Although neurodegenerative diseases have different causes, the dysfunction and loss of specific groups of neurons is common to all these disorders and may allow the development of similar therapeutic approaches to the treatment of diseases like Alzheimer’s disease (AD) and Parkinson’s disease (PD). The efforts to treat the neurodegenerative diseases by existing methods of cellular therapy are insufficiently effective. The modern methods do not provide correct restoration of cytoarchitecture and pattern of connections (the rewiring of specifically organized long-distance connections), which are essential to achieve a significant functional recovery. This article discusses existing methods of neural stem cell therapy and provides example of new approach to the treatment of various neurodegenerative diseases.

Neurodegenerative diseases are an assortment of central nervous system disorders characterized by neuronal loss and intraneuronal accumulation of fibrillary materials. Abnormal protein-protein interactions may allow the precipitation of these proteins, forming extracellular and intracellular aggregates. These abnormal interactions could play a role in the dysfunction and neuronal death that characterizes several common neurodegenerative diseases, such as Alzheimer’s Disease (AD) and Parkinson’s Disease (PD).

AD is the most common cause of dementia, with aging a major contributor to its onset. Currently, it is estimated that 40% of people over age 80 are afflicted with AD.  Autopsy examination of a patient’s brain reveals gross cerebral atrophy, signifying loss of neurons and the presence of large numbers of extracellular neuritic plaques and intracellular neurofibrillary tangles. Plaques and tangles are found predominantly in the frontal and temporal lobes, including the hippocampus. In more advance cases, the pathology extends to other regions of the cortex.  Similar plaques and tangles do occur in normal ageing brains.

PD is more common in people 60 years old and older. In the US, PD affects 1.5 million people. The degeneration and loss of dopaminergic neurons in PD causes akinesia, rigidity and tremor. Cell transplantation for the treatment of PD is the promising approach that has received most attention.

Cell therapy for PD

The potential of cell therapy for neurodegenerative diseases was demonstrated on implantation of different types of stem cells in the animals with PD (Kim J-H et al 2002, Parati EA et al 2003). Transplantation of stem cells into rat brain resulted in reinnervation of the striatal neurons and partial recovery of motor deficit associated with dopamine deficiency (Kim J-H et al 2002). The same results were obtained after transplantation of fetal dopaminergic neurons in clinical trials (Piccini P et al 2000, Freed CR et al 2001). It is possible to use different types of stem cells to generate dopaminergic neurons. Today the process of dopaminergic neurons differentiation from embryonic stem cells (ESC) in vitro is most effective and understandable (Kim J-H et al 2002, Isacson O, Ann Neurol 2003,  Isacson O, Lancet Neurol 2003, Barberi T et al 2003). Recent progress in human therapeutic cloning (Woo Suk Hwang et al 2004) makes this way to generate neurons more and more attractive. Differentiation of ESC in vitro and transplantation of dopaminergic neurons in the animal models of PD resulted in functional integration of implanted cells into recipient’s brain and partial recovery of motor functions (Kim J-H et al 2002, Barberi T et al 2003).

Although transplantation of neurons into striatum in PD model has a higher effectiveness in comparison with transplantation of neurons in other neurodegenerative disorders, it is too early to speak about full restoration of motor deficit associated with parkinsonism. In case of PD significant functional recovery requires cell replacement with, at least partial repair of original connections with neurons in the striatum. If such connections do not exist the full regress of motor deficit is impossible because dopamine release is under feedback control. This fact emphasizes the importance to develop effective methods to

The method to enhance accuracy of regeneration (Potential therapeutic strategy)

After transplantation stem cells make decisions regarding fate and patterning in response to external signals from extracellular environment and neighboring cells. The effectiveness of neural stem cell therapy may be facilitated by the ability to manipulate these signals in a temporal and spatially appropriate fashion (Liu CY et al 2003). The future methods of therapy could include in vitro processing of stem cells before implantation, supporting and guiding the cells after implantation with the help of nanorobots, as well as the in vivo creation of molecular scaffold (The Samuel I. Stupp Laboratory – sistagirl.ms.northwestern.edu, Silva GA et al 2004) for stimulating their growth in the correct direction.

During experiments on neonatal rats (Englund U et al 2002) the potential ability of neural stem cells to establish appropriate long-distance axonal projection after region-specific differentiation were shown. Unfortunately, adult brain, as compared to neonatal, has unfavorable conditions for axon growth in the correct direction. It is for this reason the stimulation of new neurons growth, for example along the surface of neurons in the zone of progressive degeneration, is necessary. The reconstruction of dysfunctional neural circuits may be facilitated in the following way . The proposed strategies are designed to increase accuracy of dysfunctional neurons regeneration.

The Paediatric School-Based Clinics were established in May of 2007, in response to the ‘Health disparity by Neighbourhood Income” study that was published by the SHR (Dr. Mark Lemstra et al). The clinics are a product of the efforts of the Department of Paediatrics, College of Medicine at the U of S, the Catholic and Public school Divisions and The Saskatoon Tribal Council, in consultation with the Core Neighbourhood communities to provide access to comprehensive paediatric care.

Acknowledging that it is the social determinants of health such as income, literacy, and housing that impact people’s health, we provide care to children in core neighbourhoods, embracing the community paediatrics model which shifts away from one child but to ‘all children in the community, within the context of the family and the community’. We adhere to the principals of cultural competency.

The clinic is collaborative; i.e. seeking to work across sectors such as Education, Social Services, Justice, Law Enforcement etc; as well as integrated, i.e. working alongside teachers, councilors, social workers psychologists, ENT, Child Psychiatry.

The clinics are currently based out of St. Mary’s Elementary School (Mon/ Tues/ Wed); as well as W.P. Bate Elementary school on Thursday afternoon. It is staffed by 2 Paediatrcians from the department of paediatrics. Appointments are not mandatory, drop-ins are welcomed. A referral by a Family Physician is not required; patients/families/ teachers, etc may all refer. We work with the family and the community, as well as the schools, to make ourselves and the other health-care professionals whom we may refer our patients to, more accessible, recognizing the many obstacles that people who live in poverty, face.

A huge part of our work is dedicated to advocacy; for the patients and for their families. money saving at payday advance

Lifestyle interventions, in the form of dietary modification and exercise, are effective means of managing and treating high serum levels of cholesterol and triglycerides in individuals diagnosed with dyslipidemia. Such interventions should always be attempted as the initial step in the management and treatment of lipid abnormalities, especially when total cholesterol levels, low-density lipoprotein (LDL) levels, or triglyceride serum levels are just above the reference range.

EFFECT OF EXERCISE ON DYSLIPIDEMIA

The acute effects of exercise on serum lipid levels are greatest with respect to elevating the levels of high-density lipoprotein (HDL). Various studies have shown HDL levels to increase by 4-43% with exercise. A reduction in triglyceride (TG) levels also occurs 18-24 hours after an acute bout of exercise and can persist for up to 72 hours. This effect is greatest in those with the highest pre-exercise TG values and does not appear to require a threshold of exertion to be demonstrated. The chronic effects of exercise were studied among endurance athletes. It was noted that they frequently had serum HDL cholesterol concentrations 10-20 mg/dL or 40-50% higher than their sedentary counterparts. Their triglyceride levels were also lower by 20%, and their LDL cholesterol concentrations were lower by approximately 5-10%.

The Health, Risk Factors, Exercise, Training, and Genetics (HERITAGE) Family Study showed that regular endurance exercise training was particularly helpful in men who have low HDL cholesterol levels, elevated TG levels, and central or abdominal obesity. The increase in HDL levels was usually noticed at 12 weeks or more and not seen at 10 weeks or less. Increased training volume predictably yielded greater results. The increase in HDL levels was more profound when exercise was combined with caloric restriction.

EFFECT OF DIET ON DYSLIPIDEMIA

Although the diet commonly recommended for patients with dyslipidemia is low in saturated fat (<10% of caloric intake), low in cholesterol (<300 mg/d), and high in soluble fibers, several other diets have also been tried with reasonable success. Among them, the Mediterranean diet was a particularly effective alternative. This diet is low in red meat; high in fruits, vegetables, whole grains, beans, nuts, and seeds; and low to moderate in fish, poultry, and dairy products. Another suggested diet alternative contains diverse cholesterol-lowering components. This diet is low in saturated fat and high in plant sterols, soy protein, viscous fibers, and almonds. The level of LDL reduction with this second alternative diet was not statistically significant from a diet very low in saturated fat plus 20 mg/d of lovastatin. Meanwhile, increasing the percentage of monounsaturated fat intake and reducing caloric intake from carbohydrates to around 40% was also shown to reduce both fasting and postprandial triglyceride levels and increase HDL levels.

DIETARY SUPPLEMENTS AND DYSLIPIDEMIA

Several over-the-counter dietary supplements are frequently selected by dyslipidemic patients or are taken upon the recommendation of health care professionals.

• Fish oil

Most of the data used to support the intake of fish oil concentrate were derived from studies that used high daily doses (>6 g/d). These studies conclusively showed significant reduction in serum triglyceride levels through inhibition of very low-density lipoprotein (VLDL) triglycerides and apolipoprotein B synthesis. In hypertriglyceridemic subjects, a dose of 15 g/d of fish oils lowered serum triglyceride levels by approximately 50%. Although many trials support the cardioprotective effects of fish oil, recent epidemiologic evidence, unfortunately, does not. The precise reasons for these controversial findings have yet to be determined. Variations in the apolipoprotein E (apoE) genotype may play a role in an individual’s specific response to fish oil therapy. In particular, an increase of LDL-C levels and a trend in the direction of reduced HDL-C levels after fish oil supplementation were observed in subjects possessing the apoE4 allele, compared to individuals possessing the homozygous apoE3 allele profile. Additionally, individuals possessing the apoE2 allele have shown improved responses to reduction of expected serum triglyceride elevations after meals.

• Oat bran supplement

Beta-glucan (the main soluble fiber component of oat bran) may decrease the absorption of ingested nutrients and bile acids by increasing the viscosity of intestinal contents. Several studies have demonstrated evidence that oat bran supplements have a substantial hypocholesterolemic effect. A daily dose of 3 grams or more is required to produce clinically relevant reductions in both total cholesterol (TC) and LDL concentrations. Combining oat bran supplementation with exercise showed consistent and substantial reduction of serum lipid levels.