Interference with the development of early generated neocortex results in disruption of radial glia and abnormal formation of neocortical layers

Early generated layers of neocortex are important factors in forming the subsequent architecture of the cerebral cortex. To further explore the role of early generated cortex, we disrupted formation of an early generated cohort of cells by intraperitoneal injections of the mitotic inhibitor methylazoxymethanol (MAM) into pregnant ferrets timed to coincide with generation of subplate neurons in the ventricular zone. Our studies demonstrate that if early development of the neocortex is interrupted by injection of MAM during embryogenesis (on embryonic day 24 or 28; E24 or E28), a distinct laminar pattern fails to form properly in the parietal cortex. A reduced number of MAP2-positive cells were observed in the region of the subplate when compared with the number of MAP2-positive cells found in normal animals. Interference with the superficial neocortical layers that form later during development (on embryonic day 33) by appropriately timed MAM injections does not result in a severely disrupted laminar pattern. The interrupted laminar pattern that arises after early MAM injections coincides with distorted radial glial cells (identified by immunoreactivity to the intermediate filament protein, vimentin), which occur after early, but not late, MAM injections. Further analysis suggests that interference with early development of neocortex leads to premature differentiation of radial glial cells into astrocytes, as demonstrated by the presence of glial fibrillary acidic protein (GFAP). Experiments involving injections of the thymidine analog, bromodeoxyuridine (BRDU), demonstrated that 4 days after E24 MAM injection cells are generated and migrate into the thin cortical plate. By E38, however, cells continue to be generated in animals treated with MAM on E24 but do not reach their normal positions in the cortical plate. In addition, immunoreactivity using the CR50 antibody, which identifies presumptive Cajal-Retzius cells present in layer 1, demonstrates that the CR50-positive cells, normally precisely located in the outer portion of layer 1, are distributed in disarray throughout the thickness of the neocortex and intermediate zone in early MAM-treated animals, but not in those treated with MAM injections later during gestation. These findings are consistent with the idea that early generated layers are important in providing factors that maintain the environment necessary for subsequent neuronal migration and formation of neocortical layers.     

Immunological disorders--the evolution of an hypothesis.

In honouring the memory of Dr Alwyn Zoutendyk, a respected member of the staff of the South African Institute for Medical Research, attention is called to the studies of the immunological disorders. While investigating serum hepatitis affecting soldiers of the US army following the administration of yellow fever vaccine, an antigen similar to that later called the Australia antigen, now hepatitis B surface antigen, was found in the acute phase serum and the corresponding antibody was found in convalescence. This finding and subsequent studies suggested there was a group of disease, which we called the hyperreactive auto-allergic disorders, of which examples were to be found in every system. The obverse of these we called the hyporeactive immunologically deficient disorders resulting from defects of the cell or serum components of the immunological reactions, of which many examples have also been found.     

The evolution of early mobilization of the repaired flexor tendon.

The most important difference between the various approaches to postoperative digital flexor tendon rehabilitation is how the repaired tendon is treated during the first three to six weeks, in the earliest stages of healing. Early mobilization is the most commonly reported method of managing the healing flexor tendon. There are many different protocols and abundant research to support published approaches to tendon management. With so many choices, today's hand therapist must understand not only what those choices are, but also why and when to use them. There is no one correct way to manage a repaired flexor tendon; the specialist who does not understand how current techniques evolved is ill-equipped to design the appropriate treatment for a given patient. This article presents an overview of management options and how they have been developed over time, with special attention to changes in splint and exercise design in the crucial first few weeks after repair.     

The free hormone hypothesis. Distinction from the free hormone transport hypothesis.

I. The free hormone transport hypothesis: distinction from the free hormone hypothesis. II. The free hormone hypothesis: importance of the rate-limiting step in tissue uptake. III. Explicit consideration of multiple plasma hormone-binding proteins in transport models. IV. Diffusion barriers in transport models. V. Functions of plasma hormone-binding proteins. VI. Conclusions and areas for future investigation.     

Prostate plasma membrane receptor: a hypothesis.

Based on 50 years of emerging knowledge about and changing views of prostate biochemistry and physiology and especially on the belief that there is an underlying mechanism of androgen control, the hypothesis is developed and tested that the rates of proliferation, biosynthesis, metabolism, and secretion are modulated through the hormone-sensitive Na, K-ATPase of the plasma membrane. These preliminary experiments, constituting a novel synthesis of technologies from endocrinology, intermediary metabolism, and membrane transport, attempt to explain the extraordinary production and secretion of citrate and how this may be coupled to sustaining prostate cell number and function. Attention is focused on learning where androgen is bound and how it interacts with the Na,K-ATPase. Both the dissimilar properties of epithelial and stromal cells in the separate regions of the acinus and the changing environment of growth factors in which these cells are bathed help account for their unlike reactivities during development and ongoing mature function. Little wonder that one hormone can have so many effects!     

A hypothesis on the origin and evolution of the response to inhaled anesthetics

In this article, I present an evolutionary explanation for why organisms respond to inhaled anesthetics. It is conjectured that organisms today respond to inhaled anesthetics owing to the sensitivity of ion channels to inhaled anesthetics, which in turn has arisen by common descent from ancestral, anesthetic-sensitive ion channels in one-celled organisms (i.e., that the response to anesthetics did not arise as an adaptation of the nervous system, but rather of ion channels that preceded the origin of multicellularity). This sensitivity may have been refined by continuing selection at synapses in multicellular organisms. In particular, it is hypothesized that 1) the beneficial trait that was selected for in one-celled organisms was the coordinated response of ion channels to compounds that were present in the environment, which influenced the conformational equilibrium of ion channels; 2) this coordinated response prevented the deleterious consequences of entry of positive charges into the cell, thereby increasing the fitness of the organism; and 3) these compounds (which may have included organic anions, cations, and zwitterions as well as uncharged compounds) mimicked inhaled anesthetics in that they were interfacially active, and modulated ion channel function by altering bilayer properties coupled to channel function. The proposed hypothesis is consistent with known properties of inhaled anesthetics. In addition, it leads to testable experimental predictions of nonvolatile compounds having anesthetic-like modulatory effects on ion channels and in animals, including endogenous compounds that may modulate ion channel function in health and disease. The latter included metabolites that are increased in some types of end-stage organ failure, and genetic metabolic diseases. Several of these predictions have been tested and proved to be correct.     

Cellular mosaics in the rat marginal zone define an early neocortical territorialization

We describe a novel neuronal group of the neocortical primordium that is formed by the pioneer neurons, unlike the Cajal-Retzius cells and the subplate component of the preplate. These pioneer neurons of the preplate and the marginal zone send transient axonal projections into the nascent internal capsule, preceding the formation of the axonal projection from the subplate neurons. In wholemount preparations, the pioneer neurons of the preplate and the marginal zone cover the prospective neocortical territory from embryonic day (E) 12 to E17. Two subpopulations of pioneer neurons (defined by differential expression of calcium-binding proteins) group into well-defined cell clusters, separated by spaces containing a lower packing density of cells immunoreactive to the corresponding calcium-binding protein. In both cases, cell clustering was concomitant with fasciculation of their axons. Although both subpopulations cohabit in the same areas of the marginal zone, their clustering occurs in specific, well-delineated territories, giving a mosaic appearance to the surface of the neocortical primordium before the arrival of thalamocortical axons. We hypothesize that the fascicles of descending axons arising from defined territories of the marginal zone may intervene in the initial guidance of the subcortical projection from the subplate.     

The early origins hypothesis with an emphasis on growth rate in the first year of life and asthma: a prospective study in Chile

BACKGROUND: There is uncertainty about the impact of the programming hypothesis in terms of nutritional status at birth, rate of growth in the first year of life, length of gestation, breast feeding, and episodes of illness on asthma. An analysis was therefore carried out to test this hypothesis. METHODS: Data were collected on 1232 children born between 1974 and 1978 in a semi-rural area of Chile. Measurements at birth and growth in the first year of life were obtained from a birth registry and clinical notes. Information on asthma was collected using the European Community Respiratory Health Survey questionnaire. Sensitisation to eight allergens and bronchial hyperresponsiveness (BHR) to methacholine were determined. All other information was obtained using a questionnaire. Polytomous logistic analyses were carried out to explore the association of factors at birth and during the first year of life with asthma symptoms, atopy, and BHR. RESULTS: Weight and length gain in the first year were positively associated with wheeze (odds ratio (OR) 1.004, 95% CI 1.001 to 1.007 and OR 1.11, 95% CI 0.98 to 1.25, respectively). A higher body mass index (BMI) at birth was protective in subjects reporting both wheeze and waking with breathlessness (OR 0.54, 95% CI 0.35 to 0.84). Length rate in tertiles divided by length at birth in tertiles was related to asthma symptoms (OR 1.68, 95% CI 1.19 to 2.37). Most other assessments were not associated with asthma. CONCLUSION: These results show promising but inconclusive evidence that a rapid rate of growth in length, especially in newborn infants of low length, might be involved in the aetiology of asthma.     

Differential origins of neocortical projection and local circuit neurons: role of Dlx genes in neocortical interneuronogenesis.

Herein we review the evidence that neocortical projection neurons and interneurons are derived from distinct regions within the telencephalon. While neocortical projection neurons are derived from the ventricular zone of the neocortex, neocortical interneurons appear to be derived from the germinal zone of the basal ganglia. These interneurons follow a tangential migratory pathway from the ganglionic eminences to the cortex. Interneurons of the olfactory bulb follow a distinct tangential migration from the basal ganglia. The Dlx homeobox genes, which are essential for basal ganglia differentiation, are also required for the development of neocortical and olfactory bulb interneurons. Furthermore, evidence is presented that retroviral-mediated expression of DLX2 in neocortical cells can induce GABAergic interneuron differentiation.     

Megautricles: embryogenic hypothesis.

We present 4 cases of megautricle emphasizing the relationship between it and the ejaculatory ducts. We develop an embryogenic hypothesis to explain the different forms of megautricles in relation to the seminal pathway.     

The muscle hypothesis: a model of chronic heart failure appropriate for osteopathic medicine.

Chronic heart failure is one of the most serious medical problems in the United States, affecting some 4 million persons. In spite of its common occurrence, and comprehensive literature regarding this condition, no unifying hypothesis has been accepted to explain the signs and symptoms of chronic heart failure. The cardiocirculatory and neurohormonal models place an emphasis on left ventricular ejection fraction and cardiac output and do not provide appropriate explanations for the symptoms of breathlessness and fatigue. The muscle hypothesis supplements these conventional models. It proposes that abnormal skeletal muscle in heart failure results in activation of muscle ergoreceptors, leading to an increase in ventilation and sensation of breathlessness, the perception of fatigue, and sympathetic activation. At least one fourth of patients with chronic heart failure are limited by skeletal muscle abnormalities rather than cardiac output. Cardiac rehabilitation exercise can lead to an increase in exercise capacity that is superior to that gained from digitalis or angiotensin-converting enzyme inhibitors. Exercise tends to reverse the skeletal muscle myopathy of chronic heart failure and reduces the abnormal ergoreflex. Other interventions that have been shown to have a favorable outcome include localized muscle group training, respiratory muscle training, and dietary approaches. The possibility that osteopathic manipulative treatment might be of benefit is an attractive, but untested, possibility.