Showing papers in "Annals of Medicine in 1997"
TL;DR: Evidence is provided suggesting that both lignans and isoflavonoids may prevent the development of cancer as well as atherosclerosis, and no definite recommendations can be made as to the dietary amounts needed for prevention of disease.
Abstract: Incidences of breast, colorectal and prostate cancer are high in the Western world compared to countries in Asia. We have postulated that the Western diet compared to the semivegetarian diet in some Asian countries may alter hormone production, metabolism or action at the cellular level by some biochemical mechanisms. Our interest has been focused on two groups of hormone-like diphenolic phyto-oestrogens of dietary origin, the lignans and isoflavonoids abundant in plasma of subjects living in areas with low cancer incidence. The precursors of the biologically active compounds detected in man are found in soybean products, whole-grain cereal food, seeds, and berries. The plant lignan and isoflavonoid glycosides are converted by intestinal bacteria to hormone-like compounds. The weakly oestrogenic diphenols formed influence sex-hormone production, metabolism and biological activity, intracellular enzymes, protein synthesis, growth factor action, malignant cell proliferation, differentiation, cell adhesion and angiogenesis in such a way as to make them strong candidates for a role as natural cancer-protective compounds. Their effect on some of the most important steroid biosynthetic enzymes may result in beneficial modulation of hormone concentrations and action in the cells preventing development of cancer. Owing to their oestrogenic activity they reduce hot flushes and vaginal dryness in postmenopausal women and may to some degree inhibit osteoporosis, but alone they may be insufficient for complete protection. Soy intake prevents oxidation of the low-density lipoproteins in vitro when isolated from soy-treated individuals and affect favourably plasma lipid concentrations. Animal experiments provide evidence suggesting that both lignans and isoflavonoids may prevent the development of cancer as well as atherosclerosis. However, in some of these experiments it has not been possible to separate the phyto-oestrogen effect from the effect of other components in the food. The isoflavonoids and lignans may play a significant inhibitory role in cancer development particularly in the promotional phase of the disease, but recent evidence points also to a role in the initiation stage of carcinogenesis. At present, however, no definite recommendations can be made as to the dietary amounts needed for prevention of disease. This review deals with all the above-mentioned aspects of phyto-oestrogens.
1,282 citations
TL;DR: The results from a trial using recombinant IL-10 in the treatment of patients with RA are available in the near future and will be important in determining the therapeutic potential of this cytokine.
Abstract: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by the accumulation of inflammatory cells into the synovium and the destruction of joints. Cytokines are important regulators of the synovial inflammation. Some cytokines, such as tumour necrosis factor (TNF)-alpha and interleukin (IL)-1, function by promoting inflammatory responses and by inducing cartilage degradation. Other cytokines, such as IL-4, IL-10 and IL-13, function mainly as anti-inflammatory molecules. Although anti-inflammatory cytokines are present in rheumatoid joints, in progressive RA their levels obviously are too low to neutralize the deleterious effects of proinflammatory cytokines. Inhibiting the action of proinflammatory cytokines by using specific cytokine inhibitors or anti-inflammatory cytokines is the basis for new therapies currently tested in patients with RA. Promising results on the use of neutralizing anti-TNF-alpha monoclonal antibodies in the treatment of RA have been reported. The results from a trial using recombinant IL-10 in the treatment of patients with RA are available in the near future and will be important in determining the therapeutic potential of this cytokine.
261 citations
TL;DR: Bisphosphonates are used successfully in diseases with increased bone turnover, such as Paget's disease, tumoural bone disease, as well as in osteoporosis, and are also effective in preventing bone loss both in corticosteroid-treated and in immobilized patients.
Abstract: The bisphosphonates are synthetic compounds characterized by a P-C-P bond. They have a strong affinity to calcium phosphates and hence to bone mineral. In vitro they inhibit both formation and dissolution of the latter. Many of the bisphosphonates inhibit bone resorption, the newest compounds being 10, 000 times more active than etidronate, the first bisphosphonate described. The antiresorbing effect is cell mediated, partly by a direct action on the osteoclasts, partly through the osteoblasts, which produce an inhibitor of osteoclastic recruitment. When given in large amounts, some bisphosphonates can also inhibit normal and ectopic mineralization through a physical-chemical inhibition of crystal growth. In the growing rat the inhibition of resorption is accompanied by an increase in intestinal absorption and an increased balance of calcium. Bisphosphonates also prevent various types of experimental osteoporosis, such as after immobilization, ovariectomy, orchidectomy, administration of corticosteroids, ...
227 citations
TL;DR: Patients with rectal cancer can now have a good prognosis, and intact image and high quality of life, as a result of TME, 5-year survival figures have risen, local recurrence rates have declined, sphincter preservation has risen, and the rates of impotence and bladder dysfunction have declined.
Abstract: Rectal cancer persists as a significant worldwide problem. Currently, surgery is associated with a poor prognosis, a high likelihood of permanent colostomy and a high rate of local recurrence in patients with regional disease (transmural penetration or involvement of regional mesenteric lymph nodes). Functional changes such as impotence and bladder dysfunction remain distressingly common consequences of conventional surgery. Over the past two decades, a fundamental change in operative technique has taken place. Conventional surgery (which is performed using blunt technique along undefinable tissue planes) has given way to sharp dissection along definable planes. The technique known as total mesorectal excision (TME) or complete circumferential mesorectal excision (CCME) produces the complete resection of an intact package of the rectum and its surrounding mesorectum, enveloped within the visceral pelvic fasia with uninvolved circumferential margins. As a result of TME, 5-year survival figures have risen from 45-50% to 75%, local recurrence rates have declined from 30% to 5-8%, sphincter preservation has risen by at least 20% for mid- and lower rectal cancers, and the rates of impotence and bladder dysfunction have declined from 50-85% to 15% or less. Patients with rectal cancer can now have a good prognosis, and intact image and high quality of life. The integration of multidisciplinary radiation therapy and chemotherapy into the care of patients undergoing TME or CCME for rectal cancer is presently under clinical trial.
219 citations
TL;DR: Preliminary studies suggest that cardiotrophin-1, produced by cardiomyocytes, is able to inhibit cytokine-induced Cardiomyocyte apoptosis in vitro, as growth hormone may also play an important role in the regulation of apoptosis induced by these cytokines.
Abstract: Cytokines have been associated with the pathogenesis of acute coronary syndromes and chronic heart failure (CHF), which are both associated with cardiomyocyte loss. In CHF, increased serum concentrations of proinflammatory cytokines, including tumour necrosis factor α (TNF-α) and also soluble TNF receptor have been found. Both TNF and Fas-ligand have been able to induce programmed cell death (apoptosis) of cardio-myocytes in various experimental studies. In ischaemic conditions of the heart, increased serum levels of soluble Fas receptor have been found. The proinflammatory cytokines interleukin 1 (IL-1), IL-2 and interferon-γ can induce TNF production from target cells, including myocytes. TNF and some other cytokines are able to induce nitric oxide production, which depresses cardiac function and can induce apoptosis. However, anti-inflammatory cytokines such as IL-10, IL-4 and IL-13, secreted by T-helper type 2 lymphocytes and other cells, inhibit the production of proinflammatory cytokines. Preliminar...
139 citations
TL;DR: In this review, exciting new insights into the aetiology, pathogenesis, diagnosis and treatment of fibromyalgia will be reviewed.
Abstract: The term fibromyalgia describes a complex syndrome characterized by pain amplification, musculoskeletal discomfort, and systemic symptoms. Although its existence has been controversial, nearly all rheumatologists now accept fibromyalgia as a distinct diagnostic entity. In fact, in the United States it is the third or fourth most common reason for rheumatology referral. Exciting new insights into the aetiology, pathogenesis, diagnosis and treatment of fibromyalgia will be reviewed.
124 citations
TL;DR: A prospective evaluation to determine whether GnRH-a administration during combination chemotherapy for Hodgkin's and non-Hodgkin's lymphoma could prevent posttreatment ovarian damage in women by inducing a temporary prepubertal hormonal milieu suggests that Gn RH-a cotreatment protects against POF during cytotoxic chemotherapy.
Abstract: Infertility represents one of the main remote sequelae of cytotoxic chemotherapy given for various malignant diseases. The impairment of gonadal function after cytotoxic chemotherapy is more frequent in the male than in the female. Because dividing cells are more sensitive to the cytotoxic effects of alkylating agents than are cells at rest, it has been hypothesized that inhibition of the pituitary-gonadal axis by gonadotropin-releasing hormone (GnRH) agonists would render the germinal epithelium less susceptible to the cytotoxic effects of chemotherapy. This hypothesis has not been thoroughly clinically tested until recently, although several investigators have demonstrated that GnRH-agonistic analogues (GnRH-a) inhibit chemotherapy-induced ovarian follicular depletion in the rat and Rhesus monkeys. Based on this rationale, we have undertaken a prospective evaluation to determine whether GnRH-a administration during combination chemotherapy for Hodgkin's and non-Hodgkin's lymphoma could prevent posttreatment ovarian damage in women by inducing a temporary prepubertal hormonal milieu. While over 93% of the surviving patients in the GnRH-a and chemotherapy group resumed spontaneous ovulation and menses, less than 40% of the women in the control group of chemotherapy without the GnRH-a cotreatment resumed normal ovarian cyclic activity. More than 60% of the women experienced premature ovarian failure (POF) in the chemotherapy alone group. Our preliminary results suggest that GnRH-a cotreatment protects against POF during cytotoxic chemotherapy. The GnRH-a and chemotherapy cotreatment may be also suggested for young women treated by cyclophosphamide pulse therapy or other gonadotoxic treatments for systemic lupus erythematosus, organ transplantation and other autoimmune diseases. The technology of cryopreservation of human ova for future fertility in these patients awaits clinical validation and substantiation. This review discusses possibilities to prevent gonadal damage induced by cytotoxic therapy and presents the clinical data currently available.
107 citations
TL;DR: This review presents recent progress in unravelling the regulation of heat shock gene expression in cells subjected to heat or other forms of stress by using inflammatory responses and myocardial ischaema as examples.
Abstract: All organisms exposed to environmental stress conditions share a common molecular response characterized by a dramatic change in the pattern of gene expression followed by an elevated synthesis of heat shock or stress proteins. These proteins function as molecular chaperones to protect cells from environmental stress damage by binding to partially denatured proteins, dissociating protein aggregates, and regulating the correct folding and intracellular translocation of newly synthesized polypeptides. Accumulating evidence supports a role for heat shock proteins in a number of disease states of which inflammatory reactions and ischaema provide the best studied examples. The inducible heat shock response involves transcriptional gene activation mediated by specific regulatory proteins called heat shock transcription factors, which bind to the promoter of heat shock genes in a sequence-specific manner. However, the signalling pathways leading to the activation of these transcription factors need to be characterized in more detail to be able to understand the role, cause, or consequence, of heat shock proteins in human diseases. This review presents recent progress in unravelling the regulation of heat shock gene expression in cells subjected to heat or other forms of stress. By using inflammatory responses and myocardial ischaema as examples, the putative use of heat shock proteins are discussed as targets for future therapeutic applications.
105 citations
TL;DR: It has become quite clear that diabetes cannot simply be divided into NIDDM and insulin-dependent diabetes mellitus (IDDM); the disease is more heterogeneous; unmasking this heterogeneity and identifying new subgroups of diabetes presents a challenge to modern molecular biology.
Abstract: Non-insulin-dependent diabetes mellitus (NIDDM) is one of the most common non-communicable diseases in the world. It has become obvious that NIDDM is the result of a collision between thrifty genes and an affluent society. Genes predisposing to NIDDM might have been survival genes for our ancestors, helping them to store energy during long periods of starvation. When these genes are exposed to a sedentary lifestyle and high caloric intake typical to the Western world, they predispose to obesity and insulin resistance. NIDDM results when beta cells cannot compensate for insulin resistance by increasing insulin secretion. Therefore, at least two inherited defects can be expected in NIDDM, one causing obesity and insulin resistance and the other inability to increase insulin secretion. In reality there may be more inherited defects. It has become quite clear that diabetes cannot simply be divided into NIDDM and insulin-dependent diabetes mellitus (IDDM). The disease is more heterogeneous; unmasking this heterogeneity and identifying new subgroups of diabetes presents a challenge to modern molecular biology.
91 citations
TL;DR: There is at least the possibility that the presence of thyroid abnormalities may influence breast cancer progression and this alone should stimulate awareness into the coincidence of the two disorders.
Abstract: The coincidence of thyroid disorders and breast cancer has long been a subject of debate. Associations with hyperthyroidism, hypothyroidism, thyroiditis and nontoxic goitre have been reported. Although no convincing evidence exists of a causal role for overt thyroid disease in breast cancer, the preponderance of published work favours an association with hypothyroidism. Geographical variations in the incidence of breast cancer have been attributed to differences in dietary iodine intake and an effect of iodide on the breast has been postulated. Recent reports have shown a direct association between thyroid enlargement, as assessed by ultrasound, and breast cancer. Although the exact mechanism for the demonstrated association between diseases of the thyroid and breast cancer remains to be elucidated, there is at least the possibility that the presence of thyroid abnormalities may influence breast cancer progression and this alone should stimulate awareness into the coincidence of the two disorders.
86 citations
TL;DR: Partial agonism, receptor subtype selectivity and novel binding sites are discussed as possible strategies to develop new drugs with fewer adverse effects than are seen in the clinical use of benzodiazepines.
Abstract: The main inhibitory neurotransmitter receptor of the brain, the gamma-aminobutyric acid type A receptor (GABA[A]), mediates the actions of several classes of clinically important drugs, such as benzodiazepines, barbiturates and general anaesthetics. This review summarizes the current knowledge on how classical benzodiazepines and novel nonbenzodiazepine compounds act on the benzodiazepine site of GABA(A) receptors and on their clinical pharmacology related to anxiolytic, sedative, hypnotic and cognitive effects or side-effects. Partial agonism, receptor subtype selectivity and novel binding sites are discussed as possible strategies to develop new drugs with fewer adverse effects than are seen in the clinical use of benzodiazepines.
TL;DR: The recent progress in the study of gp130 is reviewed and the background information from biomedical and biochemical viewpoints are reviewed, highlighting the need to understand more fully the role of membrane glycoprotein 130 in signal transduction.
Abstract: Receptors for many of the cytokines functioning in the haematopoietic system belong to the class I cytokine receptor family. In most cases these receptors share common signal transducing receptor components in the same family, which explains the functional redundancy of haematopoietic cytokines. Interleukin-6 and related cytokines, interleukin-11, leukaemia inhibitory factor, oncostatin M, ciliary neurotrophic factor and cardiotrophin-1, are all pleiotrophic, from the haematopoietic to the nervous system, and exhibit overlapping biological activities. Receptors for these cytokines fall into the class I cytokine receptor family. Functional receptor complexes for the interleukin-6 family of cytokines share a membrane glycoprotein 130 (gp130) as a critical component for signal transduction. In these receptor complexes, gp130 and ligand-specific chains possess no intrinsic tyrosine kinase domain but are associated with cytoplasmic tyrosine kinases. Ligand stimulation triggers homo- or heterodimerization of gp130, leading to activation of the associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors. This paper reviews the recent progress in the study of gp130 and the background information from biomedical and biochemical viewpoints.
TL;DR: It is concluded that new evidence is accumulating indicating that perinatal exposures may be important for the initiation of beta-cell destruction and risk factors may be targets for primary prevention strategies further studies are urgently warranted.
Abstract: There is strong evidence that the aetiology of insulin-dependent diabetes mellitus (IDDM) is due to a complex interaction between genes and the environment and that the pathogenesis is autoimmune. In early perinatal life the immune system is induceable and exposures in this period may initiate autoimmunity. Recent findings of time and space clustering of birth dates for later diabetic cases together with the early observation of a very high prevalence of diabetes in cases with rubella embryopathy suggest that foetal virus exposure may be important. Recent findings from Sweden and Finland suggest that enterovirus exposure during foetal life may initiate autoimmunity which may lead to diabetes. Other immune events, such as maternal-foetal blood group incompatibility and pre-eclampsia in the mother have also been associated with IDDM risk. Other more unspecific events in the perinatal period, such as a short gestational age, caesarean section and neonatal respiratory disease, are also indicated to increase the risk. In addition, food components such as nitrosamine components, cow's milk protein and gliadin have been proposed to initiate the slowly progressing autoimmune beta-cell destruction. Most of these epidemiological findings are supported by experimental studies in the nonobese diabetic mice but their exact mechanisms of action are still unclear. It is concluded that new evidence is accumulating indicating that perinatal exposures may be important for the initiation of beta-cell destruction. As such risk factors may be targets for primary prevention strategies further studies are urgently warranted.
TL;DR: Finland has a population with a history revealing features of founder effect, genetic drift and isolation, which is reflected in the regional enrichment of some diseases belonging to the Finnish disease heritage, which comprises some 30 diseases with a wide variety of clinical phenotypes.
Abstract: Finland has a population with a history revealing features of founder effect, genetic drift and isolation. Relatively small founder populations have slowly inhabited a large country and internal isolates have developed within Finland. This is reflected even today in the regional enrichment of some diseases belonging to the Finnish disease heritage. This concept was launched before the DNA era by skillful clinicians and today it comprises some 30 diseases with a wide variety of clinical phenotypes. Special strategies have been adapted in the initial locus assignment and in the restriction of the critical chromosomal DNA region having so far resulted in the successful isolation of 11 disease genes. Detailed analyses of these disease genes and their function have provided new insights into the structure and function of defective proteins as well as into the biology of affected tissues.
TL;DR: The mortality rate of JMCTD seems to be in the same range as that of juvenile systemic lupus erythematosus, dermatomyositis and scleroderma, however, mainly minor long-term problems are seen in the surviving patients.
Abstract: Mixed connective tissue disease (MCTD) was first reported 25 years ago. This report provides an assessment of the course of juvenile (J) MCTD in 224 patients available in the literature until 1996, including our own 33 patients. Most patients improved and remissions were observed in 3-5% (up to 27%). Among the long-term problems, a loss in joint function was seen in up to 29% of the cases, renal involvement in up to 47%, restrictive lung disease in up to 54% and gastrointestinal manifestations consisting of oesophageal dysmotility in up to 29%. Cerebral involvement was rare but severe. Cardiovascular problems observed include cardiomyopathy, myopericarditis and pulmonary hypertension. Among other long-term problems were Raynaud's phenomenon and scleroderma-like skin changes in up to 86% of the patients. Seventeen of the 224 patients had died (7.6%) because of sepsis or infection (7), cerebral complications (3), heart failure (2), pulmonary hypertension (2), renal failure (2) or gastrointestinal bleeding (1). The mortality rate of JMCTD seems to be in the same range as that of juvenile systemic lupus erythematosus, dermatomyositis and scleroderma. When compared with the other connective tissue diseases, however, mainly minor long-term problems are seen in the surviving patients.
TL;DR: According to this hypothesis, clinical markers of progression would be considered the loss of the ability to elicit a delayed-type hypersensitivity reaction to ubiquitous antigens, hyper-IgE (secondary to increased IL-4 production) and hypereosynophilia ( secondary to increasedIL-5 production).
Abstract: The progression of HIV-infected subjects to AIDS was recently postulated to be controlled by the balance between type 1 cytokines (mainly enhancing cell-mediated immunity) and type 2 cytokines (mainly augmenting antibody production). Thus, progression of HIV infection was suggested to be accompanied by a decline of in vitro production of interleukin-2 (IL-2), IL-12 and interferon gamma (IFN-γ) (type 1 cytokines) and an increase in the production of IL-4, IL-5, IL-6 and IL-10 (type 2 cytokines) by peripheral blood mononuclear cells of HIV-seropositive patients. According to this hypothesis, clinical markers of progression would be considered the loss of the ability to elicit a delayed-type hypersensitivity reaction to ubiquitous antigens (secondary to defective IL-2 production), hyper-lgE (secondary to increased IL-4 production) and hypereosynophilia (secondary to increased IL-5 production). The type 1 to type 2 shift was suggested to be predictive for the following events: (i) reduction in CD4 counts; (ii...
TL;DR: In this paper, the emergence of disease-associated autoantibodies into the peripheral circulation is usually the first noticeable sign of beta-cell autoimmunity in human insulin-dependent diabetes mellitus.
Abstract: Insulin-dependent diabetes mellitus (IDDM) is a chronic autoimmune disease with a subclinical prodromal period characterized by selective destruction of insulin-producing beta cells in the pancreatic islets. This process is assumed to be T-cell mediated, but the emergence of disease-associated autoantibodies into the peripheral circulation is usually the first noticeable sign of beta-cell autoimmunity in human IDDM. Recent observations have suggested that beta-cell autoimmunity may be induced in any individual at any time. There are also data indicating that such autoimmunity may have been initiated prenatally in some individuals. Only a proportion of those with signs of islet cell autoimmunity progress to clinical disease, and harmless beta-cell autoimmunity reflected by positivity for a single autoantibody specificity seems to appear without any relation to genetic IDDM susceptibility. One can hypothesize that in most subjects HLA-conferred protection against IDDM prevents the beta-cell process from progressing to a stage of destructive insulitis that may lead to clinical disease. Environmental factors may trigger initial beta-cell damage and subsequently accelerate the destructive process. Non-HLA genes may also be involved in the regulation of the progression rate. Prospective observations of prediabetic individuals have revealed that IDDM-associated autoantibodies tend to appear sequentially, and that those who progress to clinical disease mount a strong humoral immune response to most known disease-associated antigens. This indicates that the immune response associated with beta-cell destruction is not purely T-helper 1 biased. Antigen-specific immunotherapy may in the future offer effective measures to intervene in preclinical IDDM to prevent end-stage insulitis. Substantially more data have to be generated, however, on the mechanisms, efficacy and safety of such therapy before it is possible to judge its clinical applicability.
TL;DR: This review highlights the recent findings on angiotensin II receptors, and discusses the mechanisms behind the beneficial cardiovascular effects of interfering with the renin-angiotens in system.
Abstract: As an antihypertensive regimen, angiotensin l-converting enzyme (ACE) inhibition appears to have an antiproliferative cardiovascular effect that is not caused by blood pressure reduction alone. On the other hand, ACE inhibition has been shown to induce neocapillarization in hypertrophied myocardium. The possible mechanisms behind these beneficial cardiovascular effects of ACE inhibition are the suppression of angiotensin II formation and the potentiation of bradykinin. Angiotensin II receptor antagonism appears to have a similar antiproliferative effect on myocardium and vascular smooth muscle as ACE inhibition. This suggests that the antiproliferative action of both regimens is due only to the reduction of the pressor and growth effects of angiotensin II, or that both regimens have an additional, similarly effective antiproliferative action. Recently, knowledge about angiotensin II receptors has almost exponentially expanded. The two main classes of angiotensin II receptors, type 1 and 2 (AT1 and AT2), h...
TL;DR: Administration of sitostanol, a nonabsorbable saturated plant sterol, showed a significant reduction of serum plant sterols and cholesterol in two patients with phytosterolaemia, presumably by competitive inhibition of sterol absorption.
Abstract: Phytosterolaemla (sitosterolaemia) is a very rare inherited sterol storage disease characterized by tendon and tuberous xanthomas and by a strong predisposition to premature coronary atherosclerosis. In addition to increased or normal serum cholesterol, patients are found to have markedly elevated concentrations of the phytosterols sitosterol and campesterol. These sterols accumulate in all tissues, except the brain. Increased intestinal absorption of plant sterols, impaired biliary excretion, and decreased cholesterol synthesis are suggested as causes for this disease. However, the primary defect has not yet been identified. As well as dietary restrictions of cholesterol and plant sterols, therapeutic approaches based on interruption of the enterohepatic circulation of bile acids by administration of bile acid-binding resins or ileal bypass surgery have been recommended as therapeutic approaches to reduce all serum sterols. Administration of sitostanol, a nonabsorbable saturated plant sterol, showed a si...
TL;DR: Current data support a relationship between oestrogen and psychological well-being and suggest improvement in such symptoms via hormonal therapies or other interventions will probably lead to better quality of life for women and may actually impede the deterioration associated with ageing and certain medical illnesses.
Abstract: The last decade has seen increased interest in the role of hormones, including oestrogens, not only in regulating growth, sexual development and reproduction but in maintaining a sense of psychological well-being. Episodes of change in oestrogen levels, whether increasing or decreasing, are high-risk periods for the emergence of psychological symptoms in some women. This may be due to a ‘kindling effect’ for women with previous psychological disturbance, an effect on circadian rhythm activity and therefore altered neurovegetative functions, or an effect on central rhythmic functioning between the hypothalamus and the cerebral cortex, all mediated by effects on neurotransmitter systems. Data supporting these hypotheses come from animal studies as well as converging research in several areas including the study of psychological side-effects of oral contraceptives, the study of mood and cognitive disturbances related to the menstrual cycle, the studies of states of hormonal change such as pregnancy and the m...
TL;DR: There was a strong inverse correlation between population density and the incidence of IDDM and this also applied to the relationship between child populationdensity and incidence.
Abstract: The regional pattern of insulin-dependent diabetes mellitus (IDDM) incidence among children in Finland was analysed applying several methods attempting to describe the geographical variation in occurrence of IDDM. From 1987 to 1991 the number of newly diagnosed cases aged 14 years or less at diagnosis was 1728. The incidence, the incidence rate ratio and the Bayes relative risk (RR) for IDDM were calculated by municipality, by functional area (an urban centre with a subordinated surrounding area) and by area with a population of equal size at risk employing the Geographical Information Systems. The association of IDDM incidence with the degree of urbanization was assessed using the population density as a criterion for the degree of urbanization. The overall mean of the IDDM incidence was 35 per 100000 persons per year. Between municipalities the incidence varied from 4 to 245 per 100000 persons per year, whereas a clear regional pattern was seen among the functional areas and the incidence varied from 26...
TL;DR: It is suggested that glucocorticoid sensitivity is actually much more dynamic and common than previously thought and plays a central role in a wide variety of diseases.
Abstract: Both the unpredictability of side-effects and efficacy of glucocorticoid treatment can be problematic during clinical treatment. Here we discuss the evidence that exists for the hypothesis that individual glucocorticoid sensitivity underlies this problem. We suggest that glucocorticoid sensitivity is actually much more dynamic and common than previously thought. It is postulated that acquired tissue-specific glucocorticoid resistance could play a role in the origin and pathogenesis of depression, autoimmune disorders and AIDS. Moreover, recent genetic research has shown mutations in the glucocorticoid receptor (GR) gene and GR protein which are suggested to play a role in the pathogenesis of leukaemia, hereditary glucocorticoid resistance and Nelson's syndrome. These findings indicate that variations in the GR and in glucocorticoid resistance play a central role in a wide variety of diseases.
TL;DR: In the future, designer androgens with specific beneficial effect on sexual function, mood, bone and muscle mass but with attenuated effects on serum lipid profiles and the prostate gland may be developed.
Abstract: Androgen therapy has been primarily used for replacement therapy in symptomatic hypogonadal men. Other indications under clinical investigation include androgen replacement therapy for older men with age-associated decline in serum testosterone levels, muscle-wasting disease, male contraception and as adjunctive therapy to oestrogen (and progesterone) hormone replacement for postmenopausal women. Recent scientific and pharmaceutical interests led to development of new long-acting injectables, transdermal delivery systems and sublingual preparations. The benefits of androgen replacement must be weighed against the potential risks when androgens are used in conditions other than male hypogonadism. In the future, designer androgens with specific beneficial effect on sexual function, mood, bone and muscle mass but with attenuated effects on serum lipid profiles and the prostate gland may be developed.
TL;DR: The Diabetes Control and Complications Trial taught us to set target blood glucose (BG) and glycohaemoglobin (GHb) goals, to ensure safety regarding hypoglycaemia, to be flexible with insulin and meal planning and to offer frequent contact with diabetes educators, dieticians, psychologists and social workers as well as with diabetologists skilled in intensified management.
Abstract: The Diabetes Control and Complications Trial (DCCT) taught us to set target blood glucose (BG) and glycohaemoglobin (GHb) goals, to ensure safety regarding hypoglycaemia, to be flexible with insulin and meal planning and to offer frequent contact with diabetes educators, dieticians, psychologists and social workers as well as with diabetologists skilled in intensified management. Insulin dosage should be individualized based upon frequent BG monitoring results. Co-ordinated multidisciplinary health care teams provide optimum problem-solving rather than disaster control working with children, adolescents and their families. The patient and the family should form the central core of the diabetes team with outpatient follow-up every month and frequent telephone contact between visits. GHb should be obtained at least every 1-2 months to provide feedback as based on the DCCT intensified treatment cohort. Insulin lispro helps minimize hypoglycaemia and makes insulin administration more convenient and timely. Barriers to improvement should be identified: learning problems, concomitant significant illnesses (epilepsy, coeliac and thyroid disease, asthma) and family problems. Ensure age-appropriate transfer of self-care but continue adult supervision. Educate, motivate and re-educate. Meal planning includes not only carbohydrate counting but also maintaining normal lipids and energy needs for growth and development as well as strategies for activity compensation and hypoglycaemia prevention. Consideration of protein restriction may be required in adolescents with microalbuminuria. Individualized multidose insulin algorithms allow reactive (corrective) decisions based upon capillary BG results plus proactive (anticipatory) decisions to compensate for expected BG changes from changes in activity, food and/or illness using a multidose insulin schedule. The number of insulin injections does not define an intensified insulin treatment programme but rather the ability to target and achieve near-normal BG values as often as possible - without severe episodes of hypoglycaemia. Self BG monitoring is a key to success. Long-term monitoring should include not only frequent GHb but also at least annual fasting lipids, thyroid functions and microalbuminuria as well as dilated retinal exams, blood pressure, growth charting and Tanner staging.
TL;DR: The role of apoptosis in malignant transformation, cancer growth, and response to therapy for gynaecological cancers is reviewed and data on apoptotic index, bcl-2 and Bax expression are presented and discussed in relationship to human papillomavirus expression.
Abstract: Apoptosis is a process of single-cell deletion requiring active participation of the cell in its own demise. First described in 1972, it is now known to play a major role in embryogenesis, tissue homeostasis and neoplasia. Apoptosis can be initiated when DNA damage occurs causing the cell to pause in its reproductive cycle. If the DNA damage is beyond repair, the cell proceeds to apoptotic cell death. When the genetic mechanism(s) involved in the pathway of apoptosis is altered, the cell does not die. Further mutations occur by proliferation and such multiple mutational events can lead to a malignant phenotype and cancer growth. The tumour suppressor gene p53 causes a DNA-damaged cell to rest and attempt repair. If damage is irreparable, p53 levels will continue to increase, initiating apoptosis. Mutation of p53, found in approximately 50% of cancers, can stop the apoptotic process. Increased bcl-2 expression, an apoptosis inhibitor, also plays a role in cellular transformation and cancer growth. Its altered expression occurs in the presence of oncogene expression. This paper reviews the role of apoptosis in malignant transformation, cancer growth, and response to therapy for gynaecological cancers. For cervical cancer and its precursors, data on apoptotic index, bcl-2 and Bax expression are presented and discussed in relationship to human papillomavirus expression. In ovarian epithelial malignancies, the role that apoptosis plays in chemotherapeutic responses is reviewed. The data for endometrial cancer are currently limited to apoptotic index.
TL;DR: Although no breakthroughs in the therapeutic trials on the devastating mitochondrial diseases have so far been achieved, detection of mtDNA mutations offers an accurate diagnosis and is a prerequisite for genetic counselling, being now accessible to most clinicians.
Abstract: Mitochondrial diseases are a group of disorders characterized by morphological or functional defects of the mitochondria, the organelles producing most of our cellular energy. As the only extranuclear site carrying genetic information, the mitochondria add an important chapter into the inheritance patterns of genetic diseases. Mitochondrial DNA (mtDNA) is exclusively maternally inherited in humans, but a mitochondrial disorder may follow either maternal or Mendelian inheritance, depending on the site of the primary gene defect. After the initial finding of mtDNA mutations in rare ocular myopathies in 1988, an explosion in the amount of information on mitochondrial diseases has occurred. Because the mitochondria produce energy in all the tissues, symptoms resulting from mtDNA mutations may originate from any organ system, and the clinical spectrum of mitochondrial diseases has expanded to virtually all branches of medicine. Subgroups of several common diseases, such as diabetes, deafness and inherited cardiomyopathies, have been found to be caused by mtDNA mutations, and some mtDNA defects have been suggested to modify the outcome of diseases primarily caused by other factors, such as Parkinson's or Alzheimer's disease. Although no breakthroughs in the therapeutic trials on the devastating mitochondrial diseases have so far been achieved, detection of mtDNA mutations offers an accurate diagnosis and is a prerequisite for genetic counselling, being now accessible to most clinicians.
TL;DR: In this article, a combination of obesity, glucose intolerance, hyperinsulinaemia and an abnormal lipid profile can be observed in long-term survivors of childhood cancer, and every sixth patient had the triad of o...
Abstract: The improving survival rate of patients with childhood cancer has led to a growing awareness of the long-term effects of malignant disease and its treatment. Various endocrine abnormalities have been reported as frequent long-term adverse effects of cancer treatment in childhood, and among these growth hormone (GH) deficiency is the most common one, especially after cranial irradiation. Besides promoting growth, GH has well-established metabolic effects. Patients with GH deficiency tend to be obese, and obesity per se is also associated with insulin resistance which plays a key role in a cluster of metabolic derangements including glucose intolerance, hypertension, lipid abnormalities and atherosclerotic cardiovascular disease. This condition is known as the metabolic syndrome. Our recent observations indicate that a combination of obesity, glucose intolerance, hyperinsulinaemia and an abnormal lipid profile can be observed in long-term survivors of childhood cancer. Every sixth patient had the triad of o...
TL;DR: Although recent studies have challenged the predictive value of microalbuminuria for later development of overt diabetic nephropathy, albumin excretion rate in the micro albuminuric range and its tracking are still considered reliable markers for prediction of later overt diabetic kidney disease.
Abstract: Nephropathy is the major life-threatening complication of insulin-dependent diabetes mellitus (IDDM). The clinical syndrome is characterized by persistent albuminuria (greater than 300 mg day), a rise in arterial blood pressure, and a relentless decline in glomerular filtration rate leading to end-stage renal failure. The availability of a radioimmunoassay for detecting albumin in low concentrations in urine has allowed the study of urinary albumin excretion rates in diabetics well before clinically persistent proteinuria develops. An albumin excretion rate greater than that in normal subjects and lower than that in macroalbuminuric subjects is called microalbuminuria (range 20-200 microg/min or 30-300 mg/24 h). Although recent studies have challenged the predictive value of microalbuminuria for later development of overt diabetic nephropathy, albumin excretion rate in the microalbuminuric range and its tracking (i.e. annual increase) are still considered reliable markers for prediction of later overt diabetic kidney disease. Overnight urinary collection is preferred for calculation of the rate of albumin excretion, but may be difficult to perform precisely. The albumin:creatinine ratio of the first morning urine sample is a reliable screening method: the microalbuminuric range is considered to be 2.5-25 mg/mmol or 30-300 mg/g (3.5 mg/mol has been proposed as lower limit in females because of their lower creatinine excretion). Irrespective of the procedure used, at least two samples over a 3-6-month period should test positive before microalbuminuria is confirmed and 'persistent microalbuminuria' defined. If the albumin excretion rate is persistently in the microalbuminuric range it is of crucial importance to define strategies and carry out interventions for prevention of decline in kidney function. The goal of achieving the best glycaemic control as early as possible in as many IDDM patients as is safely possible is particularly important in microalbuminuric patients. Although it is unsafe to reduce dietary protein intake drastically, particularly in children and adolescents, moderate decrease of protein intake (i.e. 0.9-1.1/g/kg day) is advisable in diabetic patients from the very beginning of the disease. Timely treatment with an angiotensin-converting enzyme inhibitor, independently of rise in arterial blood pressure, should be considered if improvement of glycaemic control and moderate decrease of dietary protein intake for 6-12 months have failed to reduce the albumin excretion rate. Screening programmes for microalbuminuria and early intervention can substantially modify the natural history of diabetic renal involvement and disease and possibly reduce the incidence of end-stage renal failure.
TL;DR: The mouse studies indicate that mutations in ion channel genes are likely to be responsible for a broad spectrum of clinical phenotypes in human neurological disorders.
Abstract: Analysis of the molecular defects in mouse mutants can identify candidate genes for human neurological disorders. During the past 2 years, mutations in sodium channels, calcium channels and potassium channels have been identified by positional cloning of the spontaneous mouse mutants motor endplate disease, tottering, lethargic and weaver The phenotypes of four allelic mutations identified in the sodium channel gene Scn8a range from ataxia and muscle weakness through severe dystonia and progressive paralysis, indicating that human mutations in this gene could be associated with a variety of clinical syndromes. Mutations of the calcium channel subunits β 4 in the lethargic mouse and α 1A in the tottering mouse have specific effects on cerebellar function. Targeted mutation of ligand-gated ion channels has also been used to generate new models of neurological disease. We will review these recent achievements and their implications for human neurological disease. The mouse studies indicate that mutations in ...
TL;DR: It is maintained that BAL is a useful diagnostic tool for detecting the agents of pulmonary infections in patients with haematological malignancies, especially when the routine microbiological procedures fail, and it also represents a good alternative to more invasive procedures.
Abstract: In the aetiological diagnosis of pulmonary infections in patients affected by haematological malignancies we evaluated the utility of bronchoalveolar lavage (BAL). One hundred and twenty-seven BAL were performed in 119 patients. In our series, we identified the agent of pneumonia in 53.5% of episodes with the best results in aspergillosis, very common in these patients. The previous empirical anti-infective treatment was modified in 14 episodes (11%). The procedure was generally well tolerated and only one patient bled. We maintain that BAL is a useful diagnostic tool for detecting the agents of pulmonary infections in patients with haematological malignancies, especially when the routine microbiological procedures fail, and it also represents a good alternative to more invasive procedures.