Alan Mackay-Sim

Vitamin D3 and brain development

Evidence for the presence of the vitamin D receptor in brain implies this vitamin may have some function in this organ. This study investigates whether vitamin D(3) acts during brain development. We demonstrate that rats born to vitamin D(3)-deficient mothers had profound alterations in the brain at birth. The cortex was longer but not wider, the lateral ventricles were enlarged, the cortex was proportionally thinner and there was more cell proliferation throughout the brain. There were reductions in brain content of nerve growth factor and glial cell line-derived neurotrophic factor and reduced expression of p75(NTR), the low-affinity neurotrophin receptor. Our findings would suggest that low maternal vitamin D(3) has important ramifications for the developing brain.

Autologous olfactory ensheathing cell transplantation in human paraplegia: a 3-year clinical trial

Olfactory ensheathing cells show promise in preclinical animal models as a cell transplantation therapy for repair of the injured spinal cord. This is a report of a clinical trial of autologous transplantation of olfactory ensheathing cells into the spinal cord in six patients with complete, thoracic paraplegia. We previously reported on the methods of surgery and transplantation and the safety aspects of the trial 1 year after transplantation. Here we address the overall design of the trial and the safety of the procedure, assessed during a period of 3 years following the transplantation surgery. All patients were assessed at entry into the trial and regularly during the period of the trial. Clinical assessments included medical, psychosocial, radiological and neurological, as well as specialized tests of neurological and functional deficits (standard American Spinal Injury Association and Functional Independence Measure assessments). Quantitative test included neurophysiological tests of sensory and motor function below the level of injury. The trial was a Phase I/IIa design whose main aim was to test the feasibility and safety of transplantation of autologous olfactory ensheathing cells into the injured spinal cord in human paraplegia. The design included a control group who did not receive surgery, otherwise closely matched to the transplant recipient group. This group acted as a control for the assessors, who were blind to the treatment status of the patients. The control group also provided the opportunity for preliminary assessment of the efficacy of the transplantation. There were no adverse findings 3 years after autologous transplantation of olfactory ensheathing cells into spinal cords injured at least 2 years prior to transplantation. The magnetic resonance images (MRIs) at 3 years showed no change from preoperative MRIs or intervening MRIs at 1 and 2 years, with no evidence of any tumour of introduced cells and no development of post-traumatic syringomyelia or other adverse radiological findings. There were no significant functional changes in any patients and no neuropathic pain. In one transplant recipient, there was an improvement over 3 segments in light touch and pin prick sensitivity bilaterally, anteriorly and posteriorly. We conclude that transplantation of autologous olfactory ensheathing cells into the injured spinal cord is feasible and is safe up to 3 years of post-implantation, however, this conclusion should be considered preliminary because of the small number of trial patients.

Cell dynamics in the adult mouse olfactory epithelium: a quantitative autoradiographic study

The dynamics of cell genesis in the olfactory epithelium of the adult mouse were investigated using 3H-thymidine autoradiography. Mice were injected once with 3H-thymidine, and their olfactory epithelia were examined 7, 14, 30, 60, and 90 d later. The number of silver grains over each nucleus was counted, and the relative distance from the basement membrane was measured for each labeled nucleus. At 7 and 14 d, the average number of labeled cells in each section was about 20 per mm. By 30 d, and for the following 60 d, the average number of labeled cells was only about 6 per mm. Thus, most cells labeled by the injection died 2–4 weeks after injection. When the labeled cells were compared by nuclear grain density, time after injection (the “survival period”), and distance of the nucleus from the basement membrane (the “migration distance”), it was apparent that there was a small population of “nonmigrating” cells that remained close to the basement membrane. These cells, at first heavily labeled, divided a second time about 60 d after the 3H-thymidine injection, indicated by a significant decrease in nuclear grain density. This nonmigrating, slowly dividing basal cell is probably the neural stem cell, which gives rise to another stem cell and an olfactory neuron precursor by an asymmetric division. When the relative numbers of nonmigrating and migrating cells were compared, the results indicated that, after the asymmetric division, there are at least 2 or 3 rapid, symmetric divisions of the precursor cells, producing many immature receptor cells. Most of these die within 4 weeks of the 3H-thymidine injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Transplantation of nasal olfactory tissue promotes partial recovery in paraplegic adult rats

Recent reports have highlighted the potential therapeutic role of olfactory ensheathing cells for repair of spinal cord injuries. Previously ensheathing cells collected from the olfactory bulbs within the skull were used. In humans a source of these cells for autologous therapy lies in the nasal mucosa where they accompany the axons of the olfactory neurons. The aim of the present study was to test the therapeutic potential of nasal olfactory ensheathing cells for spinal cord repair. Olfactory ensheathing cells cultured from the olfactory lamina propria or pieces of lamina propria from the olfactory mucosa were transplanted into the transected spinal cord. Three to ten weeks later these animals partially recovered movement of their hind limbs and joints which was abolished by a second spinal cord transection. Control rats, receiving collagen matrix, respiratory lamina propria or culture medium, did not recover hind limb movement. Recovery of movement was associated with recovery of spinal reflex circuitry, assessed using the rate-sensitive depression of the H-reflex from an interosseous muscle. Histological analysis of spinal cords grafted with olfactory tissue demonstrated nerve fibres passing through the transection site, serotonin-positive fibres in the spinal cord distal to the transection site, and retrograde labelling of brainstem raphe and gigantocellularis neurons from injections into the distal cord, indicating regeneration of descending pathways. Thus, olfactory lamina propria transplantation promoted partial restoration of function after relatively short recovery periods. This study is particularly significance because it suggests an accessible source of tissue for autologous grafting in human paraplegia.

Multipotent stem cells from adult olfactory mucosa

Multipotent stem cells are thought to be responsible for the generation of new neurons in the adult brain. Neurogenesis also occurs in an accessible part of the nervous system, the olfactory mucosa. We show here that cells from human olfactory mucosa generate neurospheres that are multipotent in vitro and when transplanted into the chicken embryo. Cloned neurosphere cells show this multipotency. Multipotency was evident without prior culture in vitro: cells dissociated from adult rat olfactory mucosa generate leukocytes when transplanted into bone marrow–irradiated hosts, and cells dissociated from adult mouse olfactory epithelium generated numerous cell types when transplanted into the chicken embryo. It is unlikely that these results can be attributed to hematopoietic precursor contamination or cell fusion. These results demonstrate the existence of a multipotent stem‐like cell in the olfactory mucosa useful for autologous transplantation therapies and for cellular studies of disease. Developmental Dynamics 233:496–515, 2005.

A double-blind, randomized, placebo-controlled trial of macrolide in the treatment of chronic rhinosinusitis

Objectives: The antiinflammatory effect of macrolide antibiotics has been well‐established, as has their role in the treatment of certain disorders of chronic airway inflammation. Several studies have suggested that long‐term, low‐dose macrolides may be efficacious in the treatment of chronic rhinosinusitis; however, these studies have lacked a control group. To date, this effect has not been tested in a randomized, placebo‐controlled study.

Developmental Vitamin D3 deficiency alters the adult rat brain.

There is growing evidence that Vitamin D(3) (1,25-dihydroxyvitamin D(3)) is involved in brain development. We have recently shown that the brains of newborn rats from Vitamin D(3) deficient dams were larger than controls, had increased cell proliferation, larger lateral ventricles, and reduced cortical thickness. Brains from these animals also had reduced expression of nerve growth factor (NGF) and glial cell line-derived neurotrophic factor. The aim of the current study was to examine if there were any permanent outcomes into adulthood when the offspring of Vitamin D(3) deficient dams were restored to a normal diet. The brains of adult rats were examined at 10 weeks of age after Vitamin D(3) deficiency until birth or weaning. Compared to controls animals that were exposed to transient early Vitamin D(3) deficiency had larger lateral ventricles, reduced NGF protein content, and reduced expression of a number genes involved in neuronal structure, i.e. neurofilament or MAP-2 or neurotransmission, i.e. GABA-A(alpha4). We conclude that transient early life hypovitaminosis D(3) not only disrupts brain development but leads to persistent changes in the adult brain. In light of the high incidence of hypovitaminosis D(3) in women of child-bearing age, the public health implications of these findings warrant attention.

On the Life Span of Olfactory Receptor Neurons.

The life span of olfactory receptor neurons was investigated after injection of a retrograde tracer into the olfactory bulb. Mice were injected unilaterally with colloidal gold conjugated with Concanavalin A and their olfactory epithelia were examined after 7, 14, 30, 60, and 90 days. Gold particles could be seen in the epithelia at all survival periods after silver intensification. There was no gold in the epithelia on the uninjected side. In order to test whether gold could be recycled within the epithelium upon the death of receptor neurons, the olfactory bulbs of some mice were ablated 4 days after colloidal gold injection. None of the receptor neurons in these epithelia contained gold at any survival period. To investigate whether gold was continuously available at the injection site, olfactory bulbs were examined by electron microscopy. By 7 days after injection all gold was sequestered intracellularly and was presumably unavailable for uptake by the olfactory axons. These results indicate that olfactory receptor neurons live for at least three times the commonly accepted life span of 30 days. A long life span challenges the widely held view that olfactory receptor neurons are regularly replaced.

A robotic system to locate hazardous chemical leaks

Tracing leaks of airborne radioactive, poisonous or flammable materials is a potentially dangerous activity that could be undertaken by robotic systems. This paper describes a practical investigation of the possibility of developing simple, low cost, autonomous robots to perform this task. It is envisaged that these robots would be used in large numbers. This would improve reliability through redundancy and provide large area coverage from a wide distribution of robots. Failure of a single unit would not jeopardise the overall sensing operation. Sensing and control techniques developed to perform leak location in a simplified laboratory environment are described and experimental results are presented.

Neurotrophic factors in the primary olfactory pathway.

The number of identified growth factors continues to increase rapidly with many being implicated in the development of the nervous system, although for most of them the autocrine and paracrine pathways of cellular regulation still remain to be elucidated. The primary olfactory pathway, consisting of the olfactory epithelium and olfactory bulb, is presented here as a very useful model for the analysis of growth factor function. Review of the available literature suggests that a large proportion of neuroactive growth factors and their receptors are present in the olfactory epithelium or olfactory bulb. Furthermore, the primary olfactory pathway is one of the most plastic in the nervous system with neurogenesis continuing to contribute new sensory neurones in the olfactory epithelium and new interneurones in the olfactory bulb throughout adult life. The rich diversity of growth factors and their receptors in the olfactory system indicates that it will be useful in elucidating how these molecules regulate the formation of the nervous system. The olfactory epithelium in particular is proving useful as a model for the actions of growth factors in directing the neuronal lineage from stem cell to mature neurone.