Kallikrein gene therapy: a new strategy for hypertensive diseases

The effects of tolcapone, a catechol-O-methyltransferase inhibitor, on the bioavailability and efficacy of levodopa were evaluated in 12 patients with Parkinson's disease (PD), 8 of whom showed signs of daily motor fluctuations (wearing-off phenomenon). Motor disabilities were assessed in 12 patients at 7 time points before and after the chronic administration of tolcapone using the Unified Parkinson's Disease Rating Scale (UPDRS). The UPDRS score was improved at all points of determination. Eight patients with wearing-off phenomenon on levodopa showed symptomatic improvement on the combination. The area under the curve (AUC) for levodopa increased by 34% (p = 0.0059) after the administration of tolcapone. The elimination half-life (T1/2) of levodopa was significantly prolonged by 81% (p = 0.0001) after the treatment. The AUC of 3-O-methyldopa, a metabolite of levodopa, was decreased by 79% (p = 0.0001) and the Cmax (maximum concentration) was also decreased by 80%d after the administration (p = 0.0001) of tolcapone. The combination of tolcapone and levodopa was well tolerated. Our findings suggest that tolcapone improves the pharmacokinetics of levodopa in plasma and motor symptoms of fluctuating PD patients. It is suggested that tolcapone may be useful drug adjunct to levodopa in treating patients with PD with wearing-off phenomena.     

Cytokine-modified tumor vaccines: an antitumor strategy revisited in the age of molecular medicine

Serum samples were collected from 153 normoglycaemic, hypoproteinaemic dogs of known case histories, and assayed for fructosamine, glucose, total protein and albumin concentrations. This study was conducted to evaluate the relationship between serum fructosamine and total serum proteins, or more specifically serum albumin. Serum fructosamine was positively correlated with both total serum protein (r = 0.47, p < 0.00001) and serum albumin (r = 0.77, p < 0.00001). Mean serum albumin concentrations were significantly different when the data were grouped as dogs with normal versus subnormal serum fructosamine concentrations. The data indicate the value of the serum fructosamine assay in estimating the duration of hypoalbuminaemia. Concurrent hypoalbuminaemia and normal serum fructosamine indicate hypoalbuminaemia of less than one week. Concurrent hypoalbuminaemia and hypofructosaminaemia indicate persistent hypoalbuminaemia of more than one week, and concurrent normal albumin and hypofructosaminaemia indicate recovery from a condition including hypoalbuminaemia or hypoglycaemia.     

Regulating angiogenesis: a new therapeutic strategy

Angiogenesis is the proliferation of endothelial and smooth muscle cells to form new blood vessels. Largely muted after adolescence, angiogenesis may be reignited by cancerous cells. Neoangiogenesis plays a primary role in tumor growth and metastases. Antiangiogenic therapy to limit and even reverse the growth of tumors are under investigation and showing promise. A derivative of fumagillin, TNP 470, is the first angiogenesis inhibitor to be given to humans. Surprisingly, several potent inhibitors are derived from tumors themselves. Researchers nowc recognize that stimulation of angiogenesis may have a place in the treatment of cardiovascular disease. Reestablishing blood flow to ischemic tissue through angiogenesis may provide a biologic "bypass" for patients with ischemic heart disease. The same applies to the treatment of peripheral vascular disease.     

The attrition dilemma: Toward a new strategy for psychotherapy research.

Presents an analysis of the attrition dilemma in psychotherapy research and reviews the methods used to compensate for data loss. It is argued that attrition is not ultimately a problem of bias but a problem of lack of information. A reformulation is offered that integrates single-case studies with traditional group comparison methodology in an attempt to find optimal causal relations of treatments to outcomes. (10 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Nutrient regulation of gene expression: a methodological strategy

Nutrients should be viewed as the earliest of the hormone signals which allowed an organism to respond to changes in its nutrient environment. Defining nutrient function at the nuclear level will permit us to understand how our dietary environment is related to the development of nutritionally related pathophysiologies such as diabetes, heart disease, and cancer. Moreover, through the application of molecular techniques, we will begin to understand how specific nutrients govern the developmental pattern of specific organs such as the kidney. In this review, the fatty acid synthase gene is employed as a model to demonstrate how one sequentially approaches questions pertaining to the regulation of gene expression by a nutrient, and the article presents a nuclear explanation for how dietary polyunsaturated fats decrease blood triglycerides. More importantly, studies of this nature provide a basis for screening genetically susceptible populations and information that will allow the nutritionists of the 21st century to customize a diet for patients at risk.     

Equatorial breast reduction: a new technique for the correction of moderate-to-large mammary hypertrophy

The author describes a personal technique for moderate-to-large breast hypertrophy, regardless of the degree of ptosis, based upon a personal experience of more than 200 breast reductions. It is a superior monopedicle nipple-areola flap procedure, which leaves an inverted-T scar. It was used in 35 cases over the last 3 years involving tissue reductions ranging from 500 to 1950 g per gland. All patients underwent follow-up evaluations 1, 3, 6, and 12 months after surgery. No complications were observed, and areolar sensation was preserved in all cases. Apart from its effectiveness in cases of massive hypertrophy and the absence of difficulties related to elevation of the nipple-areola complex, the equatorial technique offers the significant advantages of a simple preoperative marking phase and well-defined, reproducible parameters for reduction and reshaping. These characteristics reduce the need for subjective judgment and, therefore, the risk of error. The results obtained are highly satisfactory in terms of volume reduction, form, and symmetry.     

Targeted disruption of the mouse lecithin:cholesterol acyltransferase (LCAT) gene. Generation of a new animal model for human LCAT deficiency

We have established a mouse model for human LCAT deficiency by performing targeted disruption of the LCAT gene in mouse embryonic stem cells. Homozygous LCAT-deficient mice were healthy at birth and fertile. Compared with age-matched wild-type littermates, the LCAT activity in heterozygous and homozygous knockout mice was reduced by 30 and 99%, respectively. LCAT deficiency resulted in significant reductions in the plasma concentrations of total cholesterol, HDL cholesterol, and apoA-I in both LCAT -/- mice (25, 7, and 12%; p < 0. 001 of normal) and LCAT +/- mice (65 and 59%; p < 0.001 and 81%; not significant, p = 0.17 of normal). In addition, plasma triglycerides were significantly higher (212% of normal; p < 0.01) in male homozygous knockout mice compared with wild-type animals but remained normal in female knockout LCAT mice. Analyses of plasma lipoproteins by fast protein liquid chromatography and two-dimensional gel electrophoresis demonstrated the presence of heterogenous prebeta-migrating HDL, as well as triglyceride-enriched very low density lipoprotein. After 3 weeks on a high-fat high-cholesterol diet, LCAT -/- mice had significantly lower plasma concentrations of total cholesterol, reflecting reduced levels of both proatherogenic apoB-containing lipoproteins as well as HDL, compared with controls. Thus, we demonstrate for the first time that the absence of LCAT attenuates the rise of apoB-containing lipoproteins in response to dietary cholesterol. No evidence of corneal opacities or renal insufficiency was detected in 4-month-old homozygous knockout mice. The availability of a homozygous animal model for human LCAT deficiency states will permit further evaluation of the role that LCAT plays in atherosclerosis as well as the feasibility of performing gene transfer in human LCAT deficiency states.     

A new strategy for meeting new challenges.

L. A. Berman (1970) fails to recognize that Black objections to minority group research stems from its failure to ameliorate the urgent problems Blacks endure. Political action research aims to modify the social structure, perhaps by focusing on changing group behavior or influencing decision-making bodies. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Targeted hepatitis B vaccination--a cost effective immunisation strategy for the UK?

OBJECTIVE: To compare the potential cost effectiveness of vaccination against hepatitis B virus (HBV) targeted at genitourinary clinic (GU) attendees with that of universal infant vaccination. DESIGN: A mathematical model of sexual and perinatal transmission of HBV was used to compare the effectiveness among heterosexual and homosexual populations of programmes of mass infant vaccination and targeted immunisation of genitourinary medicine (GU) clinic attendees. Each was applied to 90% of the eligible population with differing assumptions about rates of compliance and seroconversion - problems of delivery (obtaining high compliance) was considered a significant drawback of targeted vaccination. Observed relationships between GU clinic attendance and sex partner change rates for heterosexuals and for homosexuals were used to define the rates of vaccination uptake within sexual activity risk groups. SETTING: England and Wales. RESULTS: Model results showed that for heterosexuals universal infant vaccination became more effective than clinic based vaccination only approximately 40 years after the start of the programme and that the predicted cost effectiveness of GU clinic vaccination was greater at all times. For homosexuals, clinic vaccination was always more effective over the time frame considered, but by 50 years if it were carried out without prior screening it had become appreciably less cost effective than a mass infant programme. With prior screening in GU clinics this cost effectiveness deficit was only marginal. CONCLUSIONS: Targeted vaccination might have a much greater potential than is realised at present, particularly if it were possible to improve compliance of clinic attendees. A fuller comparison between mass infant and targeted vaccination must await the specific inclusion in the model of other risk groups such as intravenous drug users. An important determinant of the relative merits of the two approaches is the relationship between rates of attendance and of changing sexual partners. Further research on this is required.     

Neural stem and progenitor cells: a strategy for gene therapy and brain repair

The damaged adult mammalian brain is incapable of significant structural self-repair. Although varying degrees of recovery from injury are possible, this is largely because of synaptic and functional plasticity rather than the frank regeneration of neural tissues. The lack of structural plasticity of the adult brain is partly because of its inability to generate new neurons, a limitation that has severely hindered the development of therapies for neurological injury or degeneration. However, a variety of experimental studies, as well as moderately successful clinical engraftment of fetal tissue into the adult parkinsonian brain, suggests that cell replacement is evolving as a valuable treatment modality. Neural stem cells, which are the self-renewing precursors of neurons and glia, have been isolated from both the embryonic and adult mammalian central nervous system. In the adult human brain, both neuronal and oligodendroglial precursors have been identified, and methods for their harvest and enrichment have been established. Neural precursors have several characteristics that make them ideal vectors for brain repair. They may be clonally expanded in tissue culture, providing a renewable supply of material for transplantation. Moreover, progenitors are ideal for genetic manipulation and may be engineered to express exogenous genes for neurotransmitters, neurotrophic factors, and metabolic enzymes. Thus, the persistence of neuronal precursors in the adult mammalian brain may permit us to design novel and effective strategies for central nervous system repair, by which we may yet challenge the irreparability of the structurally damaged adult nervous system.     

Palliative medicine: a new specialty changes an old debate

The specialty of palliative care, of which palliative medicine is part, has developed from hospice care for the dying and aims to meet the various needs of those suffering from advanced incurable progressive disease. Specialist palliative care is not expensive and can be made available to all those who need it, at home, in hospital or in a hospice. Arguments in favour of permitting euthanasia for those dying as a result of a chronic disease are usually based on compassion respect for autonomy or perceived hypocrisy in existing medical practice. Each of these arguments is examined and found wanting.     

Polyprotein processing in African swine fever virus: a novel gene expression strategy for a DNA virus

This report shows that African swine fever virus (ASFV)--a large DNA-containing virus--synthesizes a polyprotein to produce several of its structural proteins. By immunoprecipitation analysis, we have found that ASFV polyprotein is a 220 kDa myristoylated polypeptide (pp220) which, after proteolytic processing, gives rise to four major structural proteins: p150, p37, p34 and p14. Processing of the ASFV polyprotein takes place at the consensus sequence Gly-Gly-X and occurs through an ordered cascade of proteolytic cleavages. So far, polyprotein processing as a mechanism of gene expression had been found only in positive-strand RNA viruses and retroviruses. According to the results presented here, ASFV is the first example of a DNA virus that synthesizes a polyprotein as a strategy of gene expression.