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 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The main goal of this study was to determine and characterise the types of mutations in two monogenic human disorders: cystic fibrosis (CF) and Duchenne/Becker muscular dystrophy (DMD, BMD) and the susceptibility allele frequency in a polygenic disease: type I insulin-dependent diabetes mellitus (IDDM). After analysing 220 chromosomes for mutations in the CF (Cystic Fibrosis Transmembrane Conductance Regulator = CFTR) gene, delta F508 mutation was most abundant (41%) and out of the non-delta F508 CF mutations 5% was identified as G542X, G551D, R553X, N1303K and W1282X. The CF haplotype analysis by using linked markers to the CFTR gene revealed that the CF "B" haplotype occurred in 66.7% of patients, and this haplotype was 57.2% in patients carrying the delta F508 mutation. Prenatal genetic diagnosis for CF was performed in 10 fetuses: 3 were affected, 6 were carriers, and 1 without any CF mutation. Fifty % of 66 patients with DMB/BMD muscular dystrophy had one or more exon deletions in the dystrophin gene. Eighty-five % of the deletions occurred at the 3' and 15% at the 5' end of the gene. Out of the three prenatal diagnosis in one case DMD was substantiated. Thirty-six % of 50 patients with IDDM possessed four, 44% three and 20% two susceptibility markers in the HLA-DQA1, -DQB1 region. The onset of the disease correlated with the number of susceptibility alleles.
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PMID:Molecular genetic studies in monogenic and polygenic human diseases. 919 7

Diabetes, known since antiquity, has been defined by glycosuria. In 1886, when Minkowski demonstrated that pancreatectomized dogs developed diabetes, the islets of Langerhans became a focus of the search for an active principle culminating in the discovery and the isolation of insulin in 1921 by Banting, Best and Collip. In 1959, the radioimmunoassay of Yalow and Berson solidified the concept of insulin resistance in non-insulin dependent diabetes (NIDDM). In 1971, the insulin receptor was defined as a cell surface protein that initiated the insulin signal transduction cascade. Today, we know that NIDDM accounts for at least 90% of all diabetes worldwide and involves approximately 100 million people. The microvascular complications of NIDDM are the same as for insulin dependent diabetes (IDDM) and are related to the intensity and duration of hyperglycaemia. Further, it is clear from the Diabetes Control and Complications Trial (DCCT) that all microvascular complications can be reduced with intensive control of the blood glucose. Macrovascular disease is also accelerated in NIDDM, including both hypertension and dyslipidemia. The major risk factor for NIDDM are age, obesity, physical inactivity, and genetic background. The earliest features seen in individuals destined to develop NIDDM is insulin resistance, but for hyperglycaemia to ensure there must be a defect in insulin secretion. Thus, insulin resistance defines the prehyperglycaemic phase of NIDDM, but varying degrees of insulin secretory deficiency define the hyperglycaemic phase. Macrovascular risk occurs throughout the lifetime of the individual, whereas microvascular risk ensues with the inception of hyperglycaemia. Tomorrow, we will understand more clearly whether lifestyle changes, such as diet and exercise, or new classes of drugs, can delay or prevent NIDDM. Clinical trials are now beginning to test whether impaired glucose tolerance (IGT) can be delayed or prevented from moving to overt NIDDM. The genetics of NIDDM are under intense study. Mutations in the insulin receptor lead to NIDDM in a small number of patients, and mutations in the glucokinase gene lead to maturity onset diabetes of the young (MODY). Work is now underway to study other candidate genes as well as work on positional cloning techniques to identify diabetes genetic loci. The hormone Leptin has just been discovered and is a major regulator of body weight. In summary, the most important new emphasis on the treatment of NIDDM is the recognition of the importance of hyperglycaemia and our ability to both treat and possibly prevent this metabolic perturbation. This joins the longer-term emphasis on cardiovascular risk reduction from both treatment and prevention of hypertension and dyslipidemia.
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PMID:Non-insulin dependent diabetes--the past, present and future. 928 27

Since its inception in 1898 the American Journal of Physiology has been a leader in diabetes research and has published many key articles on the subject. The Journal first published studies of phlorhizin-induced diabetes in 1898, and after many other contributions went on to publish the first reports of Banting, Best, Macleod, and Collip in 1922 concerning the isolation and purification of insulin (5-8, 13). This review highlights some of these key contributions of the Journal.
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PMID:Contributions of the American Journal of Physiology to the discovery of insulin. 948 48

One of insulin-dependent diabetes mellitus (IDDM) complications are bone mineral disorders called diabetic osteopathy. Because of many controversies of this subject we took a research of bone mineralisation in IDDM patients before 40 years old. The evaluation of BMD was performed with the use of X-ray dual energy absorptiometry--DEXA in the AP projection for lumbar part of vertebral column (BMD L2-L4), left femur neck (BMD-neck) and total skeleton (BMD-total). Bone tissue metabolism was evaluated with the aid of biochemical tests. The examined group consisted of 99 patients with IDDM (45 women and 54 men), without any other risk factors for changes in bone metabolism. The results were related to: sex, age in which IDDM was diagnosed, duration of IDDM, metabolic control of diabetes and to some IDDM complications. The control group consisted of 113 healthy subjects matched for age, sex, weight, height and calcium diet. We observed that BMD in IDDM patients before 40 years old was significantly lower than in healthy subject. One of some diabetic osteopathy pathomechanism seems to be an advantage of bone resorption over bone formation. Bone demineralisation which was observed to be most pronounced in femur neck, was not related to age, differed in accordance to sex and was higher of age when IDDM appeared was lower. BMD was also related to duration of IDDM and metabolic control of IDDM.
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PMID:[Bone mineralization in insulin-dependent diabetes mellitus]. 949 14

This study aimed to explore multiple determinants of BMD (bone mineral density) in 99 women with long-standing type 1 diabetes, recruited from a population based register of insulin users. BMD was measured using DEXA (dual energy X-ray absorptiometry) at the femoral neck and lumbar spine, age adjusted Z scores were calculated and results compared to those of healthy volunteers. The median age of diabetic subjects was 42 years and the median duration of diabetes was 27 years. BMD was positively associated with body mass index and height at both the lumbar spine and femoral neck. There was a positive association with oral contraceptive pill use and lumbar spine BMD, and peripheral vascular disease was negatively associated with femoral neck BMD. No correlation was seen with either age or duration of diabetes and absolute BMD values. Mean Z score at the femoral neck was -0.12 (95% confidence interval -0.37 to +0.12). At the lumbar spine, the corresponding value was -0.21 (-0.44 to +0.02). Pre- and post-menopausal values for the diabetic subjects and healthy volunteers were found to be similar. In summary, axial BMD values in subjects with long-standing diabetes were similar to those observed in healthy non diabetic populations.
Diabetes Res Clin Pract 1998 Apr
PMID:A population-based study of bone mineral density in women with longstanding type 1 (insulin dependent) diabetes. 969 88

The United Kingdom Prospective Diabetes Study (UKPDS) is the largest study ever performed in the field of diabetes. It has been carried on in more than 5000 patients with newly diagnosed type 2 diabetes and followed during almost 15 years. The main goals of the study were to investigate the effects of improving blood glucose and/or blood pressure control on diabetic complications, and to compare the advantages and inconvenients of the most important pharmacological approaches. The results of the UKPDS have been presented at the last Congress of the European Association for the Study of Diabetes (EASD) in Barcelona, September 10-11, 1998. They essentially showed that improving blood glucose or arterial blood pressure control allows to significantly reduce the incidence of complications associated to diabetes. Best results were observed in individuals in whom treatments of both hyperglycemia and hypertension were intensified. For each risk factor, no threshold has been found so that every reduction in blood glucose or arterial pressure is accompanied by a nearly linear diminution in the incidence of diabetic complications. The type of pharmacological treatment appears to have a less prominent influence, even if metformin appears to exert the most favourable effects in the group of obese patients with type 2 diabetes.
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PMID:[Lessons from the "United Kingdom Prospective Diabetes Study"]. 983 82

Male hypogonadism has been recognized as one of the major causes of secondary osteoporosis, but most cases seem to be left undiagnosed. We report a 54-year-old case of mosaicism Klinefelter syndrome lacking typical clinical features such as tall stature or low intelligence, who was found to have marked decrease in lumbar bone mineral density (BMD: 0.686 g/cm2) during treatment of diabetes mellitus. In investigation for etiologies of secondary osteoporosis, he was diagnosed as having mosaicism Klinefelter syndrome (XXY/XY/XX). Although he was infertile, he lacked typical clinical features of Klinefelter syndrome. Testosterone replacement was started, which resulted in an increase in BMD up to 0.712 g/cm2 two months after the initiation of therapy. The fact that BMD increased shortly after the initiation of testosterone replacement therapy in the present case supported a beneficial effect of testosterone on BMD, as recently suggested in idiopathic hypogonadotropic hypogonadism. Although the present case was diagnosed as having mosaicism Klinefelter syndrome by investigating etiologies for osteoporosis, it may be stressed that male hypogonadism, in general, should be adequately suspected in the presence of infertility and from the findings of physical examination.
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PMID:Low bone mineral density in a case of mosaicism Klinefelter syndrome: rapid response to testosterone therapy. 988 14

There is often a considerable lapse of time between the definition of what causes a disease in the laboratory and the development of successful therapy. However, the history of medicine teaches us that the need to understand the scientific basis of disease before the discovery of new treatments is both essential and inevitable. During the middle of the 19th century, the work of the great German pathologist, Rudolf Virchow, defined disease as having an anatomic or histologic basis. In the clinic, this scientific perspective would lead to increasingly effective and, often, increasingly aggressive surgical approaches to disease. Later in the 19th century, Koch's discovery of the tubercle bacillus (a discovery Virchow disbelieved and publication of which he thwarted, since he hypothesized that cancer, not microbes, caused consumption!), would define a microbiological basis for disease. With bacteria defined as a major cause of human suffering, the stage was set for the development of the discovery of effective antibiotics. In the early 20th century, the pioneering work of Banting, Best and others would show that disease can also have an endocrine or metabolic basis. This new body of scientific knowledge would lead not only to the specific discovery of insulin as an effective treatment for diabetes but also to a more general understanding of the role of hormones, vitamins and co-factors in human health and disease. Basic medical research and its successful translation into effective treatments has fundamentally altered the cause of human death. In the developed world, where access to the benefit of this work is available, infectious disease is not the problem it was in the days of Pasteur, Metchnikoff and Ehrlich. As we approach the millennium, science is now teaching us that diseases, particularly cancer, can have a molecular or genetic basis. Can successful application of this new knowledge be far behind? We are already seeing the application of this new knowledge in cancer drug screening and cancer drug development. At the NCI, for example, the old in vivo mouse screen using mouse lymphomas has been shelved; it discovered compounds with some activity in lymphomas, but not the common solid tumors of adulthood. It has been replaced with an initial in vitro screen of some sixty cell lines, representing the common solid tumors-ovary, G.I., lung, breast, CNS, melanoma and others. The idea was to not only discover new drugs with specific anti-tumor activity but also to use the small volumes required for in vitro screening as a medium to screen for new natural product compounds, one of the richest sources of effective chemotherapy. The cell line project had an unexpected dividend. The pattern of sensitivity in the panel predicted the mechanism of action of unknown compounds. An antifolate suppressed cell growth of the different lines like other antifolates, anti-tubulin compounds suppressed like other anti-tubulins, and so on. It now became possible, at a very early stage of cancer drug screening, to select for drugs with unknown-and potentially novel-mechanisms of action. The idea was taken to the next logical step, and that was to characterize the entire panel for important molecular properties of human malignancy: mutations in the tumor suppressor gene p53, expression of important oncogenes like ras or myc, the gp170 gene which confers multiple drug resistance, protein-specific kinases, and others. It now became possible to use the cell line panel as a tool to detect new drugs which targeted a specific genetic property of the tumor cell. Researchers can now ask whether a given drug is likely to inhibit multiple drug resistance or kill cells which over-express specific oncogenes at the earliest phase of drug discovery. In this issue of The Oncologist, Tom Connors celebrates the fiftieth anniversary of cancer chemotherapy. His focus is on the importance of international collaboration in clinical trials and the negative impact of unnecessary bureaucracy and regulation. As a student of Tom's in the 1970s in London, working on hepatoma-specific alkylating agents at Charing Cross Hospital in collaboration with his lab on the other side of town, I can attest to the fact that the regulatory hurdles to cancer drug development just twenty years later have added immeasurably to the effort and cost of cancer drug development. However, I look with optimism to the future of cancer diagnosis, prevention and treatment. It is a future where what we are learning now about the molecular and genetic basis of cancer will find their clinical outlet just as surely as the anatomic, microbial, metabolic and endocrine basis for disease has in the past. This new knowledge will provide new techniques in molecular diagnosis, which will allow us to predict which in situ cancers are destined for malignant behavior, and which can be safely watched without the need for intervention. Individual patient risk for particular cancers will be accurately predictable, so that patients can alter lifestyle habits or begin other prevention strategies. Oncogenes and growth suppressor genes give us new targets to inhibit or replace. Tumor-specific kinases will meet their inhibitors. The oncologist will play a leading role in understanding, applying and interpreting this new information in the clinic-an exciting and challenging future!
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PMID:Cancer Drug Development: New Targets for Cancer Treatment. 1038 87

In healthy persons insulin secreting beta-cells of the pancreas regulate blood glucose levels within a narrow physiological range. Since the detection of insulin in 1922 by Banting and Best, subcutaneous insulin replacement has remained the sole treatment modality for insulin-dependent diabetes mellitus (IDDM). However, even trained patients undergoing intensive insulin therapy fail to achieve normal function of the pancreatic beta-cells. One approach to solve this problem is pancreas and islet cell transplantation. Because of technical problems, limited number of transplantable organs and toxicity of immunosuppressive therapy, both are still in an experimental state. An alternative approach is the development of genetically modified insulin secreting cell lines for replacement of islet cells. So far, experiments support the expectation to develop genetically manipulated cell lines who imitate the function of islet beta-cells and are protected from the immune response. The ultimate goal is the development of an engineered human beta-cell line and, after animal experiments, to use it for treatment of patients with IDDM.
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PMID:[Development of insulinoma cells as therapy in insulin-dependent diabetes mellitus]. 1042 Apr 93

Considerable advances have been made in insulin pharmacology and pharmacotherapeutics in the 77 years since its discovery by Frederick Banting and Charles Best at the University of Toronto. Nevertheless, even the most sophisticated regimens of diabetes management still do not replace insulin in a physiological manner, i.e. by portal secretion in precise amounts to respond to ingested nutrients and other secretogogues. It is for these reasons that insulin remains just one of many facets of optimal diabetes care. Further advances in the next few years can be expected to change some aspects of insulin therapeutics. However, in the absence of perfect physiological replacement, the goal of diabetes management remains the balancing of the different components of therapy in order to achieve the best possible metabolic control.
Diabetes Nutr Metab 1999 Apr
PMID:Insulin therapy in children and adolescents with Type 1 diabetes. 1055 91


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