Airway basal stem cells: a perspective on their roles in epithelial homeostasis and remodeling.

The small airways of the human lung undergo pathological changes in pulmonary disorders, such as chronic obstructive pulmonary disease (COPD), asthma, bronchiolitis obliterans and cystic fibrosis. These clinical problems impose huge personal and societal healthcare burdens. The changes, termed 'pathological airway remodeling', affect the epithelium, the underlying mesenchyme and the reciprocal trophic interactions that occur between these tissues. Most of the normal human airway is lined by a pseudostratified epithelium of ciliated cells, secretory cells and 6-30% basal cells, the proportion of which varies along the proximal-distal axis. Epithelial abnormalities range from hypoplasia (failure to differentiate) to basal- and goblet-cell hyperplasia, squamous- and goblet-cell metaplasia, dysplasia and malignant transformation. Mesenchymal alterations include thickening of the basal lamina, smooth muscle hyperplasia, fibrosis and inflammatory cell accumulation. Paradoxically, given the prevalence and importance of airway remodeling in lung disease, its etiology is poorly understood. This is due, in part, to a lack of basic knowledge of the mechanisms that regulate the differentiation, maintenance and repair of the airway epithelium. Specifically, little is known about the proliferation and differentiation of basal cells, a multipotent stem cell population of the pseudostratified airway epithelium. This Perspective summarizes what we know, and what we need to know, about airway basal cells to evaluate their contributions to normal and abnormal airway remodeling. We contend that exploiting well-described model systems using both human airway epithelial cells and the pseudostratified epithelium of the genetically tractable mouse trachea will enable crucial discoveries regarding the pathogenesis of airway disease.

Are the native giant tortoises from the Seychelles really extinct? A genetic perspective based on mtDNA and microsatellite data.

The extinction of the giant tortoises of the Seychelles Archipelago has long been suspected but is not beyond doubt. A recent morphological study of the giant tortoises of the western Indian Ocean concluded that specimens of two native Seychelles species survive in captivity today alongside giant tortoises of Aldabra, which are numerous in zoos as well as in the wild. This claim has been controversial because some of the morphological characters used to identify these species, several measures of carapace morphology, are reputed to be quite sensitive to captive conditions. Nonetheless, the potential survival of giant tortoise species previously thought extinct presents an exciting scenario for conservation. We used mitochondrial DNA sequences and nuclear microsatellites to examine the validity of the rediscovered species of Seychelles giant tortoises. Our results indicate that the morphotypes suspected to represent Seychelles species do not show levels of variation and genetic structuring consistent with long periods of reproductive isolation. We found no variation in the mitochondrial control region among 55 individuals examined and no genetic structuring in eight microsatellite loci, pointing to the survival of just a single lineage of Indian Ocean tortoises.

Remembering from any angle: the flexibility of visual perspective during retrieval.

When recalling autobiographical memories, individuals often experience visual images associated with the event. These images can be constructed from two different perspectives: first person, in which the event is visualized from the viewpoint experienced at encoding, or third person, in which the event is visualized from an external vantage point. Using a novel technique to measure visual perspective, we examined where the external vantage point is situated in third-person images. Individuals in two studies were asked to recall either 10 or 15 events from their lives and describe the perspectives they experienced. Wide variation in spatial locations was observed within third-person perspectives, with the location of these perspectives relating to the event being recalled. Results suggest remembering from an external viewpoint may be more common than previous studies have demonstrated.

Revisiting the monoamine hypothesis of depression: a new perspective.

As the incidence of depression increases, depression continues to inflict additional suffering to individuals and societies and better therapies are needed. Based on magnetic resonance spectroscopy and laboratory findings, gamma aminobutyric acid (GABA) may be intimately involved in the pathophysiology of depression. The isoelectric point of GABA (pI = 7.3) closely approximates the pH of cerebral spinal fluid (CSF). This may not be a trivial observation as it may explain preliminary spectrophotometric, enzymatic, and HPLC data that monoamine oxidase (MAO) deaminates GABA. Although MAO is known to deaminate substrates such as catecholamines, indoleamines, and long chain aliphatic amines all of which contain a lipophilic moiety, there is very good evidence to predict that a low concentration of a very lipophilic microspecies of GABA is present when GABA pI = pH as in the CSF. Inhibiting deamination of this microspecies of GABA could explain the well-established successful treatment of refractory depression with MAO inhibitors (MAOI) when other antidepressants that target exclusively levels of monoamines fail. If further experimental work can confirm these preliminary findings, physicians may consider revisiting the use of MAOI for the treatment of non-intractable depression because the potential benefits of increasing GABA as well as the monoamines may outweigh the risks associated with MAOI therapy.

Atherosclerosis: Viewing the problem from a different perspective including possible treatment options

This paper proposes that atherosclerosis is initiated by a signaling event that deposits calcium hydroxyapatite (Ca-HAP). This event is preceded by a loss of mechanical structure in the arterial wall. After Ca-HAP has been deposited, it is unlikely that it will be reabsorbed because the solubility product constant (K sp) is very small, and the large stores of Ca +2 and PO 4-3 in the bones oppose any attempts to dissolve Ca-HAP by decreasing the common ions. The hydroxide ion (OH -) of Ca-HAP can be displaced in nature by fluoride (F -) and carbonate (CO 3-2) ions, and it is proposed that anions associated with cholesterol ester hydrolysis and, in very small quantities, the enolate of 7-ketocholesterol could also displace the OH -of Ca-HAP, forming an ionic bond. The free energy of hydration of Ca-HAP at 310 K is most likely negative, and the ionic radii of the anions associated with the hydrolysis of cholesterol ester are compatible with the substitution. Furthermore, examination of the pathology of atherosclerotic lesions by Raman and NMR spectroscopy and confocal microscopy supports deposition of Ca-HAP associated with cholesterol. Investigating the affinity of intermediates of cholesterol hydrolysis for Ca-HAP compared to lipoproteins such as HDL, LDL, and VLDL using isothermic titration calorimetry could add proof of this concept and may lead to the development of a new class of medications targeted at the deposition of cholesterol within Ca-HAP. Treatment of acute ischemic events as a consequence of atherosclerosis with denitrogenation and oxygenation is discussed. © the author(s), publisher and licensee Libertas Academica Ltd.

Visual imagery in autobiographical memory: The role of repeated retrieval in shifting perspective.

Recent memories are generally recalled from a first-person perspective whereas older memories are often recalled from a third-person perspective. We investigated how repeated retrieval affects the availability of visual information, and whether it could explain the observed shift in perspective with time. In Experiment 1, participants performed mini-events and nominated memories of recent autobiographical events in response to cue words. Next, they described their memory for each event and rated its phenomenological characteristics. Over the following three weeks, they repeatedly retrieved half of the mini-event and cue-word memories. No instructions were given about how to retrieve the memories. In Experiment 2, participants were asked to adopt either a first- or third-person perspective during retrieval. One month later, participants retrieved all of the memories and again provided phenomenology ratings. When first-person visual details from the event were repeatedly retrieved, this information was retained better and the shift in perspective was slowed.