Looking for rules in a world of exceptions: reflections on evidence-based practice

After more than a decade, evidence-based medicine (EBM) is well established as an important influence in health care. EBM has engendered a wide range of responses from near-evangelical fervor to angered rejection, with supporters convinced of its scientific superiority and detractors of its needless reductionism. EBM is not a philosophical doctrine, and its originators and proponents have, for the most part, ignored critics and foresworn theorizing. However, EBM claims to be a normative guide to being a better physician. The theoretical, practical, and philosophical dimensions of EBM are intimately intertwined. This essay is a sustained reflection on the issues raised by EBM as experienced by a clinician/teacher who has tried to apply the tenets of EBM in clinical care and teaching over the past decade, and who has sought to expand the borders of EBM from a philosophical point of view.     

Endoplasmic reticulum-associated degradation: exceptions to the rule

Quality control mechanisms in the endoplasmic reticulum (ER) ensure that misfolded proteins are recognized and targeted for degradation. According to the current view of ER-associated degradation (ERAD), the degradation does not occur in the ER itself but requires the retrotranslocation of the proteins to the cytosol where they are degraded by proteasomes. Although this model appears to be valid for many different proteins a number of exceptions from this rule suggest that additional proteasome-independent ERAD pathways may exist. In this review, we will summarize what is known about these alternative ERAD pathways.     

Larvae of lycaenid butterflies that parasitize ant colonies provide exceptions to normal insect growth rules

Fourth instar larvae of Maculinea species of lycaenid butterfly live as social parasites inside Myrmica ant nests. They show highly unusual growth patterns, with small but regular growth in early phytophagous instars, followed by >10 times the growth predicted by extrapolating the early growth rate (following Dyar's rule) during the final carnivorous instar. This produces striking allometry between head and body size in full-grown larvae (ratios of 4–5% compared with 8–10%). Larvae of the Myrmica ant hosts have a similar growth. Data for c. 150 other lycaenid species showed that species with similar life-histories exhibit the same unusual growth pattern (Phengaris spp., Lepidochrysops spp., Niphanda fused); all others have regular growth throughout their larval life, including the carnivorous species that are parasitic on ants from the first instar. It is suggested that Maculinea-type growth pattern has arisen convergently in at least three unrelated lineages of lycaenids. Selection pressures might include the need for reduced early growth to produce late instars that are small enough to be integrated as brood mimics into ant social systems, combined with the need to achieve at least the same adult size as the ancestral species. Trophic pressures that operate on both sedentary ant and butterfly larvae, which must survive long periods of starvation and grow rapidly when food is abundant, may also be involved.     

The real objective of Mendel's paper: A response to Monaghan and Corcos

Mendel's work in hybridization is ipso facto a study in inheritance. He is explicit in his interest to formulate universal generalizations, and at least in the case of the independent segregation of traits, he formulated his conclusions in the form of a law. Mendel did not discern, however, the inheritance of traits from that of the potential for traits. Choosing to study discrete non-overlapping traits, this did not hamper his efforts.     

Apparent size choice of zooplankton by planktivorous sunfish: exceptions to the rule

Synopsis Choice of the apparently largest prey has been implicated as an important component of the size choice behavior of several planktivorous fish species. In this study we describe the effect of several aspects of prey placement, apparent and absolute size, and motion on the choice behavior of bluegill or white crappie. In binary choice experiments, bluegill usually choose Daphnia prey on the basis of apparent size. However, when both prey were close to the fish and the absolutely larger prey was apparently smaller, the fish commonly chose the absolutely larger. The horizontal placement of two prey also altered choice such that the more forward directed prey was chosen even when apparently smaller. White crappie, when offered a choice between a diaptomid copepod or daphnid prey, chose the daphnid most of the time. Bluegill sunfish offered moving versus non-moving heat-killed daphnids commonly chose the one in motion. Apparent size choice is still a good overall describer of bluegill and white crappie prey choice, but it is not the only mechanism involved in prey choice behavior of these fish.     

Genetics of mammalian sex determination: some unloved exceptions

The genetics of sex determination is a child of the twentieth century, which overturned the previously held view that sex was determined by the environment. The last quarter of the century witnessed an active search for sex-determining genes in mammals. Although successful, the modus operandi of these genes remained unknown, and the relationship between the sex-determining systems of mammals and other vertebrates remained enigmatic. To overcome these problems, scientists in the 21st century should heed William Bateson's counsel to treasure exceptions, for they point the way to progress. One exception to conventional concepts of sex determination is the bilaterally asymmetrical distribution of ovaries and testes in true hermaphroditism. Ovaries favour the left side in humans and the right side in mice. Observations suggesting that a reversal of asymmetry may occur with increasing organ size may point to a possible explanation. A reevaluation is also required regarding the beginning of sex differentiation, in view of mounting evidence of a sex difference in growth rates of early embryos. Another question to be settled is whether the function of SRY is confined to the fetal gonad. The recent demonstration that Sry induces cell proliferation in the fetal mouse gonad (Schmahl et al., 2000) further emphasizes the importance of differential growth in sex determination and differentiation. It is suggested that SRY represents an additional growth-promoting gene sequestered by mammals to enable the XY embryo to undergo male sex differentiation in the female hormonal environment of the uterus. An increased awareness of the relationship between growth and gonadal differentiation should lead to a better understanding of sex determination in mammals and an ability to relate the function of sex-determining genes to the effects of environmental factors. J. Exp. Zool. 290:484-489, 2001.     

Seasonal time constraints do not explain exceptions to the temperature size rule in ectotherms

A negative relationship between rearing temperature and adult size is widespread in ectotherms yet its causes remain poorly understood. It has been suggested that summer generations of some aquatic insects provide exceptions to this temperature size rule (TSR). The hypothesis that seasonal time constraints are responsible for these exceptions was tested using the mayfly Cloeon dipterum . Simulating early-season conditions by varying photoperiod and temperature, we found that this species followed the TSR. However, under simulated seasonal time constraints, the species omitted most of its summer adult generation (delaying completion of nymphal development till the next year), which limited the scope and applicability of the hypothesis for this species. Even those animals that completed nymphal development before winter showed no weakening of the negative temperature size relationship that was predicted by the hypothesis. Moreover, these animals did not increase rates of development or growth in response to simulated time constraints. We then analysed further the study that originally indicated aquatic insect exceptions to the TSR and suggest that gaps in the data and/or experimental design can explain the apparent exceptions. From these analyses and a survey of other exceptions, we conclude that time constraints do not account for any reported counter-TSR relationship.     

Highway to the inner nuclear membrane: rules for the road

To enter the nucleus a protein must be chaperoned by a transport factor through the nuclear pore complex or it must be small enough to pass through by diffusion. Although these principles have long described the nuclear import of soluble proteins, recent evidence indicates that they also apply to the import of integral inner nuclear membrane proteins. Here we develop a set of rules that might govern the transport of proteins to the inner nuclear membrane.