Early development of the gut: new light on an old hypothesis

This review deals with the early development of the gut. It draws largely on information provided from the study of avian embryos. Evidence that concerns the early determination of the regional fate of the endoderm and mesoderm of the gut is reviewed. Gut endoderm can undergo a limited degree of differentiation from a remarkably early age when cultured in the absence of mesoderm and there is evidence that points to the establishment of a pre-pattern in the early mesoderm before the genes responsible for patterning in gut are active. Initially, at least at cranial levels, those parts of the mesoderm and endoderm that are in contact are not those parts that will ultimately be in apposition; the consequence of this for any signalling between these layers is considered. In the light of the above information, the probable role of mesenchyme in gut development is re-examined.     

Anticipation in myotonic dystrophy: new light on an old problem.

The concept of anticipation, the occurrence of a genetic disorder at progressively earlier ages in successive generations, has been debated from the early years of this century, with myotonic dystrophy as the most striking example. Throughout most of this period there has been controversy as to whether the phenomenon resulted from observational and ascertainment biases or reflected a more fundamental mechanism. The recent discovery of inherited unstable DNA sequences, first in fragile-X mental retardation and now in myotonic dystrophy, not only confirms that anticipation indeed has a true biological basis but provides a specific molecular mechanism for it; this discovery can explain many of the puzzling anomalies in the inheritance of myotonic dystrophy and may prove relevant to comparable problems in other genetic disorders.     

The role of mitochondria in pharmacotoxicology: a reevaluation of an old, newly emerging topic

In addition to their well-known critical role in energy metabolism, mitochondria are now recognized as the location where various catabolic and anabolic processes, calcium fluxes, various oxygen-nitrogen reactive species, and other signal transduction pathways interact to maintain cell homeostasis and to mediate cellular responses to different stimuli. It is important to consider how pharmacological agents affect mitochondrial biochemistry, not only because of toxicological concerns but also because of potential therapeutic applications. Several potential targets could be envisaged at the mitochondrial level that may underlie the toxic effects of some drugs. Recently, antiviral nucleoside analogs have displayed mitochondrial toxicity through the inhibition of DNA polymerase- (pol-). Other drugs that target different components of mitochondrial channels can disrupt ion homeostasis or interfere with the mitochondrial permeability transition pore. Many known inhibitors of the mitochondrial electron transfer chain act by interfering with one or more of the respiratory chain complexes. Nonsteroidal anti-inflammatory drugs (NSAIDs), for example, may behave as oxidative phosphorylation uncouplers. The mitochondrial toxicity of other drugs seems to depend on free radical production, although the mechanisms have not yet been clarified. Meanwhile, drugs targeting mitochondria have been used to treat mitochondrial dysfunctions. Importantly, drugs that target the mitochondria of cancer cells have been developed recently; such drugs can trigger apoptosis or necrosis of the cancer cells. Thus the aim of this review is to highlight the role of mitochondria in pharmacotoxicology, and to describe whenever possible the main molecular mechanisms underlying unwanted and/or therapeutic effects. mitochondrial diseases; nitric oxide; apoptosis; degenerative diseases; free radicals     

Groups of passive and active control state in longitudinal experiments: an electrophysiological study

Long-term electrophysiological experiments were carried out with rats with chronically implanted electrodes into dopaminergic brain structures. Within 4 weeks after surgery, the relative spectral power of electrical activity in the delta1 and delta2 frequency bands decreased, while the relative spectral power in the alpha, beta1 and beta2 bands increased. A delayed (to the 4-5th week after surgery) increase in the total amount of sleep and REM sleep percent was observed in the sleep architecture of these animals. Multiple (during 2 weeks daily) intraperitoneal saline injections altered the dynamic of electrophysiological indices on the 2nd-3rd postsurgery weeks. The total sleep amount being not increased, the total and mean REM sleep durations increased, and the dynamic of the relative spectral power of electrical activity in the dopaminergic brain structures in the delta1, alpha and beta2 bands was found to be changed.     

The insulin receptor family in the heart: new light on old insights

Insulin was discovered over 100 years ago. Whilst the first half century defined many of the physiological effects of insulin, the second emphasised the mechanisms by which it elicits these effects, implicating a vast array of G proteins and their regulators, lipid and protein kinases and counteracting phosphatases, and more. Potential growth-promoting and protective effects of insulin on the heart emerged from studies of carbohydrate metabolism in the 1960s, but the insulin receptors (and the related receptor for insulin-like growth factors 1 and 2) were not defined until the 1980s. A related third receptor, the insulin receptor-related receptor remained an orphan receptor for many years until it was identified as an alkali-sensor. The mechanisms by which these receptors and the plethora of downstream signalling molecules confer cardioprotection remain elusive. Here, we review important aspects of the effects of the three insulin receptor family members in the heart. Metabolic studies are set in the context of what is now known of insulin receptor family signalling and the role of protein kinase B (PKB or Akt), and the relationship between this and cardiomyocyte survival versus death is discussed. PKB/Akt phosphorylates numerous substrates with potential for cardioprotection in the contractile cardiomyocytes and cardiac non-myocytes. Our overall conclusion is that the effects of insulin on glucose metabolism that were initially identified remain highly pertinent in managing cardiomyocyte energetics and preservation of function. This alone provides a high level of cardioprotection in the face of pathophysiological stressors such as ischaemia and myocardial infarction.     

Localization of hormone secreting pathways in the brain by immunohistochemistry and light microscopy: a review.

Immunocytochemical techniques are now being used to localize hypothalamic neurosecretory hormones and related peptides in the mammalian brain. The data are probably incomplete, due primarily to false negative results. A number of previous assumptions concerning these pathways have been confirmed while other unexpected results were obtained. As expected, vasopressin and oxytocin and their associated proteins, neurophysins, were found in the magnocellular cell bodies of the hypothalamus and in their axonal projections to the neural lobe of the pituitary. Gonadotropin-releasing hormone (Gn-RH), somatostatin, and thyrotropin-releasing hormone (TRH) were located in what appears to be parvicellular nerve terminals on portal capillaries. Gn-RH has been found in perikarya in the arcuate nucleus, which is considered a source of fibers to the portal capillary bed. An extensive network of cell bodies and fibers in the preoptic area was also found to contain Gn-RH, and others in the periventricular nucleus in the anterior hypothalamus reacted with antiserum to somatostatin. Unexpected was considerable evidence that vasopressin is secreted directly into hypophyseal portal blood. This hormone and its neurophysin were also found in parvicellular neurons in the suprachiasmatic nucleus of rodents. All the hormones were found in fibers in the organum vasculosum of the lamina terminalis and in the posterior pituitary gland.     

Cerebral malaria and the hemolysis/methemoglobin/heme hypothesis: shedding new light on an old disease

Malaria causes more than 1 million deaths every year with cerebral malaria (CM) being a major cause of death in Sub-Saharan African children. The nature of the malaria-associated pathogenesis is complex and multi-factorial. A unified hypothesis involving sequestration of infected red blood cells, systemic host inflammatory response and hemostasis dysfunction has been proposed to explain the genesis of CM. In this review, we discuss the role of hemolysis, methemoglobin and free heme in CM, brought to light by our recent studies in mice as well as by other studies in humans.     

The darkness at the end of the tunnel: summary and evaluation of an international symposium on light,endocrine systems and cancer

Research on light at night and cancer is evolving at an accelerating pace, fueled largely by exciting results in rodent toxicology and basic human biology. Epidemiologic research is at a relatively early stage of development in which the exposure surrogates such as shift work and blindness predominate. Causal graphs for shift work, light at night and breast cancer illustrate some of the subtleties that can arise in the use of exposure surrogates of different kinds. Baseline data on circadian rhythms and melatonin cycles among human populations living at different latitudes are needed. Epidemiologic study of this topic is expected to mature soon as studies begin to incorporate quantitative and semiquantitative measurements and personal histories of exposure to light at night. The current emphasis on breast cancer should widen to include other cancers and intermediate outcomes. An advance in epidemiologic studies of blind persons would be to compare cancer rates between the "cortically blind" and the "retinally blind" within levels of visual impairment. Without a proposed intervention to reduce exposure to light at night, attributable fraction and attributable caseload estimates are meaningless. In the near future, both epidemiologic and laboratory research in this area are expected to grow appreciably in scope and scale.     

Peer assessment in large undergraduate classes: an evaluation of a procedure for marking laboratory reports and a review of related practices

This study provides evidence that peer marking can be a reliable tool for assessing laboratory reports in large cohorts. It was conducted over a 4-yr period with first-year undergraduates (～180 students/cohort) taking a mammalian physiology course, but the procedure adopted would be applicable to any other laboratory-based discipline. The process was found to be efficient in staff time, enabling a summative practical report to be marked in <1 h (<5% of the time that had previously been required for staff marking), facilitating rapid feedback to students on their performance. When samples of the peer-assessed reports were marked by a single member of staff, there was excellent correlation between peer and staff marks (r = 0.96-0.98), although peer-awarded marks exceeded staff marks by an average of 2.5-3.0%. The validity of peer marking was independent of both the sex of the marker and the staff score awarded to the marker for the same piece of work. Feedback from students was largely positive; they reported that the procedure adopted was effective in increasing their understanding of the underlying physiology and contributed to their understanding of best practice in presenting a laboratory report. Seventy percent of students agreed that it was acceptable for peer assessment to contribute a small (up to 5%) component of the overall mark for the course. The results are discussed in relation to other reports of peer marking, particularly when used to assess an academic product or process in a scientific discipline.     

A critical review on brain and heart axis response in COVID-19 patients: Molecular mechanisms,mediators, biomarkers,and therapeutics

Since the outbreak of highly virulent coronaviruses, significant interest was assessed to the brain and heart axis (BHA) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-affected patients. The majority of clinical reports accounted for unusual symptoms associated with SARS-CoV-2 infections which are of the neurological type, such as headache, nausea, dysgeusia, anosmia, and cerebral infarction. The SARS-CoV-2 enters the cells through the angiotensin-converting enzyme (ACE-2) receptor. Patients with prior cardiovascular disease (CVD) have a higher risk of COVID-19 infection and it has related to various cardiovascular (CV) complications. Infected patients with pre-existing CVDs are also particularly exposed to critical health outcomes. Overall, COVID-19 affected patients admitted to intensive care units (ICU) and exposed to stressful environmental constraints, featured with a cluster of neurological and CV complications. In this review, we summarized the main contributions in the literature on how SARS-CoV-2 could interfere with the BHA and its role in affecting multiorgan disorders. Specifically, the central nervous system involvement, mainly in relation to CV alterations in COVID-19-affected patients, is considered. This review also emphasizes the biomarkers and therapy options for COVID-19 patients presenting with CV problems.     

The radial-symmetric hydra and the evolution of the bilateral body plan: an old body became a young brain

The radial symmetric cnidarians are regarded as being close to the common metazoan ancestor before bilaterality evolved. It is proposed that a large fraction of the body of this gastrula-like organism gave rise to the head of more evolved organisms. The trunk was added later in evolution from an unfolding of a narrow zone between the tentacles and the blastoporus. This implies that, counter intuitively, the foot of the hydra corresponds to the most anterior part (forebrain and heart) while the opening of the gastric column gave rise to the anus. Two fundamentally different modes of midline formation evolved. In vertebrates, the organiser attracts cells from the both sides of the marginal zone. These leave the organiser as a unified band. The midline is formed sequentially from anterior to posterior. In insects, the midline forms opposite a dorsal repelling center, i.e., on the ventral side. This can occur more or less simultaneously over the whole anteroposterior extension.