Why are autism and the fragile-X syndrome associated? Conceptual and methodological issues.

Investigations of the association between autism and the fragile-X syndrome have yielded conflicting results with some studies indicating a strong correlation and others indicating no relation between the disorders. In this paper, we review the relevant research on this controversy and discuss the conceptual and methodological problems involved in such an inquiry. We conclude that autism and fragile X are associated and that this relation will prove fruitful in understanding the role of the X chromosome in a variety of behavior disorders and in unraveling various theoretical accounts on the etiology of autism.     

Altruism or solidarity? The motives for organ donation and two proposals

Proposals for increasing organ donation are often rejected as incompatible with altruistic motivation on the part of donors. This paper questions, on conceptual grounds, whether most organ donors really are altruistic. If we distinguish between altruism and solidarity--a more restricted form of other-concern, limited to members of a particular group--then most organ donors exhibit solidarity, rather than altruism. If organ donation really must be altruistic, then we have reasons to worry about the motives of existing donors. However, I argue that altruism is not necessary, because organ donation supplies important goods, whatever the motivation, and we can reject certain dubious motivations, such as financial profit, without insisting on altruism. Once solidaristic donation is accepted, certain reforms for increasing donation rates seem permissible. This paper considers two proposals. Firstly, it has been suggested that registered donors should receive priority for transplants. While this proposal appears based on a solidaristic norm of reciprocity, it is argued that such a scheme would be undesirable, since non-donors may contribute to society in other ways. The second proposal is that donors should be able to direct their organs towards recipients that they feel solidarity with. This is often held to be inconsistent with altruistic motivation, but most donation is not entirely undirected in the first place (for instance, donor organs usually go to co-nationals). While allowing directed donation would create a number of practical problems, such as preventing discrimination, there appears to be no reason in principle to reject it.     

Yolk androgens and embryo sex: maternal effects or confounding factors?

Maternal effects occur when offspring phenotype is affected by environmental factors experienced by the mother and, in egg-laying species, are often mediated via egg resources. There is currently great interest among behavioural ecologists in maternally allocated yolk androgens, especially their relationship with offspring sex and development. Such studies need embryonic tissue for sexing, however, requiring eggs to be incubated (usually for 3 days). Therefore, there are concerns about whether the androgen concentrations assayed reflect those allocated by the mother. In addition, studies showing sex biases in maternal allocation of androgens could be confounded if male and female embryos uptake or metabolise androgens at different rates. We ran a series of experiments using zebra finch (Taeniopygia guttata) eggs to address these potential confounding factors. First we showed, using eggs naturally incubated for up to 5 days, that eggs containing embryos had lower yolk androgen concentrations than eggs that had failed to form embryos. We then tested various hypotheses for this difference using controlled incubation treatments. Our results suggested that (a) embryo development causes the yolk to become progressively more diluted with albumin; and (b) between 3 and 5 days of incubation embryos start uptaking or metabolising androgens. Crucially, we found no decline in yolk androgen concentration at 3 days incubation, and no evidence for sex-specific rates of uptake or metabolism of androgens. This strongly suggests that yolk androgen levels up to 3 days incubation do reflect those allocated by the mother, and that studies of sex biased maternal allocation of yolk androgens are not confounded by sex differences in embryo development.     

Brain donation: who and why?

Understanding what influences people to donate, or not donate, body organs and tissues is very important for the future of transplant surgery and medical research (Garrick in J Clin Neurosci 13:524–528, 2006). A previous web-based motivation survey coordinated by the New South Wales Tissue Resource Centre found that most people who participated in brain donation were young, female, educated Australians, not affiliated with any particular religion, and with a higher prevalence of medical illness than the general Australian population. It discussed the main motivating factors for brain donation to be “the benefits of the research to medicine and science”. This study has been replicated in a paper-based version to capture a broader cross-section of the general population, to find out who they are and what motivates them to donate. All consented and registered brain donors (n = 1,323) were sent a questionnaire via the post and recipients were given 3 months to complete the questionnaire and return it in a reply paid envelope. Results were entered into the original web-based survey and analyzed using SPSS version 10. Six hundred and fifty-eight questionnaires were returned completed, a response rate of 53%. The results show that people from all age groups are interested in brain donation. The over 65’s are the largest of the groups (30.7%). The majority of the participants were female (60.6%), married (49.2%) with children (65.8%), employed (52.9%) and have a tertiary education (73.3%). They were either non-religious (48.2%) or Christian (41.6%) and were mostly Australian (65.4%). Most (81%) had pledged to donate other organs and tissues for transplantation. The most commonly cited reasons for the donation were to benefit science (27.6%), to benefit medicine (23.9%), a family illness (17.5%) and to benefit the community (16.6%). This study demonstrates that people across all age groups are interested in brain donation. Recruitment of new brain donors could target the over 65 female Australians, who are not religious or Christian and who have also donated other organs and tissues for transplant purposes. It also indicates the need to make donation for research part of the national transplant donation program.     

Embryo apoptosis identification: Oocyte grade or cleavage stage?

Apoptosis is a programed cell death that is vital for tissue homeostasis. However, embryo apoptosis had been known to be related to embryo fragmentation which should be avoided in in vitro fertilization (IVF). The purpose of this study was to evaluate the relationship of embryo apoptosis with the grade of immature oocytes and cleavage stage of in vitro produced (IVP) cattle embryos. This study consisted of 345 oocytes collected through ovary slicing. Immature oocytes were graded as A, B and C. This grading was based on cumulus cell thickness and compactness. All oocytes then underwent an in vitro maturation (IVM) procedure. An IVF was done 24 h after IVM culture. Prior to staining, stage of cleaved embryos was determined and classified as either 2, 4, 8 or >8-cell embryo stage. Apoptosis status of cleaved IVP embryos was determined by using annexin V-FITC staining technique at 48 and 72 h post insemination (hpi). Apoptosis status for each embryo was classified as either early or late. The result showed that there was no significant difference (p > 0.05) of apoptosis status among grade A, B and C embryos. All grades of oocytes showed embryo apoptosis where 1.5% late apoptosis for grade A, 4.5% and 10.4% of early and late apoptosis for grade B and grade C. Early apoptosis was not seen in grade A embryo. We also noted no significant difference (p > 0.05) of apoptosis status between 2, 4, 8 and >8-cell embryo stage. Early apoptosis was also not seen in >8-cell stage. Even though there were no differences in apoptosis expression between the three classes, the cleavage rate of grade A oocytes was significantly higher (p < 0.01) than grade B and grade C. In conclusion, the apoptosis expression in the embryo can occur regardless of the oocyte quality and the cleavage stage of the embryo produced.Abbreviations: ART, assisted reproductive technologies; BO, Brackett and Oliphant; BSA, bovine serum albumin; CaI, calcium ionophore; CC, cumulus cells; COC, cumulus–oocyte complex; CO₂, carbon dioxide; CR1aa, Charles Rosenkran’s 1 amino acid; DNA, deoxyribonucleic acid; DO, denuded oocyte; EA, early apoptosis; FBS, fetal bovine serum; FITC, fluorescein isothiocyanate; FSH, follicle stimulating hormone; GSH, glutathione; hpi, hours post insemination; IVC, in vitro culture; IVF, in vitro fertilization; IVM, in vitro maturation; IVP, in vitro produced; LA, late apoptosis; LH, luteinizing hormone; PBS, phosphate buffered saline; PI, propidium iodide; PS, phosphatidylserine; TUNEL, terminal deoxynucleotidyl transfer-mediated dUTP nick end-labeling.     

Hypoxia and temperature: Does hypoxia affect caiman embryo differentiation rate or rate of growth only?

In crocodilians, the rate of embryonic development and consequently many posthatch attributes are affected by temperature. Since temperature exhibits strong influences on fitness (embryo survivorship and phenotype) by shaping development, we manipulated oxygen concentration in order to uncouple the effects of developmental rate from the direct effects of temperature. Here we consider whether oxygen constrains either differentiation rate (progression from one stage to the next) or embryonic growth (size). Thus, we incubated Caiman latirostris eggs at various oxygen concentrations, and at two temperatures (31 °C, 100% female-producing temperature, and 33 °C, 100% male-producing temperature). We monitored the developmental stages of these embryos within the thermosensitive period (stages 20–24), and assessed several physiological and morphological hatchling traits. While embryonic size was strongly influenced by oxygen, differentiation rate did not seem to be affected. Very low oxygen concentrations and high temperatures inhibited embryo survival. In addition, oxygen availability affected incubation period and hatchling size, whereas temperature did not cause a significant variation in hatchling size. By investing energy in differentiation hypoxic embryos decreased their size.     

Morning sickness: adaptive cause or nonadaptive consequence of embryo viability?

"Morning sickness" is the common term for nausea and vomiting in early human pregnancy (NVP). Recent interest in why NVP occurs-that is, in the evolutionary costs and benefits of NVP-has spurred the development of two alternative hypotheses. The "prophylaxis," or "maternal and embryonic protection," hypothesis suggests that NVP serves a beneficial function by expelling foods that may contain harmful toxins and microorganisms and triggering aversions to such foods throughout pregnancy. The alternative "by-product" hypothesis suggests that NVP is a nonfunctional by-product of conflict--over resource allocation--between the pregnant woman and the embryo. The critical predictions of the prophylaxis hypothesis have been developed and tested, whereas the by-product hypothesis has not been subjected to similar scrutiny. To address this gap, we developed a graphical model and used it to derive predictions from the by-product hypothesis under two different assumptions, namely, that NVP is either (i) a by-product of current conflict between a pregnant woman and an embryo or (ii) a by-product of honest signals of viability produced by the embryo. Neither version of the by-product hypothesis is fully consistent with available data. By contrast, the timing of NVP, its variation among societies, and associated patterns of food cravings and aversions are consistent with the prophylaxis hypothesis.     

Adaptation or selection? Old issues and new stakes in the postwar debates over bacterial drug resistance

The 1940s and 1950s were marked by intense debates over the origin of drug resistance in microbes. Bacteriologists had traditionally invoked the notions of 'training' and 'adaptation' to account for the ability of microbes to acquire new traits. As the field of bacterial genetics emerged, however, its participants rejected 'Lamarckian' views of microbial heredity, and offered statistical evidence that drug resistance resulted from the selection of random resistant mutants. Antibiotic resistance became a key issue among those disputing physiological (usually termed 'adaptationist') vs. genetic (mutation and selection) explanations of variation in bacteria. Postwar developments connected with the Lysenko affair gave this debate a new political valence. Proponents of the neo-Darwinian synthesis weighed in with support for the genetic theory. However, certain features of drug resistance seemed inexplicable by mutation and selection, particularly the phenomenon of 'multiple resistance'--the emergence of resistance in a single strain against several unrelated antibiotics. In the late 1950s, Tsutomu Watanabe and his collaborators solved this puzzle by determining that resistance could be conferred by cytoplasmic resistance factors rather than chromosomal mutation. These R factors could carry resistance to many antibiotics and seemed able to promote their own dissemination in bacterial populations. In the end, the vindication of the genetic view of drug resistance was accompanied by a recasting of the 'gene' to include extrachromosomal hereditary units carried on viruses and plasmids.     

The non-human primate oocyte and embryo as a model for women, or is it vice versa?

The role of the non-human primate (NHP) oocyte and embryo in translational research is considered here including both in vitro activities directly involving oocytes or embryos as well as animal studies that impact reproductive function. Reasons to consider NHPs as animal research models along with their limitations are summarized. A case is made that in limited instances, such as in the development and application of the assisted reproductive technologies or in the study of embryonic stem cells, the human oocyte and embryo have acted as models for the monkey. The development of strategies for the preservation of fertility is used as an example of ongoing research in the non-human primate that cannot be conducted in women for ethical reasons. In animal studies, monitoring reproductive potential, responses to embryonic stem cell transplantation, along with translational research in the field of contraceptive development for women are considered as subjects that benefit from the availability of a NHP model.     

Should relatives witness resuscitation? Ethical issues and practical considerations

In winning second prize in the Logie Medical Ethics Essay Contest in 1997, Carolyn Rosenczweig raised questions about the role patients'' family members should be allowed to play during resuscitative efforts by medical staff. She concluded that even though their presence might complicate resuscitation attempts, "blanket policies that exclude all relatives from being present seem a knee-jerk reaction."     

Auxin and embryo axis formation: the ends in sight?

The major axis of polarity of the plant embryo serves as a reference for the formation of meristems and, thus, for all subsequent development. Mechanisms underlying the establishment of the embryo axis itself have remained elusive. This is now changing with recent reports documenting a role for auxin in embryo axis formation. Auxin accumulates dynamically at specific positions that correlate with developmental decisions in early embryogenesis, and this ties developmental decisions to both transport regulators and components of the response machinery. A major challenge for the future is to determine how auxin-dependent processes interact with other as yet unknown factors to mediate differential gene expression patterns in early embryogenesis.     

Infections and autoimmunity--good or bad?

The relationship between infections and autoimmunity is complex. Current evidence indicates that microbes can initiate, enhance, or, conversely, abrogate autoimmunity. In this paper, we will review experimental examples illustrating mechanisms involved in these three scenarios. Microbial infections can act as environmental triggers inducing or promoting autoimmunity resulting in clinical manifestations of autoimmune disease in genetically predisposed individuals. However, increasing evidence suggests the opposite outcome, which is the prevention or amelioration of autoimmune processes following microbial encounters. These latter observations support conceptually the "hygiene hypothesis," suggesting that cleaner living conditions will lead to enhanced incidence of autoimmune disorders, asthma, and allergies. Because proof of concept in humans is difficult to obtain, we will discuss relevant animal model data in context with likely or proven human associations. Knowledge of mechanisms that underlie either positive or negative effects of infections on autoimmunity will facilitate exploration of molecular details for prospective clinical studies in the future.     

Is Predetermined Cellular Competence Required for Alternative Embryo or Shoot Induction on Sunflower Zygotic Embryos?

Abstract: Somatic embryos and adventitious shoots can be induced simultaneously on immature zygotic embryos of sunflower, their relative distribution on the explant being constant but their relative number depending on the sucrose concentration of the culture medium. We show here that the cells at the origin of both types of structures are competent for either development and express this potential as a function of their position relative to the medium. Two zones, inductive for somatic embryos or adventitious shoots, have been established under the influence of the culture medium. The precision of their localisation is demonstrated by the existence of tissue chimeras which also indicate the presence of diffusible signal(s) responsible for the determination of cellular identity. We have further determined that commitment to the organogenic pathway occurred very rapidly, i.e. within 12 h after the onset of the culture. A synthetic model is presented in which we suggest a possible sequence of key events involved in the morphogenic processes.     

Head-tail patterning of the vertebrate embryo: one, two or many unresolved problems?

When, where and how is the head-tail axis of the embryo set up during development? These are such fundamental and intensely studied questions that one might expect them to have been answered long ago. Not so; we still understand very little about the cellular or molecular mechanisms that lead to the orderly arrangement of body elements along the head-tail axis in vertebrates. In this paper, we outline some of the major outstanding problems and controversies and try to identify some reasons why it has been so difficult to resolve this important issue.     

Anxious or Depressed and Still Happy?

This study aimed to examine cross-sectionally to what extent persons with higher symptom levels or a current or past emotional disorder report to be less happy than controls and to assess prospectively whether time-lagged measurements of extraversion and neuroticism predict future happiness independent of time-lagged measurements of emotional disorders or symptom severity. A sample of 2142 adults aged 18–65, consisting of healthy controls and persons with current or past emotional disorder according to DSM-IV criteria completed self-ratings for happiness and emotional well-being and symptom severity. Lagged measurements of personality, symptom severity and presence of anxiety and depressive disorder at T0 (year 0), T2 (year 2) and T4 (year 4) were used to predict happiness and emotional well-being at T6 (year 6) controlling for demographics. In particular persons with more depressive symptoms, major depressive disorder, social anxiety disorder and comorbid emotional disorders reported lower levels of happiness and emotional well-being. Depression symptom severity and to a lesser extent depressive disorder predicted future happiness and emotional well-being at T6. Extraversion and to a lesser extent neuroticism also consistently forecasted future happiness and emotional well-being independent of concurrent lagged measurements of emotional disorders and symptoms. A study limitation is that we only measured happiness and emotional well-being at T6 and our measures were confined to hedonistic well-being and did not include psychological and social well-being. In sum, consistent with the two continua model of emotional well-being and mental illness, a ‘happy’ personality characterized by high extraversion and to a lesser extent low neuroticism forecasts future happiness and emotional well-being independent of concurrently measured emotional disorders or symptom severity levels. Boosting positive emotionality may be an important treatment goal for persons personally inclined to lower levels of happiness.