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Control of sand fly larvae remains impossible because the breeding sites of most species are unknown discount 50 mg atenolol with visa, and even when they can be identified it is usually impractical to do any thing to reduce larval numbers order atenolol 50 mg without a prescription. For example in some areas of north Africa clearing vegetation around villages reduces gerbil populations generic atenolol 50 mg overnight delivery. The tsetse is the vector of African trypanosomiasis or African sleeping sickness buy atenolol 50 mg free shipping, which may be caused by either Trypanosoma brucei gambiense or Trypanosoma brucei rhodesiense. Occurrence Tsetse flies are generally confined to the area of tropical Africa, south of the Tropic of Cancer. Their wing at rest is closed over one another like a closed scissors, and the tip of the wing is then extended beyond the abdomen. They can be distinguished from other large biting diptera by their forward, pointing mouth part and high pitched buzzing sounds. They are somewhat more restricted between the thorax and the abdomen than most other flies and have wings that fold over the abdomen in a scissor-like fashion that extends well beyond the abdomen. The bayonet-like proboscis extends outward in front of the head when the fly is in a resting position. The matured larvae after deposited burrow in to the ground and pupate and finally emerge as adult fly. They bite by day or at dusk Tsetse fly is greatest single hindrance to animal production and agricultural 119 development in tropical Africa. Adult tsetse flies can transmit trypanosomiasis (African sleeping sickness) to man and animals. Both males and females are avid blood feeders and can fly at speeds over 20 miles per hour. Unlike most flies, the female tsetse fly gives birth to a full grown larva, one at a time every 10 to 12 days over her lifetime. All tsetse flies, both male and female feed on blood having their mouth parts adopted to pierce and suck blood of their hosts. The proboscis is connected with salivary duct that brings salivary secretion and salivary secretion contains anti-coagulants that keep blood liquid during passage to the digestion portion - They are attracted by large moving objects and carbon dioxide. Another human form of trypanosomiasis (Human American Trypanosomiasis) occurs in the Americas and is known as Chagas disease. Human African Trypanosomiasis or Sleeping Sickness Human African trypanosomiasis, known as sleeping sickness, is a vector-borne parasitic disease. Trypanosoma, the parasites concerned, are protozoa transmitted to humans by tsetse flies (glossina). Tsetse flies live in Africa, and they are found in vegetation by rivers and lakes, gallery-forests and vast stretches of wooded savannah. Congolense Sleeping sickness occurs only in sub-Saharan Africa, in regions where tsetse flies are endemic. For reasons as yet unknown, there are many regions where tsetse flies are found, but sleeping sickness is not. The rural populations that live in such environments and depend on them for agriculture, fishing, animal husbandry or hunting are the most exposed - along with their livestock - to the bite of the tsetse fly. Sleeping sickness affects remote and rural areas where health 121 systems are least effective, or non-existent. It spreads with socio- economic problems such as political instability, displacement of populations, war and poverty. Within a given focus, the intensity of the disease can vary considerably from one village to the next. Human African trypanosomiasis takes two forms, depending on the parasite involved: Trypanosoma brucei gambiense (T. A person can be infected for months or even years without obvious symptoms of the disease emerging. It is more virulent than the other strain and develops more rapidly, which means that it is more quickly detected clinically. Major epidemics There have been three severe epidemics in Africa over the last century: one between 1896 and 1906, mostly in Uganda and the Congo Basin, one in 1920 in several African countries, and one that began in 1970 and is still in progress. The 1920 122 epidemic was arrested due to mobile teams systematically screening millions of people at risk. After that success, screening and effective surveillance were relaxed, and the disease has reappeared in endemic form in several foci over the last thirty years. The geographical distribution of the disease Sleeping sickness threatens over 60 million people in 36 countries of sub-Saharan Africa. Only 3 to 4 million people at risk are under surveillance, with regular examination or access to a health centre that can provide screening. Detection of the disease calls for major human and material resources, such as well-equipped health centers and qualified staff. Because such resources are lacking, most people with sleeping sickness die before they can ever be diagnosed. The 45 000 case figure shows not the true situation but rather the lack of screening in many foci. Reported cases in recent years are from countries where surveillance coverage is no more than 5%. In certain villages of many provinces of Angola, the Democratic Republic of Congo and southern Sudan, the prevalence is between 20% and 50%. In each country the spatial distribution of the disease is very diverse; it is found in foci and micro-foci. Infection and symptoms The disease is transmitted with the bite of the tsetse fly. At first the trypanosomes multiply in the blood, and that process can last for years with T. Causative agent Protozoan parasites of the genus Trypanosoma, which enter the blood stream via the bite of blood Feeding tsetse flies (Glossina spp. Transmission Its transmission is via the bite of infected bloodsucking male and female tsetse flies that transfer the parasites from human to human. Tsetse flies can acquire parasites by feeding on these animals, or on an infected person. Early symptoms, which include fever and enlarged lymph glands and spleen, are more severe and acute in T. A range of symptoms including headache, anaemia, joint pains and 126 swollen tissues follows early signs; advanced symptoms include neurological and endocrine disorders. As the parasites invade the central nervous system, mental deterioration begins, leading to coma and death. The early phase entails bouts of fever, headaches, pains in the joints and itching. The second, known as the neurological phase, begins when the parasite crosses the blood-brain barrier and infests the central nervous system. This is when the characteristic signs and symptoms of the disease appear: confusion, sensory disturbances and poor coordination. Disturbance of the sleep cycle, which gives the disease its name, is the most important feature. If the patient does not receive treatment before the onset of the second phase, neurological damage is irreversible even after treatment. The two human and animal forms of the disease remain a major obstacle to the development of rural regions of sub-Saharan Africa: human loss, decimation of cattle and abandonment of fertile land where the disease is rife. The very complex developmental cycle of the trypanosome within the tsetse vector is further complicated by several of other factors related to the biology of the vector, pathogen, and host. In addition, there are wide intraspecific variations in both morphology and pathogenicity of trypanosomes. Certain parasite antigens that stimulate production of protective antibodies by the host change before the parasites are completely eliminated; new antibodies are then produced by the host, and the parasites change their antigenic constitution again to maintain themselves. Animal trypanosomiasis is greatest hinderance in animal production and agricultural development in tropical Africa. In the past, this has involved extensive clearance of bush to destroy tsetse fly breeding and resting sites, and widespread application of insecticides Control Measures: - Clearing forest and bushy habitat of tsetse clear 10 - 12 meters on both sides of forest crossing roads. Trapping adults, killing pupa use nets or / odor attracted traps, use animals as bait / visual targets to trap, Inspection of people and treating cases. Since the vector ecology varies, it is necessary to identify the species common to a specific area before taking appropriate pest management measures. Strict vegetation management includes clearing dense brush along waterways and around contaminated areas (preferably up to a mile away if possible). Aircraft pesticidal applications that give a small droplet size (approximately 250 microns or less) can be effective in areas where it is not practical to eliminate or reduce thick brush for at least a quarter of a mile.

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The femoral nodes are a tuberculous lymph node with the naked eye discount atenolol express, and in 70% often enlarged order discount atenolol on line, especially if no shoes are worn and the feet of cases by microscopy best 100 mg atenolol. You will often be able to get extremely important Excising cysts may not be easy generic 50 mg atenolol amex, especially in the neck: information from examination of lymph nodes. Excision biopsy of a lymph node in the neck may not be You should not use a trucut biopsy needle (24-3) for a neck easy, and it will be worthwhile to develop a cytology node. Most useful biopsies come from the neck or axilla; the groin often has low-grade infection and fibrosis and Macroscopic examination of a lymph node is useful if no unless the node is obviously abnormal, it will not be worth histology is available removing. A node may feel quite superficial, but then on exploration be under important structures, so familiarize Do not forget that not every swelling in the neck is a lymph yourself with the anatomy of the region you are operating node! Therefore, make sure you have a good supine; if the hair is likely to be in the way, shave it but operating light, and preferably diathermy available. Make a 5cm incision in the If not, be certain to have sufficient haemostats, gauze and groin crease or over the node, away from anywhere where a suction that is working available. Deepen the wound through and take a representative sample: do not try to be heroic the fascia. Keep the wound edges apart with self-retaining and excise a huge node without seeing what is underneath! There are many superficial veins; tie these or Try to handle the node as gently as possible because you diathermy them to keep a dry field. There are superficial distort the architecture if you are rough, and this makes nodes just below the inguinal ligament and around the long histological interpretation difficult. Tuberculous lymphadenitis (if fine needle aspiration is damaged, clamp it and ligate it. Suspicion of metastatic disease with the primary you are prepared for a block dissection (17. Make an incision over the node in the A normal node has a pale colour and is uniform; direction of Langers skin lines, and extend it 1cm to either you may be able to distinguish the cortex and medulla with side of the node. Deepen the incision and make sure histology and so you should not assume it to be normal; of haemostasis. Keep the wound edges apart with a however direct examination of nodes can give valuable self-retaining retractor. Under a good light, look for caseation or tuberculomas which are present in 75% of tuberculous nodes. Dissect gently down to the node, dividing only what you Pus within the node or showing purulent necrosis suggests can see. You should examine the pus and a smear of the cut see this to tie it off, or diathermy it. Ensure there is no bleeding; if there is some oozing, close the wound with interrupted non-absorbable 3/0 If you see hypervascular nodes, especially with a sutures around a small Penrose drain (4. Make a transverse If you cannot control the bleeding, do not plunge incision at least 5cm long and deepen it through the haemostats blind deep into a cavity. This exposes the fat of the under a good light so you can see properly, and apply a axilla and the tail of the breast; here are the pectoral group haemostat to the bleeding vessel. There are more nodes adjacent and behind the from a major vein or artery, and you cannot control it, axillary vein which is at the upper border of the axillary pack the wound again and press on it. Once you have sampled the node, ensure there is no When everything is ready, extend the incision to get good bleeding and close the wound as above. If all this fails, tightly pack the A very noticeable facial feature is bilateral parotid gland wound, wait 24hrs and re-explore the next day. The parotids may feel lumpy or cystic or both; aspiration produces a yellowish fluid, If the node is actually not a node but a tumour occasionally opaque. Repeat aspiration is often necessary, (benign or malignant), proceed as above to try to excise it and superadded infection not uncommon. If it is stuck, just take part of it for biopsy, may become quite grossly enlarged, particularly with and close the wound. If it bursts, try to remove as much of the lining facial nerve palsy is a real hazard. Bilateral parotid enlargement may be caused by: If you find malignant melanoma (34. Look for the primary, and make sure that is widely (3) sarcoidosis, excised then, if necessary with skin grafting of the defect. If these are not treated, abscesses may (2) actinomycosis, form and discharge through the skin, to leave (3) tumours (17. After many months, these abscesses may heal The distinction may be difficult and fine needle aspiration spontaneously, to cause severe fibrosis and lymphatic is very helpful. This is due to Facial nerve palsy implies malignancy of the parotid hypersensitivity to tuberculoprotein. There are three types: cannulate the duct and inject contrast to get a sialogram (1). Remember the facial nerve lies Somalia & Ethiopia owing to frequent chewing of Qhat. It afflicts children from mouth clear; otherwise the endotracheal tube has to be 2-16 (mean age 7); is unknown under 1, and is rare strapped well out of the way on the opposite side of the >20yrs. Put in a pharyngeal pack with a long thread and in some areas it is as common as all other childhood hanging out of the mouth, so it is not forgotten! In endemic areas the genome of the mouth open with a gag and get an assistant to hold the Epstein-Barr virus is present in 100% of tumours; tongue out of the way by pulling on it with a towel-clip. Find the parotid duct opening and pass a probe along it; It presents as: put a 2/0 stay suture 5mm above and below the papilla and (1). Swelling of the mandible or maxilla (1-4 quadrants): then cut along the duct starting at the orifice till you reach the commonest presentation in Africa. Proptosis, which may be marked, but is usually not wall and mucosa of the mouth, and keep it like that. Intra-abdominal tumours, especially of the and it is more likely a stone will pass naturally. Lymphomatous masses can also occasionally better to remove the whole gland with the stone. Lymph node enlargement is also uncommon, except in a ligature round the duct proximal to the stone to prevent the abdomen. Firm, painless, non-tender swellings, sometimes of Prepare the mouth as for a parotid sialolithotomy. When the bone is involved, radiographs then cut directly onto the stone and lever it out. Instead cut back on the parotid duct as importance of: far as you can, and introduce an embolectomy catheter down it and try to manipulate the stone out by distending (1). If this fails or you central nervous system is involved, there is about a 50% do not have an embolectomy catheter, try to crush the chance of surviving 4 more years, and probably long-term. If you can remove more than 90% of it, you will should alert you to the diagnosis. Unfortunately, you are unlikely Carry out a fine-needle aspiration for cytology (17. Resection of most of the tumour before An abdominal swelling: tuberculous lymph nodes (17. The excretion of cyclophosphamide in the urine can Stage B Two sites excluding abdomen, thorax, cause a haemorrhagic cystitis. Both cyclophosphamide alone, and the 3-drug regime described below, give a complete response rate of 95%. Cyclophosphamide alone gives a relapse rate of 50 to 60% (but only 10% in stage A disease); the 3-drug regime reduces this to 30%. If there is no relapse within 6 months of starting treatment, there is a >90% chance of a complete cure. Relapse after 1yr is unlikely, if there is complete response to the initial treatment. If there is a large intra-abdominal mass, or an accessible mass elsewhere, try to resect it urgently.

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In C plants both light reactions and 3 dark reactions occur in mesophyll cells generic atenolol 100 mg visa, whereas in C4plants buy atenolol 50 mg on-line, the mechanism of photosynthesis requires two types of photosynthetic cells mesophyll cells and bundle sheath cells generic 50 mg atenolol. One takes place in chloroplasts of mesophyll cells and another in chloroplasts of bundle sheath cells buy discount atenolol 100 mg. The first step involves the carboxylation of phosphoenol pyruvic acid in the chloroplasts of mesophyll cells to form a 4C compound, oxaloacetic acid. This reaction is catalysed by the enzyme phosphoenol pyruvate carboxylase Phosphoric acid 2. The pyruvic acid produced in step (3) is transferred to the chloroplasts of mesophyll cells where it is phosphorylated to regenerate phosphoenolpyruvic acid. Examples of C plants are rice, Examples of C plants are maize, 3 4 wheat and potato. But in certain green plants, there are two distinct types of respiration photorespiration and dark respiration. Respiration that occurs in photosynthetic tissues in the presence of light and results in increased rate of carbondioxide evolution is called photorespiration or light respiration. Photorespiration involves three organelles chloroplasts, peroxisomes and mitochondria. From the chloroplast, the glycolic acid diffuses into the peroxisome where it is oxidised to glyoxalic acid and hydrogen peroxide. The aminoacid serine is taken to peroxisome where, it is converted into hydroxy pyruvic acid. Photorespiration is also known as photosynthetic carbon oxidation cycle or C2 cycle. However, photorespiration utilizes part of the light energy and saves the plant from photooxidative damage. Difference between photorespiration and dark respiration Photorespiration Dark respiration 1. It takes place only in photo - It takes place in all living cells in the synthetic cells in the presence mitochondria. It is the function of chloroplast, It is the function of mitochondria peroxisomes and mitochondria. Factors affecting photosynthesis Photosynthesis is influenced by both environmental and genetic factors. According to Blackmann who postulated Law of Limiting factor in 1905, photosynthesis is limited by slowest step of the most limiting factor in the pathway. This means that at a given time, only the factor that is most limiting among all will determine the rate of photosynthesis. Light between the wavelength of 400nm to 700nm is most effective for photosynthesis and this light is called photosynthetically active radiation. Photochemical reactions and dark reactions of photosynthesis respond differently to temperature. Photochemical reactions in the thylakoid remain unharmed by temperature, whereas the enzymatic dark reactions get influenced adversely. Since, nitrogen is a basic constituent of chlorophyll and all enzymes involved in dark reactions, any reduction in nitrogen supply to plants has an adverse effect on photosynthesis. The photosynthetic enzymes also get inactivated resulting in reduced rate of photosynthesis. A few branches of Hydrilla are kept in a beaker containing pond water in which a small amount of sodium bicarbonate is dissolved. The branches are covered with a glass funnel and a test tube full of water is kept inverted over the Test tube stem of the funnel as shown in the figure. The gas Beaker bubbles may be observed from the ends of hydrilla branches kept within the glass funnel. These gas bubbles are collected Water in the test tube by the downward displacement of water. When a burnt splinter is Hydrilla taken near the mouth of the tube, it glows brightly and proves that the gas is oxygen. Ganongs light screen experiment Ganongs light screen experiment demonstrates that light is essential for photosynthesis. When a pot plant is kept for 48 hours in dark room, the leaves become free from starch. Ganongs light screen is a clip like instrument with a tin foil disc having a star shaped opening through which light can enter. The advantage of light screen is to allow free ventilation and at the same time it cuts off light. The light screen is fixed to a leaf of the destarched potted plant as shown in the figure. The Ganongs light screen experiment demonstrates that light is essential for photosynthesis. Mode of nutrition Autotrophic nutrition Most of the green plants are self- dependent, because they synthesize their own food materials by photosynthesis. Epiphytic plants are not parasitic on these trees, but they only make use of the place to grow. Clinging roots fix the epiphytes to the bark of the tree and also absorb the little nutrients found in the debris accumulating on the bark. These roots are usually green and covered by a spongy tissue called velamen which absorbs the moisture in the air as well as rain water. Heterotrophic nutrition Due to lack of chlorophyll or nitrogen defeciency, some plants have to depend on other plants, insects or dead organic matter for their food. Heterotrophic plants are grouped into saprophytic, parasitic and insectivorous plants. Cuscuta Tentacle Parasite Haustorium Host stem Partial parasite Insectivorous plant eg. Parasitic plants Some plants get their nourishments from other living plants or animals. The plants or animals from which the parasites get their nourishments are called hosts. Parasites have some special roots, which penetrate the host plants and absorb food from the phloem and water and minerals from xylem. Therefore, it is totally dependent on the host stem for organic food materials, water and minerals. It twines around the stem of the host and sends haustoria into it to absorb nourishments. The haustoria of these plants have connection only with the xylem of the host to absorb water and mineral salts. Insectivorous plants Though insectivorous plants are capable of manufacturing carbohydrates by photosynthesis, they are not able to synthesize enough proteins due to the deficiency of nitrogen. This fluid shines in sunlight and appears as dew; hence the plant is called sundew plant. The digested food is finally absorbed by the leaves and the tentacles again come in their original straight position. Chemosynthesis Chemosynthesis is a process by which certain organisms synthesize carbohydrates by using energy obtained by the oxidation of inorganic substances. Most of the bacteria obtain their food materials from external sources and they cannot synthesize their food by themselves. Whereas, some bacteria are capable of synthesizing their food either by photosynthesis or chemosynthesis. Organisms which use sunlight energy for synthesis of food materials are called photosynthetic organisms or photoautotrophs. Those organisms which use chemical energy for the synthesis of carbon compounds are called chemosynthetic organisms. There are two groups of chemosynthetic organisms namely, chemosynthetic autotrophs and chemosynthetic heterotrophs. Chemosynthetic autotrophs Examples for chemosynthetic autotrophs are Nitrosomonas, Beggiatoa. The energy liberated during this process is used for the synthesis of carbohydrates. For example, en- ergy is released when glucose is oxidised in the process of respiration.

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During their development from single progenitor cells to endo- metriotic lesions leading to various symptoms order atenolol with paypal, endometriotic cells presumably need to make a series of sequential buy generic atenolol 100mg on line, perhaps dichotomous order atenolol 50 mg free shipping, and irrevocable cell fate choices cheap atenolol online mastercard. To maintain cellular identity, the gene expression program must be iterated through cell divisions in a heritable fashion by epigenetic processes. Post-translational modications of protein products, localization and higher-order interactions with other transcription factors, coac- tivators or corepressors are one set of mechanisms through which transcription can be controlled at another level. In light of these, epigenetics is very likely to be involved in maintaining cellular identity in ectopic endometrial cells. It is expressed in human endometrium, and its expression is dramatically increased during the midsecretory phase of the menstrual cycle, corresponding to the time of implan- tation and increase in circulating progesterone [77]. In mouse, surgical induction of endometriosis also resulted in the down- regulation of Hoxa10 as well as hypermethylation [83]. Besides serving as a validation of the human observation, these two experimental studies also challenge the view that endometriosis may originate from eutopic endometrium that harbor certain, yet to be identied, molecular aberrations through retrograde menstruation. What is puzzling and remains unanswered is just how endometriotic lesions situated in the peritoneal cavity apparently result in molecular genetic changes in eutopic endometrium. It is well-known that there is a general tendency of progesterone resistance in endometriosis [1]. The discrepancy is likely due to the use of different materials: the former study used endometriotic epithelial cells harvested through laser capture microdis- section while the latter used tissue culture, which consists of several, mixed cell types. Since these genes are involved in de novo as well as maintenance methylation, their aberrant expression suggests that aberrant methylation may be widespread in endometriosis. Further study by the same group found that a stretch of CpG demethylation within a non-promoter CpG island of the aromatase gene in endometriotic cells while the same region is heavily methylated and associated with methyl- CpG-binding proteins in endometrial cells [93]. Endometriotic cells are found to lack the intercellular adhesion protein E-cadherin, a known metastasis-suppressor protein in epithelial tumor cells whose deregulation also seems to be associated with invasiveness of endometriotic cells [94,95]. This seems to suggest that, at least in endometriotic cell lines, E-cadherin silenced by methyl- ation is associated with invasiveness. There are 11 hypermethylated and nine hypomethylated chromosomal regions common to all three subtypes of endometriosis. Hypermethylated regions appear to be located at the ends of chromosomes, while hypomethylated regions are found to be randomly distributed along the chromosomes [98]. While this high-thoughput technology can identify many aberrant methylations in a single study, caution should be made. First, not all aberrant methylations are associated with aberrant gene expression, as evidenced by the poor correlation coefcient between the gene expression induction ratio and methylation ratio (r 0. In fact, among 20 transcription factors for which expression data were also available, the agreement between expression levels (in direction and in terms of statistical signicance) and methylation patterns is merely 20% (or four out of 20). Second, while the use of paired eutopic and ectopic endometrium can effectively minimize the between-individual variation and reveal difference between the two tissues, the study design cannot detect aberrant methylations that are shared by the two tissues. The H3 and H4 histones, in particular, have long tails protruding from the nucleosome and can be covalently modied post-translationally at various residuals and in various ways. Thus, the combinations of modications are proposed to constitute a code for gene expression, the so-called histone code [100,101]. For ease of exposition, we shall review published work, albeit few, in writers and erasers of histone acetylation and methylation. Acetylated histones are generally associated with euchromatin and transcriptional activation. Hisone lysines can be methyl- ated in different forms: mono- (me1), di- (me2), or trimethylated (me3). Histone arginine methylation can be monomethylated, symmetrically or asymmetrically dimethylated. While histone methylation has been known since the early 1960s, it was generally thought that histone methylation, unlike acetylation and phorsphorylation, was biochemically stable and irreversible. Histone acetylation, methylation, and phosphorylation are the most investigated histone modications. By recruiting these reader/ effector proteins, histone modications lead to changes in chromatin structure as well as dynamics [111]. As at time of writing, there has been no published account on aberration of any reader/effector modules in histone modications. Given the reported epigenetic aberrations in endometriosis, one question is whether these aberrations are the cause or merely the consequence of endometriosis. In a linearly causal relationship, the cause and consequence can be clearly dened, with temporal sequences, and necessary and sufcient cause distinguished. In many ways, a complex transcription network often has a highly optimized tolerance featuring high efciency, performance, and robustness to designed-for-uncertainties yet hypersensitive to design aws and unanticipated perturbations [114]. In such a system, the demarcation of cause and consequence could be difcult since the removal of one part may affect other parts of the system, especially when the system is redundant. Therefore, it may be difcult to prove that in endometriosis aberrant methylation is a cause rather than a consequence. Despite this challenge, it is known that methylation can be induced by various factors. This provides evidence that certain phenotypic changes in endometriosis, such as increased production of proin- ammatory cytokines, may also cause epigenetic aberrations, which in turn result in changes in gene expression and subsequently other phenotypic changes such as increased cellular 454 proliferation [126] and perhaps some phenotypic changes. Remarkably, developmental exposures to chemicals can also result in aberrant methylation. Nevertheless, the developmental origins of many chronic diseases such as type 2 diabetes have now been demonstrated epidemiologically [134]. Further research in this area is sorely needed, not just for the sake of understanding of endometriosis pathogenesis but also because proper nutritional intervention may reverse the aberrant epigenetic changes [136,137]. Hence, enzymes that regulate the epigenetic changes could be ideal targets for intervention by pharmacological means. Given the accumulating evidence that endometriosis may be an epigenetic disease, naturally one may wonder as to whether endo- metriosis can be treated by correcting epigenetic aberrations through pharmacological means. It has been shown that women with endometriosis have aberrant uterine contractility during menses with increased frequency, amplitude, and basal pressure tone as compared with those without [159]. There is a sign that in the uterus of women with dysmenorrhea there is a lack of synchronization in fundal-cervical contraction [160]. Incidentally, progesterone, a traditional drug for treating endometriosis-associated dysmenorrhea, can also inhibit myometrial contraction [161]. After all, endometriosis is not a fatal disease even if left untreated, hence the demand for better safety and side effect proles is higher than anticancer drugs [35]. While the percentage of affected genes is generally small, it is still possible that these affected genes may be important enough in causing unacceptable side effects, even though such data are lacking as of now. As Paracelsus, considered to be the father of modern toxicology, said, Sola dosis facit venenum (only dose makes the poison). Hence the extrapolation of the observation under the high dosage to the situation of low dosage should be made with extreme caution. The divergent developmental pathways of the queen and workers are asso- ciated with changes in subtle gene expression patterns in a particular group of genes encoding conserved physiometabolic proteins [204,205]. Thus, reduced methylation, or the change of epigenome, in young larvae can mimic the effects of royal jelly. Any biomarker, in order to be clinically useful, should ideally have high specicity and sensi- tivity. In addition, it should be easily detectable in specimens procured through a minimally invasive manner. It is also unclear as to whether they would be of value for the differential diagnosis of endometriosis, which could be more challenging. In any case, very 460 little has been published in this area, even though it is an area that is likely to be clinically most useful and could bring tangible results to better patient care. The identication of patients with high risk of recurrence should accord for further intervention. On the other hand, patients with low risk of recurrence may be advised not to take any medication, which often have side effects. Despite these advances, however, our current knowledge on the epigenetics of endometriosis, and its pathophysiological signicance is still in its infancy.

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Recent evidence has hinted at the possibility of high levels of particular brain tissue-specic imprinting in a mouse model [67] order 100 mg atenolol visa. Soitis plausible that there is still an underestimation of imprinted loci generic 50 mg atenolol free shipping, particularly with the inclu- sion of tissue-specic and developmental-stage-specic variation order atenolol 100mg overnight delivery. Moreover whilst there is as yet no denitive set of human or other eutherian mammalian imprinted genes order atenolol paypal, there does appear to be signicant dissimilarities between the species. These differences could be reconciled with the paternal conict theory, for instance, as being driven by variation in litter size between mouse and human [73]. This includes the paternally expressed genes Dlk1 (delta-like 1 homolog, Drosophila), Mest (mesoderm specic transcript) (also known as Peg1) and Ndn (Necdin) [74]. Two further paternally expressed genes Mest(Peg1) and Peg3 are involved not only in fetal and postnatal growth, but also can affect maternal nurturing success [77,78]. These imprinted genes are strongly expressed in hypothalamus, preoptic area, and septum, therefore they are excellent candidates for neuronal programming [39]. Metastable epialleles are so termed as these loci of epigenetically variability are established very early in embryogenesis and subsequently remain stable whilst permeating through all ensuing developmental stages and germ layers [79]. In the wild-type mouse the Agouti gene encodes a signaling molecule that produces either black eumelanin (a) or yellow phaeomelanin (A). Transcription is normally initiated from a hair- specic promoter in exon 2, with transient expression of the A allele leading to the mottled brown fur. This overaction results in a lightening of the coat color as ectopic expression of the inverse agonist at melanocortin receptors, agouti, antagonizes the action of melanin [79]. The viable yellow heterozygote vy (A /a) mouse has a shortened live span with yellow fur, obesity, and an increased suscep- tibility to neoplasia [81]. Dietary impact on imprinted genes nevertheless has been documented, in the imprinted Igf2 locus in a mouse model [85]. Instalment of a methyl-donor-decient diet post-weaning led to loss of imprinting at this locus with subsequent modication of expression. The inbred mouse strain C57Bl/6J is documented as being highly susceptible to diet-induced obesity, but furthermore has also been observed to show a wide range of variability in this weight gain when fed a high-calorie diet [86]. Phenotype divergence into those who would become high weight-gainers versus low was even evident in measures before commencing an obesity- 280 promoting diet. Additionally these dissimilarities persisted even when the mice were switched back to a calorie- restricted diet. Overfeeding in rats, induced by limiting the litter size, led to an obese phenotype [87]. Leptin and insulin stimulate this pathway via two Sp1-related binding sequences within this promoter. This can be perceptibly displayed by the observation that the common genetic susceptibilities towards the trait are not acted upon, unless certain compounding causes are encountered. Lifestyle contributors such as diet and exercise are central in liability to metabolic disease and also have a substantial aggregate effect [90]. It has been proposed that the etiology of common diseases are under both genetic and epigenetic inuence and these disease-related epigenetic factors could be environmentally induced with subsequent modulatory effects on genetic susceptibility [91]. Epigenetic effect on gene expression by the modication of the target cell epigenome [93], thereby changes metabolic risk [79,94]. The signicant role of epigenetics in the pathogenesis of cancer is well established [96] but has also been seen in other diseases such as in the etiology of athero- sclerotic plaques [97], and evidence is accumulating in the metabolic syndrome. This may be caused by accrued environ- mental effect and/or epigenetic drift due to defective transmission through multiple mitotic replications. Therefore it has been speculated these shifts may modify metabolic path- ways, becoming gradually suboptimal, leading to slow late-onset weight gain [100]. The major stages are at postfertilization and at germ cell differentiation in males and females. Experimental evidence in mice shows that the preimplantation embryo is sensitive to epigenetic modications [102]. Direct evidence of dietary modulation during these time-points, and the latent ability to affect long-term risk of chronic metabolic disease health has been attempted using murine models, through from the periconceptual period to postweaning [105]. The epigenetic state of the transcription factor Hnf4a was investigated in the pancreas of rats that had been subjected to poor maternal diet and controls [106]. Poor maternal diet during critical periods of development, as well as aging, was shown to down-regulate an islet-specic promoter and the interaction between the promoter and an enhancer was also down-regulated. Cellular memory in the pancreatic cells of the developmental intra- uterine environment was sought by the investigation of approximately 1 million CpG sites in the rat methylome of these cells at the later age of 7 weeks. This proposes that the peri- conceptual, in utero, and postnatal developmental environment can impact on long-term risk for adult-onset disease by set point adaptive changes [109e111]. This suggests that poor nutrition at critical growth stages increases the chance of developing the metabolic syndrome (insulin resistance, obesity, dyslipidemia, and hypertension) in later life and these develop- mental origins of adult disease put forward epigenetic inheritance as the possible mechanism 282 in this programming [92]. Although ischemic heart disease increases in a population as it becomes wealthier, it was noted that those in the poorest regions suffered disproportionately [112]. An early epidemiological study in England and Wales identied a connection between poor nutrition in early life and increased susceptibility to ischemic heart disease, that was suggested to be due to a more detrimental effect of an adiposity-promoting diet in these individuals [112]. Furthermore, impaired glucose tolerance in men aged 64 was correlated to low weight at birth and at 1 year [113]. Documented historical famines furthermore allow these questions to be proposed to age cohorts, and the Dutch Hunger Winter of November 1944 to May 1945 has been a classic example in the literature. Upon reaching the army draft age of 19 years the obesity rates of 300 000 men were compared [115]. The outcomes were dependent on when during their development the severe wartime famine had occurred. Those exposed in the last trimester or the rst months of life were less likely to be obese, whilst those whose mothers had been in early or mid-pregnancy during this severe wartime famine were twice as likely to be obese at army draft. This would imply early changes may differ in programming from later changes, tting with hypotheses of developmental programming and critical epigenetic windows. Individuals conceived during the famine were compared against a sibling of the same sex to attempt to reduce environmental and genetic modulators. Follow-up work investigated a further 15 loci with known involvement in growth and metabolism [117]. These studies have highlighted the periconceptual period as a volatile spatiotemporal window in epigenomic development with additional support for this coming from animal models [118]. Manipulation of dietary vitamin B and methionine during this periconceptual period in sheep led to heavier, fatter, and insulin-resistant animals [119]. In a large population-based obesity study, the maternal impact on this trait was shown to be greater [120], possibly due to maternally imprinted genes. As these imprinted loci are strongly interconnected with resource allocation, energy balance, and feeding behavior, early envir- onmental effects may have long-reaching consequences. This makes these parental-specic marks obviously strong initial candidates in any fetal programming or plasticity inuence on chronic disease. It may be that these imprinting resource allocation tools are subverted by the fetal programming mechanism, enabling a shift of resource regulation over the course of a lifetime and subsequent risk for adult-onset disease [39]. This metabolic plasticity enables a non-changed genome to produce a range of phenotypes in response to variation in envir- onment, specically early nutritional status [121,122]. Subtle modulation of imprinting pathways could be a mechanism, or it may be that they are too critical for an adaptive process and changes are only seen in severe disease manifestations [123]. Two independent, but sometimes overlapping, pathways showing how the nutritional state through development can lead to increased susceptibility to later-onset obesity have been proposed [123]. First, this may be a mismatch pathway, which can be either severe or predictive. These are developmental plasticity modications of the genetically driven pheno- 283 type cued by prenatal undernutrition or possibly stress, which then may not be correctly geared, if the postnatal environment is obesogenic. Second, a pathway due to the risks caused by maternal obesity and the hypernutrition experienced by the fetus in this situation. Fetal growth retardation leads to changes in gene expression driven by epigenetic changes [114]. Recent work has shown that via the imprinted Peg3 placental sacrice will occur in order to protect brain development [124].

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