Cellular distribution of the new growth factor Pleiotrophin (HB-GAM) mRNA in developing and adult rat tissues

Summary Pleiotrophin (PTN), also known as HBGAM, belongs to an emerging cytokine family unrelated to other growth factors. We report here the first comprehensive study using in situ hybridization on the cellular distribution of this new heparin-binding growth factor mRNA in rat tissues. PTN mRNA was developmentally expressed in many — but not all — neuroectodermal and mesodermal lineages, whilst no PTN mRNA was detected in endoderm, ectoderm and trophoblast. PTN mRNA was found in the nervous system throughout development, with a post-natal peak of expression. In the adult nervous system, significant expression persisted in hippocampal CA1 pyramidal neurons and in cortical neurons, but also in different non-neuronal cells types in various locations (olfactory nerve, cerebellar astrocytes, pituicytes, Schwann cells surrounding the neurons in sensory ganglia). PTN mRNA was also found during development in the mesenchyme of lung, gut, kidney and reproductive tract, in bone and cartilage progenitors, in dental pulp, in myoblasts, and in several other sites. Expression was differently regulated in each location, but usually faded around birth. In the adult, PTN mRNA was still present in the meninges, the iris, the Leydig cells of the testis and in the uterus. PTN mRNA was also strongly expressed in the basal layers of the tongue epithelium, which is the only epithelium and ectodermal derivative to express PTN mRNA, and this only after birth. PTN is known to be a growth factor for perinatal brain neurons and a mitogen for fibroblasts in vitro. Recently, trophic effects on epithelial cells and a role as a tumour growth factor have been reported. The mechanisms of regulation and the functions of PTN are however still uncertain. Its expression pattern during development suggests important roles in growth and differentiation. Moreover, the presence of PTN mRNA in several adult tissues and the up-regulation of PTN mRNA expression in the gravid uterus indicate that PTN also has physiological functions during adulthood.     

Nitric oxide synthase activity in infantile hypertrophic pyloric stenosis.

BACKGROUND. Hypertrophic pyloric stenosis is a common infantile disorder characterized by enlarged pyloric musculature and gastric-outlet obstruction. Its physiopathologic mechanism is not known, but a defect in pyloric relaxation (pylorospasm) has been postulated. Nitric oxide is a mediator of relaxation in the mammalian digestive tract, raising the possibility that pylorospasm could be caused by a defect in nitric oxide production. Since neuronal nitric oxide synthase and NADPH diaphorase are identical, we used the NADPH diaphorase histochemical reaction to study the distribution of nitric oxide synthase in pyloric tissue from patients with infantile hypertrophic pyloric stenosis. METHODS. We studied pyloric tissue from nine infants with infantile hypertrophic pyloric stenosis and seven control infants and children. Cryostat sections were processed for NADPH diaphorase histochemical analysis. A polyclonal tau antiserum was used to identify the enteric nervous system by immunohistochemical methods. RESULTS. NADPH diaphorase activity was restricted to the enteric nervous system and blood vessels. In the pyloric tissues from the control patients, intense diaphorase activity was present in the nerve fibers of the circular musculature, in the neurons and nerve bundles of the myenteric plexus, and in some nerve fibers of the longitudinal musculature. In the pyloric tissues from patients with infantile hypertrophic pyloric stenosis, the enteric nerve fibers in the hypertrophied circular musculature were enlarged and distorted and did not contain diaphorase activity, whereas the activity in the myenteric plexus and the longitudinal musculature was preserved. CONCLUSIONS. We suggest that a lack of nitric oxide synthase in pyloric tissue is responsible for pylorospasm in infantile hypertrophic pyloric stenosis.     

Interrelations between age and plasma renin,aldosterone and cortisol,urinary catecholamines,and the body sodium/volume state in normal man

Summary Interrelations between age and plasma renin, aldosterone and cortisol levels, urinary catecholamines, plasma and blood volumes, exchangeable body sodium and blood pressure were studied in 28 young (19 to 29 years), 16 middle-aged (32 to 58 years) and 15 elderly (60 to 74 years) healthy subjects. Supine and upright plasma renin and supine aldosterone levels decreased while urinary noradrenaline excretion rate increased progressively with aging (r0.34;p<0.05), with significant differences in mean values between young and elderly subjects (p<0.02). There was also an age-related decrease in upright plasma aldosterone concentration, although this was not statistically significant. Furthermore, mean plasma cortisol concentrations increased in response to upright posture in elderly (+50%;p<0.02), but not in young (–10%) or middle-aged (–8%) subjects. Blood pressure correlated with age (r=0.35;p<0.05) or noradrenaline excretion rate (r=0.34) in the entire study population and with blood volume in the elderly (r=0.68), but not in the young or middle-aged study groups. There were no significant age-related differences in the body sodium/volume state, basal plasma cortisol levels or urinary adrenaline excretion rate, and plasma renin or aldosterone levels did not correlate with these parameters or with blood pressure. It is concluded that the influence of age on plasma renin or aldosterone levels, plasma cortisol responsiveness to upright posture, and urinary noradrenaline excretion should be taken into consideration, whenever these factors have to be interpreted in patients with arterial hypertension or other clinical disorders. Furthermore, these data are consistent with the possibility that in normal man increases in supine blood pressure with aging may be related at least partly to concomitant changes in free peripheral noradrenaline.This investigation was supported by the Swiss National Science Foundation     

Lysosomal inclusions in gastric parietal cells in mucolipidosis type IV: a novel cause of achlorhydria and hypergastrinemia

Mucolipidosis type IV (ML-IV) is an autosomal recessive lysosomal storage disease that causes severe neurologic abnormalities. The brain disease is characterized by pigmented cytoplasmic granules in neurons and accumulation of lamellated membrane structures in lysosomes. The gastrointestinal disease in ML-IV was not previously recognized. Clinical examination of 20 patients with ML-IV (age range, 2-23 years) at the National Institutes of Health showed hypergastrinemia and constitutive achlorhydria. Endoscopic biopsy specimens from the gastric fundus, body, and antrum and from the duodenum of four such patients (ages 4, 6, 7, and 22 years) were evaluated histologically and by electron microscopy. Histologically, all gastric fundus and body biopsy specimens showed parietal cells in normal numbers. However, a striking cytoplasmic vacuolization of parietal cells was seen on hematoxylin and eosin stain. Electron microscopy showed the parietal cells to be markedly distended by large lysosomes containing lamellar, concentric, and cystic membranous inclusions. Additionally, chronic atrophic gastritis and enterochromaffin-like (ECL) cell hyperplasia were observed. Foveolar and chief cells in stomach and duodenum biopsy specimens were normal. We conclude that the cytoplasmic lysosomal inclusions in gastric parietal cells is a unique histologic feature of gastric biopsy in ML-IV.     

A new approach to teaching Normal Human Growth and Development

A new approach to teaching Normal Growth and Development to preclinical medical students is described. By using specially constructed multidisciplinary clinical simulations as training and evaluation devices, students were gradually and simultaneously exposed to: (1) subject matter; (2) the concept of multidisciplinary health care delivery; and (3) the objectives, strategies, and techniques of problem solving and diagnostic reasoning that characterize experienced physicians. The course, designed by a child psychiatrist and medical educators, was taught by a multidisciplinary teaching team drawn from faculty and health care representatives. Student evaluations of the course were favorable.     

Fabry disease and vascular risk factors: future strategies for patient-based studies and the knockout murine model

Fabry disease is secondary to deficiency of the lysosomal enzyme α-galactosidase A, leading to altered glycosphingolipid metabolism and accumulation that is often associated with endothelial dysfunction. Current evidence suggests that there is impairment of the vascular nitric oxide pathway, with abnormalities evident in the cerebral circulation and in the dermal vasculature of patients with Fabry disease. Some of these findings have been confirmed in a mouse model of Fabry disease. The murine model, however, allows investigation of Fabry disease at a non-clinical level and a near complete investigation of biological processes within an affected tissue. This is of particular utility in allowing gene expression analysis of clinically inaccessible tissues such as the aorta.
Conclusion: Future developments in array technology for proteins and DNA single nucleotide polymorphism analysis, together with gene expression microarray analysis, may open a new chapter in our understanding of the biology of lysosomal storage disorders.     

Ablation of striatal somatostatin interneurons affects MSN morphology and electrophysiological properties,and increases cocaine‐induced hyperlocomotion in mice

The striatum is mainly composed by medium spiny neurons (95 %) (MSNs). Although outnumbered, in other brain regions such as the hippocampus and the cortex, somatostatin interneurons (SSTi) are known to control and fine‐tune the activity of principal cells. This information is still fragmented for the striatum. Here, we questioned the striatal functional consequences of the selective ablation of SSTi in the striatum at the behavioural and cellular levels. We identified increased excitability coupled with decreased distal spine density in MSNs from SSTi‐ablated mice. Although the ethological behavioural analysis did not reveal differences between the groups, SSTi‐ablated mice were significantly more sensitive to the locomotor effects of cocaine without changes in motivation. This was accompanied by increased expression of the dopamine transporter (DAT) in the ventral striatum. Altogether, we show that SSTi are important players in the maintenance of MSN excitability and spine density impacting on mechanisms towards hyperdopaminergic states.     

Therapeutic approaches for neuronopathic lysosomal storage disorders

Therapy of the central nervous system (CNS) manifestations of lysosomal storage diseases (LSDs) has remained a major challenge because of its inability to deliver therapeutic agents efficiently across the intact blood–brain barrier. Non-specific therapies such as hematopoietic stem cell transplantation have been useful in globoid cell leukodystrophy (Krabbe disease) and in some mucopolysaccharidoses. Anti-inflammatory agents also show promise as adjuvant therapy. High doses of replacement therapy with native or modified enzyme show renewed promise for correction of CNS cells. Alternatively, small molecules can enter the brain relatively easily and promote reduction of accumulated substrate or function as pharmacological chaperones to enhance the level of the deficient enzyme. Gene therapy is still being developed and tested in patients. It is therefore likely that, thanks to a better understanding of disease mechanism, a variety of therapeutic approaches, used alone or in combination, will be useful to treat the devastating neurological complications of LSDs.