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By I. Sven. Gwynedd-Mercy College.

Effect of antioxidants in cardiovascular disease It has been suggested a protective effect of antioxidants such as vitamin C order 80mg super levitra, A (-carotene) and E plus selenium in cardiovascular disease purchase super levitra 80mg without a prescription. Prospective studies so far have documented an inverse relationship between vitamin C intake and cardiovascular disease cheap 80mg super levitra with mastercard, and a strong protective effect of vitamin E supplementation on coronary patients. Finnish and Swiss studies showed that blood levels of ascorbate and therefore a diminished nutritional status of vitamin predicts myocardial infarction. Mediterranean studies showed a 70% reduction in mortality and risk of myocardial infarction independent of the effect on blood pressure and lipids. The infection may contribute to the inflammatory process observed in atherosclerosis. C-reactive protein and alpha-1 antichymotrypsin are acute phase proteins are synthesized in hepatocytes in large numbers in inflammatory processes. Elevated fibrinogen favors these mechanisms and therefore an increased cardiovascular risk. In this way a reduction in diet ary intake in winter for instance, would lead to lower serum ascorbate levels, an increase in susceptibility to infection and the factors haemostatic factors and therefore to an increase in cardiovascular mortality. Increased intake of vitamin C to 90-100 mg/day can increase in these subjects more than 60 umol/L, which has a significant effect on all risk factors. Ascorbic acid and immunity In stress situations the adrenal glands react liberating a large number of active and ready hormones. It has been suggested that 200 mg of vitamin C per day can reduce stress levels caused by these hormones. Megadoses of vita min C increases the body levels of antibodies in animal models (rats stressed and un stressed) having the highest values stressed rats. Healing is characterized by synthesis of connective tissue, whose main component is colla gen. Ascorbic acid supplementation is necessary for healing since this is oxi dized during the synthesis of collagen. The collect ed cells from the blood, peritoneal or alveolar fluid usually contain high concentrations of vitamin C (1-2 ug/mg protein). Guinea pig neutrophils produced H O and destroy staphy2 2 lococci in the same way they do control cells. Neutrophils can avoid self-poisoning absorb extra amounts of ascorbic acid, which can neutralize the antioxidants. Although the addition of large amounts of ascorbate can inhibit myeloperoxidase activity is not altered its bactericidal capacity. It has been an increase in the bactericidal activity in mouse peritoneal macrophages by the addition of ascorbate to the medium. Besides ascor bate increase the motility and chemotactic activity of these cells. The motor functions of cells as the random motion and chemotactic migration of neutrophils and macrophages is dam aged in the absence of vitamin C. Ascorbic acid can also influence the ability of certain cell lines to produce interferon. Vitamin C is also necessary for thymic function and operation of certain cells involved in the production of thymic humoral factor. Thymic content of dehydroascorbate diminishes in di rect proportion to vitamin C intake. The hormonal activity of thymic extracts correlates with thymic ascorbate and inversely with dehydroascorbate. Ascorbic acid and gallbladder The gallbladder disease is highly prevalent in the U. Because of this it has been hypothesized that the deficiency in humans may be a risk factor for this disease in humans. It was also observed a low prevalence of clinical biliary disease between women taking ascorbic acid supplements. In another study, Simon showed that the use of ascorbic acid supplementation correlates with biliary disease among postmenopausal women with coronary disease. Among women who consumed alcohol, the use of ascorbic acid supplementation was associated independ ently with a 50% reduction in the prevalence of gallstones and 62% for cholecystectomies. Reflecting the low prevalence of the disease in men and reduced statistical power to detect such an association. Supplementa tion with ascorbic acid increases the activity of the enzyme up to 15 times compared with the vitamin-deficient animals that develop the formation of cholesterol gallstones. Addition ally there is a hypersecretion of mucin, a glycoprotein that is secreted by the epithelium of the gallbladder, which precedes cholesterol destabilization and gallstone formation. These symptoms result from lymphocytic infiltration and destruction of these tissues. The diagnosis is based on clinical examination of the eyes and mouth, blood tests specif ic (auto antibodies) and biopsy of minor salivary gland (taken from inside the inner lip). However, there is no therapy available that removes" these symptoms because all thera pies are directed at eliminating the symptoms and prevent complications. A frank deficiency of vitamin C causes scurvy, a disease character ized by multiple hemorrhages. The diagnosis of scurvy, is achieved by testing plasma ascorbic acid, low concentration indi cates low levels in tissues. It is generally accepted that ascorbic acid concentration in the lay er of coagulated lymph (20-53 ug/10 leukocytes) is the most reliable indicator of nutritional8 status regarding vitamin C and its concentration in tissues and serum. Pharmacological data Ascorbic acid is specific in the treatment of scurvy; the dose required can best be meas ured by determining urinary excretion after a dose of saturation, depending on the speed at which the saturation is required is the recommended daily dose ranging from 0. In the vitamin deficiency C tissue saturation is achieved with three daily doses of 700 mg c/u, for three days. Harris defined as saturation of tissues, a suffi cient store where an ascorbic acid excretion 50 mg or more occurs in a period of 4 to 5 hours after a dose of 700 mg/day. In their study, Hood study 5 subjects men whose diets did not contain ascorbic acid, for 84 to 97 days. In 1992, Gomez et al, from the National Institute of Medical Sciences and Nutrition Salva dor Zubiran, observed values less than 0. Role of vitamin C in other body disorders It is reported that the diabetic individual has low levels of vitamin C in plasma and leuko cytes, which is our immune defense. However, more clinical studies, in a large scale, are needed to determine whether the supplementation with large doses of the vitamin are bene ficial or not. Some studies have shown that supplementation with 2 g/d, decreased glucose levels in diabetics and reduce capillary fragility. It was men tioned that vitamin C also helps to reduce body glycosylation, which shows abnormali ties in the binding of sugars and proteins. In addition vitamin C reduces the accumulation of sugar sorbitol which damages eyes and kidneys. Vitamin C lowers blood pressure and plasma cholesterol helping to keep the blood flowing and protected from oxidation in a synergistic action with vitamin E.

Pathology (Morphology): When a sodium urate crystal precipitates from super saturated body fluids order super levitra 80 mg with amex, they absorb fibronectin buy 80 mg super levitra otc, complement discount 80mg super levitra free shipping, and number of other proteins of their surfaces. In phagocytizing those protein coated crystals, Neutrophiles release inflammatory mediators resulting in local inflammatory reaction Uric acid crystals may be found intracellularly in leukocytes of the synovial fluid. Extra cellular soft tissue deposits of these crystals (tophi), are surrounded by foreign body giant cells and an associated inflammatory response of mononuclear cells. These granuloma like areas are found in the cartilages and in any soft tissue around the joints. Acute gouty arthritis Initially there is a monoarticular involvement and later in the course of the disease, poly articular involvement with fever is common. Tophaceous Gout - Develops in the untreated patient in the form of tophi in the cartilage, synovial membrane, tendons and soft tissue. Classic locations are on the ear, heads, olecranon bursa, and in the Achilles tendon. Urate stones - Constitute10 percent of all kidney stones Diagnosis: The presence of long needle- shaped crystals that are vely bisfrinegent under polarized light is diagnostic of gout. Summary - Gout represents a heterogeneous group of diseases where there is an increased serum uric acid revel and the depositions of sodium urate crystals in joints and soft tissues around joints and kidneys. Diabetes is a disturbance of carbohydrate metabolism that does not affect the metabolism of lipids and proteins 2. If one monozygotic twin has type 1 diabetes, the other one has or will develop that disease in at least 50% of cases. A family history of diabetes is more common in patients affected by type 1diabetes than type 2. Introduction Environmental diseases include those caused by exposure to harmful substances in the environment, in a sense that it encompasses all nutritional, infectious, chemical and physical in origin. International labor organization has estimated that work related injuries and illnesses kill 1. Environmental diseases constitute an enormous burden financially and in disability and suffering. With this overview of the nature and magnitude of these diseases we will concentrate on the more important once. Agents from the air like microorganisms contaminating food and water, chemical and particulate pollutants found in the air are common causes of diseases. There are six major pollutants, which collectively produce the well-known smog making some big cities difficult to live in. To emphasize on some important points: Ozone is the most important pollutant in that it is produced in large amounts and has serious health consequences. It is highly reactive producing free radicals, which injures airways by virtue of release of inflammatory mediators. When healthy individuals are exposed, they experience mild respiratory symptoms, but its effects are exaggerated in people already having asthma and emphysema. Larger particles are filtered out in the nares or mucocilliary system along the airways. The size of smaller particles helps them to reach into airspaces (alveoli) where they are phagocytosed by macrophages and neutrophils. Inflammatory mediator released from these cells are the once which result in the damage. Here, large number of family members dwell in single rooms where cooking activities are also undertaken. So wood smoke produced in large quantities is accumulated to affect the health of adults and children. It contains oxides of nitrogen and carbon particulates which are irritants predisposing children to repeated lung infection. Tobacco smoke is the commonest pollutant in the house of people living in developed countries but additional offenders are listed in the table below 233 Table 11. Industrial Exposures Industrial workers are exposed to a wide range of organic and inorganic substances, which have different kinds of consequences on their health. Diseases can range from mere irritation of mucosa of airways due to organic fumes to lung cancer due to inorganic dusts and leukemia due to prolonged exposure to benzene and uranium. Pneumoconiosis is a typical example of the conditions which are brought by industrial exposures. Pathogenesis Pneumoconioses is a result of lung reactions towards offending inhaled substances. The reaction depends on the size, shape, solubility and reactivity of the particles. Particles greater than 10m are not harmful because they are filtered out before reaching distal 234 airways. When they are less than 1m in diameter they tend to move in and out of alveoli like gases so that they will not deposit and result in an injury. Silica, asbestos & beryllium are more reactive than coal dust bringing about fibrotic reaction, while coal dust has to be deposited in huge amounts if it has to result in reaction because it is relatively inert. Most inhaled dust is removed out through the ciliary movement after being trapped in the mucus linings. The more reactive particles activate macrophages to release fibrogenic factors, toxic factors and proinflammatory factors. Free radicals: reactive oxygen and reactive nitrogen species that induce lipid peroxidation and tissue damage 2. A- Coal workers Pneumoconiosis _Due to coal dust B- Silicosis _Due to silica C- Asbestosis _Due to asbestos D- Berylliosis _Due to beryllium Coal workers pneumoconiosis Since earlier times of industrialization it has been noticed that coal miners were drying of black lung complicated by tuberculosis. Coal dust mainly contains carbon but has a variety of trace metals inorganic mineral and crystalline silica. Anthracite (hard) coal contains significantly more quartz than bituminous (soft) coal. Anthracite (hard) coal is more frequently associated with lesions in the lungs; hence the name pulmonary anthracosis is coined for coal induced pulmonary lesions. Anthracosis:- Where pigments are accumulated without cellular reaction and symptoms ii. Simple coal workers pneumoconiosis With minimal cellular reaction and little or no pulmonary dysfunction iii. Progressive massive fibrosis:- With extensive fibrosis and compromised pulmonary function Morphology Pulmonary arthracosis - Macrophages in the alveoli and interstitium are found laden with carbon pigments. These macrophages are also seen along the lymphatics including pleural lymphatics or lymphoid tissue along bronchi and lung hilus. Coal macules constitutes of carbon-laden macrophages aggregated, coal nodule is when the macule additionally contains collagen fibers. It is characterized by coal nodules intermingled with collagen fibers with central necrosis, size ranging from 2cm to 10cm. When it progress to progressive massive fibrosis in minority of cases it results in pulmonary hypertension and corpulmonale. Asbestos Related Disease Asbestos is a generic name that embraces the silicate minerals that occur as long, thin fibers. Asbestosis refers to the pneumoconiosis that results from the inhalation of asbestos fibers Pathogenesis Asbestos fibers are thin and long so that they can reach the bifurcations of bronchioles and alveoli.

In the course of the last year she gradually developed complaints in her left knee buy super levitra 80 mg on line, right above the kneecap buy 80mg super levitra, with pain and tenderness as well as stiffness discount super levitra 80 mg with mastercard. Her complaints were particularly evident when she was standing on her left leg and shooting and running. She had never before had any symptoms from her left knee, and there was no known trauma to her left knee. A medical specialist in a clinical examination diagnosed her with left-sided jumpers knee (patellaris tendinitis), consistent with the tendon attachment to the upper part of the kneecap, which was confirmed by an ultrasound examination. In the course of her 3 years as a professional player she practised on an average 4-5 times a week and from 3 to 5 hours at a time. The training alternated between handball training and various handball exercises, stamina training by means of running, and various strength and weight-lifting exercises. To this should be added games about once a week, which, like most of the training apart from running, took place indoors in a sports centre 1 The European version of handball 128 on a hard surface. Practice as well as games were characterised by quick changes in pace and many quick starts and stops as well as jumping up and down, which led to stresses on the left kneecap tendon. For more than 3 years the handball player played handball and practised more than 12 hours per week on average and after 3 years she was diagnosed with left-sided jumpers knee consistent with the tendon attachment at the upper part of the kneecap. Training as well as games were characterised by high pressure on the kneecap in connection with jumping/running with frequent starts and stops (acceleration/deceleration) while flexing and extending of the knee. In addition, by far the major part of the load occurred indoors on a hard surface. Example 3: Recognition of right-sided jumpers knee (professional badminton player for 4 years) A 28-year-old woman had for 4 years worked as a professional badminton player in a big Danish club when she developed a right-sided jumpers knee with pain, tenderness, swelling and slightly restricted motion of the knee. Her career as a professional badminton player had involved hard training for several days a week and matches more or less every weekend. The matches involved jumping/running with continued starts/stops while flexing and extending her knee. The badminton player suffered an exposure relevant for the development of jumpers knee, in the form of jumping/running 25-30 hours a week for several years and with frequent starts and stops while flexing and extending the knee. Example 4: Claim turned down left-sided jumpers knee (professional football player working part time) A 25-year-old man in a clinical examination was diagnosed with left-sided jumpers knee (tendinitis patellaris) consistent with the tendon attachment to the lower part of the kneecap. He was a part time employee in a bank and worked 25 hours a week as a bank adviser. Furthermore he was employed the last 2 years on a part time contract in a Jutland League football club. The training mostly consisted in football playing and exercises on a grass course. One of the 3- 4 weekly training sessions consisted in intensive weight-training and strength training. Even if there is a diagnosis of left- sided jumpers knee, the load as a semi-professional football player was not sufficient. The football player on an average practised and played games 8 hours a week, including 2 hours of weight-training. Therefore he does not meet the requirements for exposure in the form of jumping/running with quick and frequent starts and stops while flexing and extending the knee at least 12 hours a week, perhaps in combination with intensive weight-training at least 5 hours a week or playing on a hard surface, which might give grounds for reducing to 8 hours the requirement to the total weekly load. Nor are there grounds for submitting the claim to the Occupational Diseases Committee, the football player not having experienced any extraordinary knee loads constituting any particular risk of developing left-sided jumpers knee. Example 5: Claim turned down right-sided jumpers knee (professional football player for 6 months) 129 A 25-year-old female football player was diagnosed by a medical specialist with right-sided jumpers knee with severe and chronic degeneration (tendinosis patellaris), consistent with the tendon attachment to the lower part of the kneecap. By then she had been a professional football player for 6 months and practised several hours a day, including approx. In addition she had played 20 whole football games as a professional in the course of 6 months. Games as well as training were characterised by jumping/running with frequent starts and stops while bending and extending the knee, and there was pressure on the kneecap. It appeared that a year previously she had jumpers knee in the same place, which developed in connection with football playing in her leisure time as member of an ordinary football club. But there had been a continued tendency to pain in the knee after severe loads during training. Even though the stresses as a professional football player for 6 months were sufficient to develop jumpers knee, the football player previously, and without correlation with work, suffered from jumpers knee. This substantially increases her disposition to develop the disease again due to chronic degeneration of the tendon attachment. Nor are there any grounds for submitting the claim to the Occupational Diseases Committee. This is because it was not possible to recognise the disease, it not being likely beyond reasonable doubt that the disorder was caused, solely or mainly, by working as a football player. Medical glossary (jumpers knee) Latin/medical term English translation Anterior In front of Arthritis Inflammatory degeneration of one or several joints Arthrosis Degenerative arthritis Arthroscopy Scoping or looking into a joint Bursitis Inflammatory degeneration of a bursa Chondromalacia patella Softened cartilage behind the knee cap Femoral Of the femur Femoro-patellar pain Pain in the joint between kneecap (patella) and thigh bone (femur) syndrome Femur Thigh bone Lateral On the outer side Ligamentum cruciatum Cruciate ligament Ligamentum patellae The common tendon, which continues from the patella (knee cap) to the tibia (shin bone) 130 Meniscus lateralis External meniscus, half-moon-shaped cartilage disc between thigh bone and shin bone Meniscus medialis Internal meniscus, half-moon-shaped cartilage disc between thigh bone and shin bone M. Hand-arm vibration disorders (white finger, peripheral neuropathy, degenerative arthritis (C. Exposure requirements for recognition of degenerative arthritis (arthrosis) of wrist and elbow joint 1. Item on the list The following vibration-induced diseases of the hand and arm are included on the list of occupational diseases (group C, item 3): Disease Exposure C. Vibration-induced white finger Work with heavily vibrating hand tools (hand-arm (Raynauds syndrome, Raynauds disease) vibration) C. Degenerative arthritis of elbow or wrist (arthrosis primaria/other specified forms of arthrosis) Carpal tunnel syndrome: See item C. The diagnosis is made against the background of a combination of the injured persons subjective complaints (symptoms) a clinical objective examination The clinical diagnosis of white finger is in principle made in a clinical objective examination. If the clinical objective examination cannot immediately confirm the diagnosis of white fingers, an attempt can be made at documenting the disease in the ways stated below. If the attempt at provoking an attack of white fingers is not successful, the disease cannot be deemed to have been documented and the claim cannot be recognised on the basis of the list. As the attacks are triggered after exposure to cold, part of the examination can also be made by way of a simple cold provocation test where the person in question keeps his/her fingers under cold running water or inserts the finger in ice water for 5 minutes in order to provoke a white-finger attack Photo documentation. When an attack occurs, a witness confirms the white fingers by way of a photo of the person reporting the white fingers. The photo needs to show the face and hands of the person in question Certification by a doctor. An examining doctor (for example a specialist of occupational medicine) certifies that, in the examination, he or she has seen white finger attacks in the person in question with a detailed symptom description as set out below Perhaps a vascular-physiological examination. The examination is performed in a special laboratory with registration of finger blood pressure before and after finger cooling.

This is interesting since it appears that the promoters of some of the developmental regulatory genes are controlled simultaneously by activators and repressors order super levitra 80 mg. These genes are normally silent in pluripotent stem cells cheap super levitra 80mg overnight delivery, but may be expressed upon differentiation super levitra 80 mg visa. According to this model, some lineage-specic genes are marked with both repressive and active modications at the same time. Specically, some of the neural-specic genes continue to be expressed (H3K4me3), but lose their repressing (H3K27me) histone modications. In contrast, inactive pluripotent genes preserved the repressor mark (H3K27me3), while losing the activator (H3K4me3) changes. These two groups have the opposite functions in modifying gene expression within PcG complexes and are crucial in early development and differentiation. Oct4 can up-regulate Jmjd1a and Jmjd2c genes, which are responsible for H3K9me2 and H3K9me3 demethylation. Predominantly, histone demethylases play a prominent role in self-renewal and pluri- potency. Yamanakas group Epigenetics in Human Disease used the same cocktail in mouse, while Thomsons group replaced c-Myc and Klf4 with Nanog and Lin28. It has been postulated that c-Myc and Klf4 488 modify the organization of chromatin enabling Oct4 and Sox2 access to their targets, thereby increasing the expression of downstream genes [61]. It has been proposed that c-Myc induces the up-regulation of histone acetyltransferase gene (Gcn5), which is a key factor in histone structure, there by improving the accessibility of target genes to Oct4. Klf4 is also acetylated by p300 (acetyl transferase protein) and has the capacity to control gene transcription through regulation of histone acetylation [77]. As mentioned earlier, two histone demethylases, Jmjd1a and Jmjd2c have been identied to be part of the groups of the genes regulated by Oct4 [60]. A positive feedback loop between transcriptional circuitry and epigenetic modication has also been found. In 1957, Waddington proposed his famous epigenetic landscape model by comparing the early developmental differentiation with a ball travelling downward a canal. This journey starts from a fertilized totipotent embryo and ends up as different lineage-committed cells. According to this developmental model, cells inside the canal move through various one-way branched valleys and select their nal irreversible cellular fates during this trip [79]. The cells can now move back within the valley from somatic cell to pluripotent state or even transdifferentiate from one lineage to the other without returning back to the pluripotent state [80]. As they begin their journey backwards along the slope toward pluripotency, some epigenetic obstacles hinder the cells from rolling back and consequently they will achieve self-renewal capability. The second group of cells will be partially reprogrammed and lose their pluripotency state and differentiate into specic cell lineage without constant expression of reprogramming factors. The third category may trans-differentiate as a result of insufcient and improper expression of ectopic factors. This event requires other downstream activated epigenetic modiers, since the factors used in direct reprogramming do not have known demethylating activity. Other cells are trapped inside a semi-reprogrammed state due to inefcient epigenetic modication and travel back down their valley in the absence of ectopic expression of pluripotency factors (2). Some of the cells may move to other neighboring valleys and transdifferentiate into other cell types due to inefcient expression of reprogramming factors (3). Several studies indicate that the H3 and H4 histones within the Oct4 and Nanog promoters are hyperacetylated [84,85]. It mediates chromatin modication by increasing the expression of Gcn5 recruiting it for the modication of target genes [86]. These two histone modications show the bivalent chromatin characteristics of pluripotent genes, which are accomplished by simulta- neous methylation at H3K27me3 and H3K4me3. Any variation in these epigenetic apparatus may alter gene expression, which in turn has enormous and critical clinical consequences. Cancer comprises a multistep process wherein both genetic and epigenetic abnormalities work together to transform a normal cell into an abnormal malignant tumor cell. Cancer is generally characterized by global hypomethylation and gene-specic hypermethylation [91]. Recent studies have shed light over the role of stem cell chromatin marks in cancer development. Also, methylation of H3K27 by polycomb protein, along with the previously mentioned repressive marks, targets some genes for de novo methylation by methyltransferases in cancer [99]. Understanding the exact epigenetic mechanism governing cancer cells can have signicant therapeutic consequences. For instance, it has been revealed that any modication in chro- matin organization can affect normal development and cellular tumorigenic transformation [100]. Elucidation of chromatin defects, which transform a normal cell to a malignant tumor, may lead to the development of new designs for cancer treatment as well as its early diagnosis. Recent studies have evaluated the role of epigenetic defects in the onset of various pediatric and adult neurodegenerative disorders [103] (Table 24. This overexpression inhibits the activity of Reelin protein in patients with bipolar disorders and psychosis, which is normally needed for proper memory composition and normal neurotransmission [104,105]. Some studies revealed the connection between the hypomethylation of presenilin I gene and its up- regulation and beta-amylois production. Also, a role for folate-mediated methylation in Alzheimers disease has been suggested [107,108]. Recently, a connection between genetic/epigenetic changes and autism has been proposed [109]. Autism is a disease of neural development in the brain which impairs an individuals normal development of social and communication interactions. Based upon all of these ndings, there may be a potential future role for epigenetics in the diagnosis and treatment of neurological diseases. With this tool, the molecular mechanism of disease, as well as drug and therapeutic screening, can be performed using derived affected cells. The mutation affects postnatal neural development and results in communication defects and mental retardation in affected children. Differentiated cells demonstrated abnormalities in neural characteristics including smaller size, modied calcium signaling, diminished synapse, and electrophysiological abnormalities [112]. Such state-of-the-art cell characterization is going to open a new era in molecular medicine for revealing mechanisms of disease and new approaches for drug screening. Genomic imprinting is a genetic event by which particular gene loci become transcribed in a parent-of-origin-determined way. This means that the phenotype triggered from a certain locus is differentially altered by the sex of the parent providing that specic allele. These epigenetic hallmarks are placed during germline establishment and are preserved throughout the lifetime of an organism. Multiple genetic diseases are associated with defects in imprinting loci such as Angelman and PradereWilli syndromes, BeckwitheWiedemann syndrome and SilvereRussell syndrome [114]. It is characterized by speech impairment, frequent seizures, intellectual disability, and ataxia and affected children have typically a happy and excitable demeanor.

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