the Umm El Tlel excavations near El Kown in Syria, was reported in 1996 in Boëda et al. At that time, the origin of the bitumen had not been elucidated due to contamination problems. Last year, a ball of natural oil-stained sands, unearthed from the same archaeological layer, allowed us to determine the source of the bitumen used. This source is regional and located in the Jebel Bichri, nearly 40 km from the archaeological site. The last case history was selected to illustrate another aspect of the investigations carried out. Recent geochemical studies on more than 20 balms from Egyptian mummies from the Intermediate, Ptolemaic and Roman periods have revealed that these balms are composed of various mixtures of bitumen, conifer resins, grease and beeswax. Bitumen occurs with the other ingredients and the balms studied show a great variety of molecular compositions. Bitumen from the Dead Sea area is the most common source but some other sources (Hit in Iraq?) are also revealed by different molecular patterns. The absolute amount of bitumen in balms varies from almost zero to 30% per weight.
doi:10.1098/rstb.1999.0358
PMCID: PMC1692448
11.  The Roles of the Learned Societies in Improving Quality of Life in the context of Globalisation 
This manuscript is an adapted text of an address to the Thai Royal Institution during the ‘International Conference for the Celebrations on the Auspicious Occasion of His Majesty the King's 7th Cycle Birthday Anniversary’.
There are many problems facing the world in the context of increasing globalization. “Thou shalt love thy neighbour as thyself.” The Old Testament (Leviticus 19:18), reminds us all that whatever race, religion, or culture we come from, the simple command to love ones neighbour as ourselves, is the bedrock of civilization. In response to this command, we have to ask ourselves two simple questions; how do we best express our love, and who do we consider to be our neighbour?
If one loves oneself, then what is the single most important gift one would grant him/herself? Most would say the gift of good health. Therefore, if one loves others, then the gift one wants for them is also good health. These others, who one should love in an unconditional way, are one's parents, spouses, children, and grandchildren. But to whom does this duty or commandment to love extend? How wide is this circle of love? Is it the immediate family, the extended family, our village, our tribe, or our nation state?
doi:10.1016/S2049-0801(12)70005-5
PMCID: PMC4523166  PMID: 26257900
Breast Cancer; Globalisation; Public Health; Screening; Resource Allocation
12.  Calculation of Local Water Densities in Biological Systems — A Comparison of Molecular Dynamics Simulations and the 3D-RISM-KH Molecular Theory of Solvation 
Water plays a unique role in all living organisms. Not only is it nature’s ubiquitous solvent, but it also actively takes part in many cellular processes. In particular, the structure and properties of interfacial water near biomolecules like proteins are often related to the function of the respective molecule. It can therefore be highly instructive to study the local water density around solutes in cellular systems, particularly when solvent-mediated forces like the hydrophobic effect are relevant. Computational methods like molecular dynamics (MD) simulations seem well suited to study these systems at the atomic level. However, due to sampling requirements, it is not clear that MD simulations are indeed the method of choice to obtain converged densities at a given level of precision. We here compare the calculation of local water densities with two different methods, MD simulations and the three-dimensional reference interaction site model with the Kovalenko-Hirata closure (3D-RISM-KH). In particular, we investigate the convergence of the local water density to assess the required simulation times for different levels of resolution. Moreover, we provide a quantitative comparison of the densities calculated with MD and with 3D-RISM-KH, and investigate the effect of the choice of the water model for both methods. Our results show that 3D-RISM-KH yields density distributions that are very similar to those from MD up to a 0.5 Å resolution, but for significantly reduced computational cost. The combined use of MD and 3D-RISM-KH emerges as an auspicious perspective for efficient solvent sampling in dynamical systems.
doi:10.1021/jp102587q
PMCID: PMC3407544  PMID: 21174421
interfacial water; solvation; confined water; hydrophobic effect; MD; box size
13.  Fed-batch process for the psychrotolerant marine bacterium Pseudoalteromonas haloplanktis 
Background
Pseudoalteromonas haloplanktis is a cold-adapted γ-proteobacterium isolated from Antarctic sea ice. It is characterized by remarkably high growth rates at low temperatures. P. haloplanktis is one of the model organisms of cold-adapted bacteria and has been suggested as an alternative host for the soluble overproduction of heterologous proteins which tend to form inclusion bodies in established expression hosts. Despite the progress in establishing P. haloplanktis as an alternative expression host the cell densities obtained with this organism, which is unable to use glucose as a carbon source, are still low. Here we present the first fed-batch cultivation strategy for this auspicious alternative expression host.
Results
The key for the fed-batch cultivation of P. haloplanktis was the replacement of peptone by casamino acids, which have a much higher solubility and allow a better growth control. In contrast to the peptone medium, on which P. haloplanktis showed different growth phases, on a casamino acids-containing, phosphate-buffered medium P. haloplanktis grew exponentially with a constant growth rate until the stationary phase. A fed-batch process was established by feeding of casamino acids with a constant rate resulting in a cell dry weight of about 11 g l-1 (OD540 = 28) which is a twofold increase of the highest densities which have been obtained with P. haloplanktis so far and an eightfold increase of the density obtained in standard shake flask cultures.
The cell density was limited in the fed-batch cultivation by the relatively low solubility of casamino acids (about 100 g l-1), which was proven by pulse addition of casamino acid powder which increased the cell density to about 20 g l-1 (OD540 = 55).
Conclusion
The growth of P. haloplanktis to higher cell densities on complex medium is possible. A first fed-batch fermentation strategy could be established which is feasible to be used in lab-scale or for industrial purposes. The substrate concentration of the feeding solution was found to influence the maximal biomass yield considerably. The bottleneck for growing P. haloplanktis to high cell densities still remains the availability of a highly concentrated substrate and the reduction of the substrate complexity. However, our results indicate glutamic acid as a major carbon source, which provides a good basis for further improvement of the fed-batch process.
doi:10.1186/1475-2859-9-72
PMCID: PMC2954877  PMID: 20858251
14.  In vitro targeting of Polo-like kinase 1 in bladder carcinoma 
Cancer Biology & Therapy  2013;14(7):648-657.
Despite the improvements in neoadjuvant chemotherapy, the outcome of patients with advanced bladder cancer has changed very little over the past 30 years. In the present study we tested and compared the in vitro antitumor activities of four different inhibitors of Polo-like kinase 1 (PLK1) (BI 2536, BI 6727, GW843682X, and GSK461364), against 3 bladder carcinoma cell lines RT4, 5637 and T24. The impact on radiosensitivity and drug interactions in simultaneous treatments with cisplatin, methotrexate, and doxorubicin were also investigated. Our results showed that PLK1 inhibition prevented cell proliferation and clonogenicity, causing significant inhibition of invasion of tumor cells, though modest differences were observed between drugs. Moreover, all PLK1 inhibitors induced G2/M arrest, with the subsequent induction of death in all 3 cell lines. Drug interactions studies showed auspicious results for all PLK1 inhibitors when combined with the commonly used cisplatin and methotrexate, though combinations with doxorubicin showed mostly antagonistic effects. Comparably, the four PLK1 inhibitors efficiently sensitized cells to ionizing radiation. Our findings demonstrate that irrespective of the inhibitor used, the pharmacological inhibition of PLK1 constrains bladder cancer growth and dissemination, providing new opportunities for future therapeutic intervention. However, further laboratorial and pre-clinical tests are still needed to corroborate the usefulness of using them in combination with other commonly used chemotherapeutic drugs.
doi:10.4161/cbt.25087
PMCID: PMC3742494  PMID: 23792639
PLK1 inhibition, bladder cancer; cell lines
15.  Absence or presence? Complexities in the donor narratives of single mothers using sperm donation 
STUDY QUESTION
How do single mothers who have conceived a child via anonymous or identity-release sperm donation represent the donor?
SUMMARY ANSWER
While the majority of mothers described their anonymous and identity-release donors as symbolically significant to their families, others were more likely to emphasize that their lack of information limited their thoughts about him.
WHAT IS KNOWN ALREADY
There is limited understanding of the factors that impact upon how single mothers represent the donor, and whether or not they are determined by specific donor programmes (anonymous or identity-release).
STUDY DESIGN, SIZE, DURATION
Qualitative interviews were conducted with 46 women who had treatment at a UK licensed fertility clinic during the years 2003–2009. Twenty mothers (43%) had used an anonymous donor, and 26 (57%) had used an identity-release donor.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Among the 46 mothers interviewed, all had at least one child conceived via donor insemination who was between the ages of 4 and 9 years. Mothers were heterosexual and were currently without a live-in and/or long-term partner. Interview data were analysed qualitatively according to the principles of thematic analysis.
MAIN RESULTS AND THE ROLE OF CHANCE
Findings indicated marked diversity in single mothers' representations of the donor. Most (n = 27) mothers talked about the donor as symbolically significant to family life and were likely to describe the donor as (i) a gift-giver, (ii) a gene-giver and (iii) a potential partner. Others (n = 16) talked about the donor as (i) unknown, (ii) part of a process and (iii) out of sight and out of mind. There were mothers with anonymous and identity-release donors in each group. Several mothers explained that their feelings about the donor had changed over time.
LIMITATIONS, REASONS FOR CAUTION
All mothers conceived at a licensed fertility clinic in the UK. Findings are limited to individuals willing and able to take part in research on donor conception.
WIDER IMPLICATIONS OF THE FINDINGS
The study offers greater insight into the factors influencing the donor narratives produced in single-mother families. It has implications for the counselling and treatment of single women seeking fertility treatment with donor gametes in both anonymous and identity-release programmes. Given that the number of clinics offering identity-release programmes worldwide seems to be increasing, the finding that single women may have varying preferences with regard to donor type, and varying interest levels with regard to donor information, is important. It is recommended that clinicians and other fertility clinic staff guard against making assumptions about such preferences and any thoughts and feelings about the donor or donor information on the basis of marital status.
STUDY FUNDING/COMPETING INTEREST(S)
This study was funded by the Wellcome Trust [097857/Z/11/Z]. The authors have no conflicts of interest to declare.
doi:10.1093/humrep/dev275
PMCID: PMC4677963  PMID: 26545622
Single motherhood; sperm donation; family narratives; information provision; identity-release donation
16.  Potential Capacity of Aptamers to Trigger Immune Activation in Human Blood 
PLoS ONE  2013;8(7):e68810.
Target specific short single-stranded DNA (ssDNA) molecules, called aptamers, are auspicious ligands for numerous in vivo applications. However, aptamers are synthetic molecules, which might be recognized by the immune cells in vivo and induce an activation of the innate immune system. Thus, immune activation potential of synthetic ssDNA oligonucleotides (ODNs) was determined using a well established closed-loop circulation model. Fresh human blood was incubated at 37°C for 2 or 4 hours with ssDNA ODNs (SB_ODN) or CpG ODN as positive control. Transcriptional changes were determined by microarray analyses. Blood samples containing SB_ODN demonstrated after 4 hours a significant regulation of 295 transcripts. Amongst others, CCL8, CXCL10, CCL7 and CXCL11 were highest regulated genes. Gene Ontology terms and KEGG pathway analyses exhibited that the differentially expressed genes belong to the transcripts that are regulated during an immune and inflammatory response, and were overrepresented in TLR signaling pathway. This study shows for the first time the potential of aptamers to activate immune system after systemic application into the human blood. Thus, we highly recommend performing of these preclinical tests with potential aptamer-based therapeutics.
doi:10.1371/journal.pone.0068810
PMCID: PMC3720859  PMID: 23935890
17.  Mass Fatality Management following the South Asian Tsunami Disaster: Case Studies in Thailand, Indonesia, and Sri Lanka 
PLoS Medicine  2006;3(6):e195.
Background
Following natural disasters, mismanagement of the dead has consequences for the psychological well-being of survivors. However, no technical guidelines currently exist for managing mass fatalities following large natural disasters. Existing methods of mass fatality management are not directly transferable as they are designed for transport accidents and acts of terrorism. Furthermore, no information is currently available about post-disaster management of the dead following previous large natural disasters.
Methods and Findings
After the tsunami disaster on 26 December 2004, we conducted three descriptive case studies to systematically document how the dead were managed in Thailand, Indonesia, and Sri Lanka. We considered the following parameters: body recovery and storage, identification, disposal of human remains, and health risks from dead bodies. We used participant observations as members of post-tsunami response teams, conducted semi-structured interviews with key informants, and collected information from published and unpublished documents.
Refrigeration for preserving human remains was not available soon enough after the disaster, necessitating the use of other methods such as dry ice or temporary burial. No country had sufficient forensic capacity to identify thousands of victims. Rapid decomposition made visual identification almost impossible after 24–48 h. In Thailand, most forensic identification was made using dental and fingerprint data. Few victims were identified from DNA. Lack of national or local mass fatality plans further limited the quality and timeliness of response, a problem which was exacerbated by the absence of practical field guidelines or an international agency providing technical support.
Conclusions
Emergency response should not add to the distress of affected communities by inappropriately disposing of the victims. The rights of survivors to see their dead treated with dignity and respect requires practical guidelines and technical support. Mass fatality management following natural disasters needs to be informed by further field research and supported by a network of regional and international forensic institutes and agencies.
Case studies were conducted to systematically document how the bodies of those killed in the tsunami were managed in Thailand, Indonesia, and Sri Lanka. Many lessons can be learned, though more research is needed.
Editors' Summary
Background.
Some 226,408 people died in the tsunami that hit countries across South Asia on 26 December 2004. As well as providing assistance to the living, a crucially important part of the disaster relief effort was the recovery, identification, and disposal of the dead. However, there is very little consensus about the best way to handle and identify large numbers of bodies. Although natural disasters that kill many people occur frequently, most guidelines for the management of large numbers of dead bodies have come out of the experience gained from transport accidents and from terrorist incidents, and these guidelines are not directly relevant; for example, natural disasters often cause many more deaths than transport accidents or terrorist attacks. It is important for survivors that the bodies of the dead are handled with respect and that the dead are identified so that survivors know what has happened to missing relatives. However, at the same time many people are afraid of what the effect of many dead bodies might be on the living; one belief is that dead bodies are a source of disease. Such a belief can lead to the inappropriately rapid burial of bodies before identification has been done.
Why Was This Study Done?
The tsunami of 2004 provided an opportunity to study four different aspects of how the dead were handled in a number of different countries: how the bodies were recovered, how the bodies were identified, how the bodies were disposed of, and what, if any, were the health effects of the large number of bodies on survivors. The authors wanted to then use the results to make recommendations for use in future natural disasters.
What Did the Researchers Do and Find?
The authors interviewed in person, in writing, and by E-mail key people involved in the handling of the dead in three of the countries affected by the tsunami: Thailand (where 8,345 people died), Indonesia (where 165,708 people died), and Sri Lanka (where 35,399 people died). The authors discovered that there were a huge number of people and agencies involved in the handling of the dead; for example, in Indonesia 42 different organizations were involved in recovering bodies.
None of the countries had sufficient refrigerated storage available to store bodies until they could be identified. Some effective alternatives were used, such as temporary burial in shallow graves—where the temperature is lower than in the ambient air—with the intention of exhuming the bodies later for identification. However, many bodies were hurriedly buried in mass graves because they were decomposing; these bodies were almost impossible to identify.
Methods and efficiency of identification varied between and within countries. One hospital in Sri Lanka excelled by systematically photographing all bodies brought in and recording sex, height, and personal effects: 87% of the bodies brought here were identified. But in most areas rates of identification were much lower. It seemed that simple methods of identification were the most useful: photographs taken quickly before the bodies started to decompose, dental records, and personal effects found on the bodies. DNA analysis was only useful for a small number of bodies.
When it came to disposal of the bodies, again procedures differed widely, and in some cases were dictated by religious needs—for example, in some Muslim communities all bodies were buried within 24 hours, making counting and identification of the dead very difficult. Mass graves were often used, but these caused problems; for example, haphazard arrangement of the bodies meant that later exhumation and identification would be impossible.
The authors concluded that there was virtually no health impact of the dead bodies on survivors. Other studies found that there were no epidemics among the surviving population, and that most effects were on those who handled bodies in temporary morgues, where there were the expected variety of sharp-implement injuries and mucosal splashes with body fluids, along with heat stress and dehydration due to overuse of personal protective equipment such as respirators.
What Do These Findings Mean?
How efficiently bodies were handled after the tsunami varied widely across and even within countries. The authors conclude that much of this variety was because of a lack of national or local plans for such mass fatalities, along with a lack of practical field guidelines. There was little coordination of all of the different organizations involved. However, in some places bodies were handled very well. The authors drew on their findings to suggest guidelines for the possible future management of large numbers of bodies, and also suggested that further research should be done. Reassuringly, the large numbers of bodies did not cause problems for the survivors, so in the future survivors should be encouraged to systematically identify the dead rather than rushing to bury them because of fear of disease.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030195.
• The World Heath Organization has a Web page that brings together much information on the tsunami and its aftermath
• News from the United Nations special envoy for the tsunami can be found on its Web site
• An article published by the Pan American Health Organization called “Disaster Myths That Just Won't Die”
• Field guidelines for managing mass fatality natural disasters developed by an international workshop following the tsunami
doi:10.1371/journal.pmed.0030195
PMCID: PMC1472696  PMID: 16737348
18.  Gold(I)-Triphenylphosphine Complexes with Hypoxanthine-Derived Ligands: In Vitro Evaluations of Anticancer and Anti-Inflammatory Activities 
PLoS ONE  2014;9(9):e107373.
A series of gold(I) complexes involving triphenylphosphine (PPh3) and one N-donor ligand derived from deprotonated mono- or disubstituted hypoxanthine (HLn) of the general composition [Au(Ln)(PPh3)] (1–9) is reported. The complexes were thoroughly characterized, including multinuclear high resolution NMR spectroscopy as well as single crystal X-ray analysis (for complexes 1 and 3). The complexes were screened for their in vitro cytotoxicity against human cancer cell lines MCF7 (breast carcinoma), HOS (osteosarcoma) and THP-1 (monocytic leukaemia), which identified the complexes 4–6 as the most promising representatives, who antiproliferative activity was further tested against A549 (lung adenocarcinoma), G-361 (melanoma), HeLa (cervical cancer), A2780 (ovarian carcinoma), A2780R (ovarian carcinoma resistant to cisplatin), 22Rv1 (prostate cancer) cell lines. Complexes 4–6 showed a significantly higher in vitro anticancer effect against the employed cancer cells, except for G-361, as compared with the commercially used anticancer drug cisplatin, with IC50 ≈ 1–30 µM. Anti-inflammatory activity was evaluated in vitro by the assessment of the ability of the complexes to modulate secretion of the pro-inflammatory cytokines, i.e. tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), in the lipopolysaccharide-activated macrophage-like THP-1 cell model. The results of this study identified the complexes as auspicious anti-inflammatory agents with similar or better activity as compared with the clinically applied gold-based antiarthritic drug Auranofin. In an effort to explore the possible mechanisms responsible for the biological effect, the products of interactions of selected complexes with sulfur-containing biomolecules (L-cysteine and reduced glutathione) were studied by means of the mass-spectrometry study.
doi:10.1371/journal.pone.0107373
PMCID: PMC4167326  PMID: 25226034
19.  The Mad Genius Stereotype: Still Alive and Well 
Scientists and laypeople agree on high ability as a defining feature of giftedness. Yet their views on gifted people's socioemotional characteristics diverge. Most studies find the gifted to be similar or slightly superior to average-ability persons in these domains (“harmony hypothesis”). However, subjective conceptions and media representations, most of which have focused on gifted children and youth, stress the socioemotional downsides of giftedness (“disharmony hypothesis”), affecting highly able individuals and those around them, thus hampering individual development. To date, most studies on gifted stereotypes have examined selective samples, mostly teachers. The present study is the first to provide representative data on conceptions of gifted individuals in general. A brief survey of 1029 German adults assessed quality and prevalence of stereotypes about gifted individuals, without an explicit focus on children and/or adolescents. Latent class analysis (LCA) revealed two conceptions of giftedness, with twice as many “disharmonious” than “harmonious” raters. Male gender, single parenthood, unemployment, higher income or negative attitudes toward the gifted predicted disharmonious ratings. However, effects were small, suggesting future studies look deeper into the processes of stereotype formation and maintenance.
doi:10.3389/fpsyg.2016.00368
PMCID: PMC4800426  PMID: 27047409
giftedness; harmony hypothesis; disharmony hypothesis; gifted stereotypes; social perception; big two; warmth and competence; stigma of giftedness
20.  Interactions between Non-Physician Clinicians and Industry: A Systematic Review 
PLoS Medicine  2013;10(11):e1001561.
In a systematic review of studies of interactions between non-physician clinicians and industry, Quinn Grundy and colleagues found that many of the issues identified for physicians' industry interactions exist for non-physician clinicians.
Please see later in the article for the Editors' Summary
Background
With increasing restrictions placed on physician–industry interactions, industry marketing may target other health professionals. Recent health policy developments confer even greater importance on the decision making of non-physician clinicians. The purpose of this systematic review is to examine the types and implications of non-physician clinician–industry interactions in clinical practice.
Methods and Findings
We searched MEDLINE and Web of Science from January 1, 1946, through June 24, 2013, according to PRISMA guidelines. Non-physician clinicians eligible for inclusion were: Registered Nurses, nurse prescribers, Physician Assistants, pharmacists, dieticians, and physical or occupational therapists; trainee samples were excluded. Fifteen studies met inclusion criteria. Data were synthesized qualitatively into eight outcome domains: nature and frequency of industry interactions; attitudes toward industry; perceived ethical acceptability of interactions; perceived marketing influence; perceived reliability of industry information; preparation for industry interactions; reactions to industry relations policy; and management of industry interactions. Non-physician clinicians reported interacting with the pharmaceutical and infant formula industries. Clinicians across disciplines met with pharmaceutical representatives regularly and relied on them for practice information. Clinicians frequently received industry “information,” attended sponsored “education,” and acted as distributors for similar materials targeted at patients. Clinicians generally regarded this as an ethical use of industry resources, and felt they could detect “promotion” while benefiting from industry “information.” Free samples were among the most approved and common ways that clinicians interacted with industry. Included studies were observational and of varying methodological rigor; thus, these findings may not be generalizable. This review is, however, the first to our knowledge to provide a descriptive analysis of this literature.
Conclusions
Non-physician clinicians' generally positive attitudes toward industry interactions, despite their recognition of issues related to bias, suggest that industry interactions are normalized in clinical practice across non-physician disciplines. Industry relations policy should address all disciplines and be implemented consistently in order to mitigate conflicts of interest and address such interactions' potential to affect patient care.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Making and selling health care goods (including drugs and devices) and services is big business. To maximize the profits they make for their shareholders, companies involved in health care build relationships with physicians by providing information on new drugs, organizing educational meetings, providing samples of their products, giving gifts, and holding sponsored events. These relationships help to keep physicians informed about new developments in health care but also create the potential for causing harm to patients and health care systems. These relationships may, for example, result in increased prescription rates of new, heavily marketed medications, which are often more expensive than their generic counterparts (similar unbranded drugs) and that are more likely to be recalled for safety reasons than long-established drugs. They may also affect the provision of health care services. Industry is providing an increasingly large proportion of routine health care services in many countries, so relationships built up with physicians have the potential to influence the commissioning of the services that are central to the treatment and well-being of patients.
Why Was This Study Done?
As a result of concerns about the tension between industry's need to make profits and the ethics underlying professional practice, restrictions are increasingly being placed on physician–industry interactions. In the US, for example, the Physician Payments Sunshine Act now requires US manufacturers of drugs, devices, and medical supplies that participate in federal health care programs to disclose all payments and gifts made to physicians and teaching hospitals. However, other health professionals, including those with authority to prescribe drugs such as pharmacists, Physician Assistants, and nurse practitioners are not covered by this legislation or by similar legislation in other settings, even though the restructuring of health care to prioritize primary care and multidisciplinary care models means that “non-physician clinicians” are becoming more numerous and more involved in decision-making and medication management. In this systematic review (a study that uses predefined criteria to identify all the research on a given topic), the researchers examine the nature and implications of the interactions between non-physician clinicians and industry.
What Did the Researchers Do and Find?
The researchers identified 15 published studies that examined interactions between non-physician clinicians (Registered Nurses, nurse prescribers, midwives, pharmacists, Physician Assistants, and dieticians) and industry (corporations that produce health care goods and services). They extracted the data from 16 publications (representing 15 different studies) and synthesized them qualitatively (combined the data and reached word-based, rather than numerical, conclusions) into eight outcome domains, including the nature and frequency of interactions, non-physician clinicians' attitudes toward industry, and the perceived ethical acceptability of interactions. In the research the authors identified, non-physician clinicians reported frequent interactions with the pharmaceutical and infant formula industries. Most non-physician clinicians met industry representatives regularly, received gifts and samples, and attended educational events or received educational materials (some of which they distributed to patients). In these studies, non-physician clinicians generally regarded these interactions positively and felt they were an ethical and appropriate use of industry resources. Only a minority of non-physician clinicians felt that marketing influenced their own practice, although a larger percentage felt that their colleagues would be influenced. A sizeable proportion of non-physician clinicians questioned the reliability of industry information, but most were confident that they could detect biased information and therefore rated this information as reliable, valuable, or useful.
What Do These Findings Mean?
These and other findings suggest that non-physician clinicians generally have positive attitudes toward industry interactions but recognize issues related to bias and conflict of interest. Because these findings are based on a small number of studies, most of which were undertaken in the US, they may not be generalizable to other countries. Moreover, they provide no quantitative assessment of the interaction between non-physician clinicians and industry and no information about whether industry interactions affect patient care outcomes. Nevertheless, these findings suggest that industry interactions are normalized (seen as standard) in clinical practice across non-physician disciplines. This normalization creates the potential for serious risks to patients and health care systems. The researchers suggest that it may be unrealistic to expect that non-physician clinicians can be taught individually how to interact with industry ethically or how to detect and avert bias, particularly given the ubiquitous nature of marketing and promotional materials. Instead, they suggest, the environment in which non-physician clinicians practice should be structured to mitigate the potentially harmful effects of interactions with industry.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001561.
This study is further discussed in a PLOS Medicine Perspective by James S. Yeh and Aaron S. Kesselheim
The American Medical Association provides guidance for physicians on interactions with pharmaceutical industry representatives, information about the Physician Payments Sunshine Act, and a toolkit for preparing Physician Payments Sunshine Act reports
The International Council of Nurses provides some guidance on industry interactions in its position statement on nurse-industry relations
The UK General Medical Council provides guidance on financial and commercial arrangements and conflicts of interest as part of its good medical practice website, which describes what is required of all registered doctors in the UK
Understanding and Responding to Pharmaceutical Promotion: A Practical Guide is a manual prepared by Health Action International and the World Health Organization that schools of medicine and pharmacy can use to train students how to recognize and respond to pharmaceutical promotion.
The Institute of Medicine's Report on Conflict of Interest in Medical Research, Education, and Practice recommends steps to identify, limit, and manage conflicts of interest
The University of California, San Francisco, Office of Continuing Medical Education offers a course called Marketing of Medicines
doi:10.1371/journal.pmed.1001561
PMCID: PMC3841103  PMID: 24302892
21.  Aqueous Ethanolic Extract of Tinospora cordifolia as a Potential Candidate for Differentiation Based Therapy of Glioblastomas  
PLoS ONE  2013;8(10):e78764.
Glioblastomas are the most aggressive primary brain tumors and their heterogeneity and complexity often renders them non responsive to various conventional treatments. Search for herbal products having potential anti-cancer activity is an active area of research in the Indian traditional system of medicine i.e., Ayurveda. Tinospora cordifolia, also named as ‘heavenly elixir’ is used in various ayurvedic decoctions as panacea to treat several body ailments. The current study investigated the anti-brain cancer potential of 50% ethanolic extract of Tinospora cordifolia (TCE) using C6 glioma cells. TCE significantly reduced cell proliferation in dose-dependent manner and induced differentiation in C6 glioma cells, resulting in astrocyte-like morphology as indicated by phase contrast images, GFAP expression and process outgrowth data of TCE treated cells which exhibited higher number and longer processes than untreated cells. Reduced proliferation of cells was accompanied by enhanced expression of senescence marker, mortalin and its translocation from perinuclear to pancytoplasmic spaces. Further, TCE showed anti-migratory and anti-invasive potential as depicted by wound scratch assay and reduced expression of plasticity markers NCAM and PSA-NCAM along with MMP-2 and 9. On analysis of the cell cycle and apoptotic markers, TCE treatment was seen to arrest the C6 cells in G0/G1 and G2/M phase, suppressing expression of G1/S phase specific protein cyclin D1 and anti-apoptotic protein Bcl-xL, thus supporting its anti-proliferative and apoptosis inducing potential. Present study provides the first evidence for the presence of anti-proliferative, differentiation-inducing and anti-migratory/anti-metastatic potential of TCE in glioma cells and possible signaling pathways involved in its mode of action. Our primary data suggests that TCE and its active components may prove to be promising phytotherapeutic interventions in gliobalstoma multiformae. 
doi:10.1371/journal.pone.0078764
PMCID: PMC3811968  PMID: 24205314
22.  Towards Universal Coverage: Examining Costs of Illness, Payment, and Coping Strategies to Different Population Groups in Southeast Nigeria 
This study investigated the costs of illness to households in different socio-economic status (SES) groups and geographic places of abode in addition to the mechanisms that the different population groups used to pay for health services and cope with payments. A cross-sectional descriptive study of 3,200 households selected from six communities in two states was conducted using interviewer-administered pre-tested questionnaires. An SES index was used to divide the households into quartiles, and χ2 analysis was used to determine the relationship of SES and geographic abode of households with cost of illness, payment mechanism, and coping strategies. The results show that malaria was the illness that most people had. The average cost of transportation for malaria was 86 Naira ($0.6 US), and the total cost of treatment was 2,819.9 Naira ($20 US); of this cost, drug costs alone contributed more than 90%. Out of pocket was the main method of payment. Treatment costs differed by geographic location and socio-economic status. Policy measures should establish targeted mechanisms to protect the general population, especially rural dwellers and poorer households, against the financial burden of direct healthcare payments.
doi:10.4269/ajtmh.2012.11-0090
PMCID: PMC3247109  PMID: 22232451
23.  eGIFT: Mining Gene Information from the Literature 
BMC Bioinformatics  2010;11:418.
Background
With the biomedical literature continually expanding, searching PubMed for information about specific genes becomes increasingly difficult. Not only can thousands of results be returned, but gene name ambiguity leads to many irrelevant hits. As a result, it is difficult for life scientists and gene curators to rapidly get an overall picture about a specific gene from documents that mention its names and synonyms.
Results
In this paper, we present eGIFT (http://biotm.cis.udel.edu/eGIFT), a web-based tool that associates informative terms, called iTerms, and sentences containing them, with genes. To associate iTerms with a gene, eGIFT ranks iTerms about the gene, based on a score which compares the frequency of occurrence of a term in the gene's literature to its frequency of occurrence in documents about genes in general. To retrieve a gene's documents (Medline abstracts), eGIFT considers all gene names, aliases, and synonyms. Since many of the gene names can be ambiguous, eGIFT applies a disambiguation step to remove matches that do not correspond to this gene. Another additional filtering process is applied to retain those abstracts that focus on the gene rather than mention it in passing. eGIFT's information for a gene is pre-computed and users of eGIFT can search for genes by using a name or an EntrezGene identifier. iTerms are grouped into different categories to facilitate a quick inspection. eGIFT also links an iTerm to sentences mentioning the term to allow users to see the relation between the iTerm and the gene. We evaluated the precision and recall of eGIFT's iTerms for 40 genes; between 88% and 94% of the iTerms were marked as salient by our evaluators, and 94% of the UniProtKB keywords for these genes were also identified by eGIFT as iTerms.
Conclusions
Our evaluations suggest that iTerms capture highly-relevant aspects of genes. Furthermore, by showing sentences containing these terms, eGIFT can provide a quick description of a specific gene. eGIFT helps not only life scientists survey results of high-throughput experiments, but also annotators to find articles describing gene aspects and functions.
doi:10.1186/1471-2105-11-418
PMCID: PMC2929241  PMID: 20696046
24.  Generationing, Stealthing, and Gift Giving: The Intentional Transmission of HIV by HIV-Positive Men to their HIV-Negative Sex Partners 
Health Psychology Research  2014;2(3):1582.
Gift giving is the process by which an HIV-positive person purposely infects an HIV-negative person with HIV, usually with that person’s knowledge and consent. Little has been written about this HIV transmission practice. In this paper, two specific types of gift giving – generationing and stealthing – are explained and introduced to the scientific literature. Generationing is a type of gift giving in which one gift giver successfully infects a previously-uninfected man with HIV, and then the two men collaborate in an effort to seroconvert another man, and so forth. Stealthing is another type of gift giving in which an HIV-positive man actively tries to infect an HIV-negative man with HIV, without the latter’s knowledge or consent. The present study reports on the prevalence of gift giving (4.6%) in a population of men who use the Internet specifically to identify partners for unprotected sex. The research is based on a national random sample of 332 men who have sex with men, identified from 16 websites. Data were collected via telephone interviews conducted between January 2008 and May 2009. The paper concludes with a discussion of the implications of these findings for HIV prevention and intervention efforts. Most notably, to the extent that generationing, stealthing, and gift giving occur among MSM, they represent a very high risk of HIV transmission. More work needs to be done to understand these behaviors, the factors that underlie them, and to determine how prevalent they are in the bare-backing population of MSM.
doi:10.4081/hpr.2014.1582
PMCID: PMC4768590  PMID: 26973945
men who have sex with men; HIV risk practices; Internet; gift giving; HIV transmission; generationing
25.  Faculty Member’s Views, Attitude and Current Practice As Regards International Committee of Medical Journal Editors Criteria for Authorship 
Iranian Journal of Public Health  2013;42(10):1092-1098.
Abstract
Background
The objective of this study was to assess the knowledge and views of faculty members on criteria for authorship by International Committee of Medical Journal Editors (ICMJE), their current practice of choosing the authors, views on gift authorship and problems they had faced concerning authorship.
Methods
It was a cross sectional survey from January 2011 to July 2011 among faculty members of various private and public sector medical institutions of Pakistan through a self-administered questionnaire. Main outcome measures included awareness and use of ICMJE criteria, which contribution to research merit authorship and their perceptions about gift authorship.
Results
Two hundred eighteen faculty members (180 males, 38 females) participated in the study. One hundred twenty eight (58.7%) were from surgery and allied disciplines. Ninety six percent had published between one to five papers while 60(27.5%) had six to ten papers to their credit. One hundred eleven (50.9%) claimed they were aware about the authorship criteria, only twenty two (19.8%) could name this document. Only four (1.8%) could correctly state this. Only one hundred twenty (55.0%) said that all three criteria’s must be met to be eligible for authorship. Ninety three (42.7%) said that they were not included as authors though they deserved it while sixty three said they did not merit but were still included. Forty two (19.3%) said that they were not aware when they were listed as authors.
Conclusion
A vast majority of young faculty members are not aware of the existence of authorship criteria and gift authorship is quite common.
PMCID: PMC4436536  PMID: 26060616
ICMJE; Journalism; Authorship criteria; Gift authorship; Faculty members

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