Developmental neurobiology and clinical disorders: lost in translation?

Advances in defining mechanisms of cortical development have been paralleled in recent years by an intense interest in translating these findings into greater insight of both childhood- and adult-onset cognitive and mental health disorders of developmental etiology. Successful integration of basic and clinical findings have been applied to monogenic disorders. The greater challenge lies in studying cortical development in the context of gene x environment interactions, which underlie the pathogenesis of the most common neurodevelopmental disorders. This can occur through an improved delineation of pathophysiological characteristics unique to specific complex disorders and the application of this information to the refinement of the most relevant model systems.     

Prebiotic co-evolution of self-replication and translation or RNA world?

A prebiotic scenario is proposed, based on the recent "domain hypothesis" model (Lahav, 1989, J. molec. Evol. 29, 475-479), suggested for domain propagation of RNA-like molecules in a fluctuating environment. The same system is suggested now not only for the evolution of ribozymes, but also for the evolution of directed peptide synthesis, as follows: Short, self-structured strands (termed prebioectons), each possessing a templatable domain which is chargeable by an amino acid, are the predecessors of tRNA (proto-tRNA). Complementary domains are formed on these prebioectons during an environmental cycle such as wetting-drying, followed by their dissociation from their template domain and ligation, to form the predecessor of mRNA (proto-mRNA). The evolution of directed peptide synthesis is suggested to be based on the ability of the charged prebioectons to attach preferentially to their complementary domains on the proto-mRNA. Two stages of this process are envisioned, namely: (a) Template-directed, random peptide synthesis taking place when non-specifically-charged prebioectons are sequentially attached each to its complementary domain on the proto-mRNA, followed by peptide bond formation. (b) Template-and-sequence-directed peptide synthesis, which can be realized after the "invention" of a catalytic molecule capable of specifically charging a proto-tRNA by an amino acid; this is the crucial evolutionary stage, where a crude genetic code becomes functional. Gradually, catalytic peptides and ribozymes are selected for their functions and evolve, while being encoded in the primitive "memory" of the emerging system. Thus, rather than the RNA monopoly postulated by the RNA World hypothesis, an early co-evolution of primitive enzymes and ribozymes is suggested.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differences in mortality from acute myocardial infarction between coronary care unit and medical ward: treatment or bias?

To analyse the effectiveness of coronary care units in reducing mortality from myocardial infarction 18 hospitals ranging from large urban teaching hospitals to small country hospitals were stratified into four levels of care. Previous analysis had failed to show significant differences in the overall mortality in hospital among levels. There were significant differences in mortality, however, between those patients allocated to be cared for in the coronary care unit and those in the medical wards in the more advanced hospitals. The differences were largest in the hospitals with the most elaborate facilities (level 1) and non-existent in those with the least (level 4). Several analytical approaches to these observed differences indicated that they were: (a) reduced by adjustment for age and severity of infarction; (b) paralleled by differences in coexisting disease recorded on death certificates; (c) no longer significant at level 1 after allowing for differences in coexisting disease; and (d) not significant at any level after exclusion of patients first diagnosed at necropsy. These findings suggest that the observed differences in mortality between coronary care units and medical wards are largely due to bias in selection and diagnosis.     

Pain relief in medical patients: does clinical judgment and prescribing knowledge suffice?

The aim of this study was to evaluate the quality of pain management in hospitalised patients. A cross-sectional study design that included all medical patients experiencing pain was used. Out of 167 patients hospitalized at the Department of Medicine at the University Hospital Zagreb, 41 patients were experiencing pain and 40 out of them received analgesics. Twenty-two out of 38 patients were treated for malignant pain, 16 for non-malignant pain, and 2 patients could not be classified. Adequate pain relief was reported in less than 25% of patients in both groups. Our study revealed under-prescribing of combination therapy, low utilization rates of strong opioids and prevailing "as needed" prescribing practice. In conclusion, unsatisfactory pain management in medical patients is often present if left solely to the clinical judgement and knowledge of the prescribing physician. Regular pain assessment, evidence-based guidelines, education and regular audits of implementation of these measures are a prerequisite for effective pain treatment, and should all be employed in patients experiencing pain.     

Neonatal incubator or artificial womb? Distinguishing ectogestation and ectogenesis using the metaphysics of pregnancy

A 2017 Nature report was widely touted as hailing the arrival of the artificial womb. But the scientists involved claim their technology is merely an improvement in neonatal care. This raises an under-considered question: what differentiates neonatal incubation from artificial womb technology? Considering the nature of gestation—or metaphysics of pregnancy—(a) identifies more profound differences between fetuses and neonates/babies than their location (in or outside the maternal body) alone: fetuses and neonates have different physiological and physical characteristics; (b) characterizes birth as a physiological, mereological and topological transformation as well as a (morally relevant) change of location; and (c) delivers a clear distinction between neonatal incubation and ectogestation: the former supports neonatal physiology; the latter preserves fetal physiology. This allows a detailed conceptual classification of ectogenetive and ectogestative technologies according to which the 2017 system is not just improved neonatal incubation, but genuine ectogestation. But it is not an artificial womb, which is a term that is better put to rest. The analysis reveals that any ethical discussion involving ectogestation must always involve considerations of possible risks to the mother as well as her autonomy and rights. It also adds a third and potentially important dimension to debates in reproductive ethics: the physiological transition from fetus/gestateling to baby/neonate.     

Children in medical research: balancing protection and access--has the pendulum swung too far?

This paper examines the changes in policies regarding children in research between 1966 and 2003. The changes reflect a shift in focus from protection to access. The need for protection was brought to light in 1966, with the publication of Henry Beecher's "Ethics and Clinical Research," which described 22 research projects that he considered unethical. Four of these involved child subjects. Within a few years, Paul Ramsey and Richard McCormick debated the ethical acceptability of enrolling children in any non-therapeutic research. The first U.S. policies to address the protection of human subjects were written in the 1970s and 1980s, and additional protections (Subpart D) were provided to child subjects, who were considered particularly vulnerable. In the 1990s, however, several new policies were implemented by the National Institutes of Health, the Food and Drug Administration, and Congress, in which the focus had shifted from protecting children from research risks to ensuring access. The article describes the new policies, examines the motivations for the change, and describes some of the effects of these policies. It concludes by suggesting that greater attention must be paid to ensure that increased access is not achieved by undermining the additional protections to children provided by Subpart D.     

Population biobanks and returning individual research results: mission impossible or new directions?

Historically, large-scale longitudinal genomic research studies have not returned individual research results to their participants, as these studies are not intended to find clinically significant information for individuals, but to produce ‘generalisable’ knowledge for future research. However, this stance is now changing. Commentators now argue that there is an ethical imperative to return clinically significant results and individuals are now expressing a desire to have them. This shift reflects societal changes, such as the rise of social networking and an increased desire to participate in medical decision-making, as well as a greater awareness of genetic information and the increasing ability of clinicians to use this information in health care treatment. This paper will discuss the changes that have prompted genomic research studies to reconsider their position and presents examples of projects that are actively engaged in returning individual research results.