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This type of scan is good at showing Ultrasound if the cancer has spread outside of the ovaries. But, it An ultrasound is a test that uses sound waves to is not good at showing small tumors. It is often the also show if nearby lymph nodes are bigger than frst imaging test given to look for ovarian cancer. The dye may be put in a the ovary and whether the mass is solid or flled with glass of water for you to drink, injected into your vein, fuid. Tell your this test uses a hand-held device called an doctors if you have had bad reactions in the past. During the scan, you will lie computer uses the echoes to make a picture that face up on a table that moves through the tunnel. There are two types of the scanner will rotate an x-ray beam around you ultrasounds that may be used to look for ovarian to take pictures from many angles. You may hear cancer: transabdominal ultrasound and transvaginal buzzing, clicking, or whirring sounds during this time. A computer will combine all the x-ray pictures into For a transabdominal ultrasound, a gel will be one detailed picture. This for a few days since a radiologist needs to see the includes your belly (abdomen) and the area between pictures. Your doctor will place the probe on your skin and guide it back and forth in the gel. For a transabdominal ultrasound, the probe will be placed on the skin of your belly. Transabdominal ultrasound Transvaginal ultrasound Ultrasound picture Ultrasound picture Ultrasound probe Sound waves Ultrasound probe Sound waves Illustration Copyright © 2019 Nucleus Medical Media, All rights reserved. This type of scan is good at this test may be given with other initial tests when showing the spine and soft tissues like the brain. A scope is a long, thin tube that can be guided a contrast dye may be used to make the pictures into your body, often through the mouth, anus, or clearer. One end of the scope has a small since a radiologist needs to see and interpret the light and camera lens to see inside your body. To create pictures, a sugar radiotracer frst needs to be put into your body with an injection into a vein. The radiotracer emits a small amount of energy that is detected by the machine that takes pictures. Chest x-ray An x-ray uses small amounts of radiation to make pictures of organs and tissues inside the body. But, it may be done along with other initial tests if your doctor suspects ovarian cancer. It may Blood chemistry profle also be done during and after treatment to check A blood chemistry profle measures the levels of treatment results. Chemicals in your blood come from your liver, bones, and other organs Other tumor markers you may be tested for are and tissues. Inhibin Abnormal blood chemistry levels—too high or too Inhibin is a hormone produced by cells in the ovaries low—may be a sign that an organ isn’t working well. Testing for inhibin levels may Abnormal levels may also be caused by the spread be helpful in diagnosing some less common types of of cancer or by other diseases. Your doctor will ovarian tumors, including granulosa cell tumors and consider your health and look at the whole profle mucinous epithelial tumors. Alpha-fetoprotein this is a protein that is usually only detectable in the blood of pregnant women, because it is produced by the fetus. Review of tumor tissue Sometimes ovarian cancer is confrmed by a prior There are two kinds of laboratory tests for this surgery or biopsy performed by another doctor. Both results mean the pathologist will examine the tumor tissue with a same thing. Your doctors will also want to know if the surgery left the goal of testing for this tumor marker is to fnd out any cancer in your body. All of this will help your if treatment with an immune checkpoint inhibitor may current doctors plan treatment done during and after help you. There are other factors that your doctors will weigh to fnd out if this treatment is right for you. Genetic counseling may help you decide whether to be tested for hereditary ovarian cancer. Families with a history of Lynch syndrome may also be at risk for ovarian and other cancers. This chapter describes the staging process surgical staging be done by a and defnes the stages of ovarian gynecologic oncologist. But, to know the true extent of ovarian Surgery to remove nearby lymph nodes is cancer, surgery is needed. It is the most important Which surgical staging procedures you will have stage and is used to plan treatment. During surgery to remove the cancer, your doctor will perform a number of tests to fnd out exactly how far Your doctor will also take biopsy samples from it has spread. It is the nearby tissues where it looks like the cancer hasn’t most complete and accurate way to stage ovarian spread. Your During surgical staging, your doctor will carefully doctor will take samples from places where ovarian inspect tissues and organs near the tumor to see cancer often spreads. Biopsy abdomen sites may include the following: If you don’t have ascites, your doctor may “wash” Nearby lymph nodes – groups of disease the space inside your belly (peritoneal cavity) with fghting cells a special liquid. Samples of the liquid will then be tested for cancer Pelvis – the area below the belly (abdomen) cells. Biopsy samples will be taken from the tumor Lymph nodes Cancer in ovary as well as other organs and tissues near the ovaries. This may include the diaphragm, omentum, peritoneum, ascites, and nearby lymph nodes. A prognosis is the likely or staging systems for ovarian cancer: the American expected course and outcome of a disease. The outer sac (capsule) of the spread of cancer to distant sites the ovary is intact. Stage 1B the next section describes each cancer stage as Cancer is in both ovaries. Stage 1C Cancer is in one or both ovaries and one or more of the following has also happened: Stage 1C1 – the capsule of the ovary broke open (ruptured) during surgery. Stage 2A Cancer has grown into and/or spread implants on the Stage 3C uterus, fallopian tubes, ovaries, or all of these areas. Cancer has spread to the tissue lining the abdomen and it can be seen without a microscope. Cancer Cancer has grown into and/or spread implants may have spread to lymph nodes in the back of on other organs or tissues in the pelvis. It may have also spread to the outer include the bladder, sigmoid colon, rectum, or the surface of the liver or spleen. The peritoneum is the tissue that lines the inside of the abdomen and pelvis and covers most organs in this space. Stage 4 Cancer has spread to areas far from the pelvis and abdomen, such as the lungs, brain, or skin. It has spread Cancer may have also spread to lymph nodes outside the pelvis to tissues in the belly (abdomen). And, one or both of the following has happened: 1) cancer has spread to the tissue lining the inside Stage 4A of the abdomen (peritoneum); or 2) cancer may There are cancer cells in the fuid around the lungs. Stage 3A1 Stage 4B Cancer has spread outside the pelvis, but only to Cancer has spread to the inside of the liver or lymph nodes in the back part of the abdomen—called spleen, to distant lymph nodes, or to other organs retroperitoneal lymph nodes. Stage 3A2 Cancer has spread to the tissue lining the abdomen, but it is so small it can only be seen with a microscope. The cell subtype Ovarian cancer is also classifed based on what is based on the features of the cancer cells. Cancer grades the cancer grade is a rating of how much the cancer cells look like normal cells. Based on the features of the cancer cells, the pathologist will score the cancer as Grade 1, 2, or 3. Some pathologists describe the grading in only two classes: high grade or low grade.

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Of (Duquesnay 1994), and is the single most important source of these costs, 75% are devoted to the prolonged absenteeism and disability and health care expenditures, with 7 to 10% of chronic healthcare provided to chronic sufferers. Nevertheless, only 5 to 10% of patients need to stop work as population and the frst in subjects over 45 years of age. Briefy, there is a high prevalence and incidence of low back pain that is the current objectives of France’s healthcare system are as follows: increasing exponentially in a pseudo-epidemic manner (4-fold increase in. The considerable medicosocioeconomic cost, both direct and indirect, amounts to 6 billion euros per year in the options are to develop indices for assessing physical, professional, France, of which 75% is accounted for by only 7 to 10% of all low back psychosocial and medicolegal factors, and to offer early management pain sufferers. It is the main cause of disability in the under-45 group, starting fve weeks following diagnosis. Just a 1% reduction in the number of chronic sufferers would lead to annual savings of 100 million euros. Among the psychological factors, anxiety and depression are the most prevalent (Polatin 1993, Kessler 1996, Schermelleh-Engel 1997, Clauw the somatic factors in chronic low back pain are well known and not 1999, Epping-Jordan 1998, Fisher 1998, Pincus 2002, Duplan 2005, determinant. Poor physical condition and inadequate muscular strength in the Very few mentally ill subjects suffer from low back pain (psychiatric trunk are consequences of low back pain rather than the cause. Physical treatment is required only in 5%), and such patients tend to be managed training can prevent relapses, but it is not predictive of the absence of by health psychologists in order to assess their cognitive and emotional chronicity (Cady 1979, Leino 1993). Cognitive factors in pain with the fear of moving and low psycholo There is no direct relationship between chronic low back pain and gical adjustment to pain or the inability to cope with pain are related spinal degeneration, as evidenced by imagery (Carragee 2005). The prevalence negative aspects of chronic low back pain (intensity of pain, disability of chronic low back pain in adolescents is 3% (Taimela 1997). Moreo and fragile emotional state), while cognitive restructuring and pain ver, many chronic adult sufferers were already affected at 15 years of control are associated with favourable progression (Tuttle 1991, Dozois age, so primary prevention at school and in sports clubs is important 1996, Kröner-Herwig 1996, Lin and Ward 1996, Robinson 1997, Mc (Salminen 1999). In the prospective studies, catastrophism and fear of movement the occupational risk factors of low back pain are present for people were the most predictive factors of pain and disability (Hasembring who perform arduous physical work, must maintain prolonged stressful 1994, Burton 1995, Klenerman 1995, Linton and Hallden 1998, Picavet working positions, and are exposed to vibration. Passive psychological adjustment to pain or coping (Potter and tors are associated with low back pain, such as work that is monotonous, Jones 1992), hoping and praying (Burton 1995) and self-perception of repetitive and stressful, and that provides little satisfaction or prestige. All While these studies examined the level of pain and functional criteria these occupational factors are highly associated with chronic back pain (disability, return to work and quality of life), the relationships between (Waddell 2000). Previous studies have shown that psychosocial factors are more important in lumbar disability related to biomechanical and medical factors (Carragee 2005, Linton 2000, Waddell 1998). During this study, patients were asked to complete initial and fnal psychological and functional assessment questionnaires. At the studies have demonstrated that chronic evolution may be predicted by same time, they have been found to provide psychological support in analyzing its social and psychosocial parameters (Hasembring 1994). Functional were less affected by catastrophism and hypokinesia (Chaory 2004, rehabilitation programs are now recognized as having an impact on low Jousset 2004, Kole-Snidjers 1999, Spinhoven 2004). On the other hand, pants are randomly divided into a control group and an experimental there is substantial evidence that in chronic low back pain patients group. Professional training and reclassifcation is both muscular and central (involving gestures and proprioception) and impacts professional movement. Kinesiophobia and maladapted the team is co-ordinated in review meetings where the improvement in motor control often make the symptoms chronic. It is not possible to include the rare psychiatric patients nor those who are In most studies on rehabilitation, the outcome is favourable (Alaranta unable to accept the constraints that working in a rehabilitation 1994, Frost 1995, Hazard 1989, Järviloski 1993, Lindström 1992, Man group places on them. Nor can one include those who are waiting niche 1990, Mannion 1999, Mayer 1994) with a more rapid return to for reclassifcation or disability. However, the assessment process work, improved mobility and muscle strength at 3, 6 and 12 months is subject to bias because there will always be patients who cannot after multifactorial management, and subjective improvement of physical be treated owing to psychosocial factors. The type of physical programme seems to have little infuence on the multidisciplinary approach in managing programme participants the outcome, whether it is isometric, dynamic or isokinetic. The most demonstrated that when several healthcare professionals of different important point is to recover fexibility, muscle strength and endurance, skills are involved in the same medical problem with the aim to conti and to learn how to cope with pain by using coping strategies. Of all the patients, 85% occupational therapist, psychometrician, dietician and social assis were keeping up with their exercise routine, and 77% had returned to tant. The aim of treatment is to wean the patient off of medication, dedramatize their suffering, make them accountable and motivate them so that they can play an active role in their own rehabilitation. For patients who cannot be included in such programmes, it is possible to offer them adapted and reduced routines aimed at improving their daily lives, even if they are unable to return to work. Moreover, it is essential to begin combined psychosocial and physical rehabilitation early, to prevent chronicity. The slippery slope into chronic pain is only favoured in situations where the patient keeps their old habits, if prolonged time off work and rest are prescribed, medication (especially morphinic drugs) is given without any objective signs calling for its use, and loses contact with his/her place of work (Nordin, Abenhaïm, Rossignol, Bortz, Buckwalter). A state of permanent disability is a good choice neither for the patient nor for the healthcare system. Indeed, there is much scope for developing ancillary patient-oriented services that do not fall within the realm of traditional medicine, but that meet the psychosocial and professional needs of patients. Search for medical contraindications to physical of perceived health with the concept of health associated with real, rehabilitation (cardiovascular). The E/F ratio was the Biering-Sorensen test for the extensor muscles and to use the inverted. Currently, a distinction is drawn between the role of the axial muscles the endurance test demonstrates the patient’s aptitude to lift a load 4 of the trunk (multifdus, psoas, tranversus abdominalis, rectus) and times in 20 seconds from ground level to a height of 50 cm. The weight the peripheral muscles (longissimus, iliocostalis, internal and external increments are 5 kg for men and 2. I], Spine, 1999, 24 (19) : among school children; a feld survey with analysis of some associated 2036-2041. Physical progress and residual chroniques : du modèle médical au paradigme multifactoriel. Relationship between epidural subchronic low back trouble, Spine, 1995, 20 (6) : 722-728. Approche du traitement psychodynamique de la a prospective study in subjects with persistent back pain. Psycho Lombalgies chroniques et écoles du dos, Aix-les-Bains, Table ronde social factors and coping strategies as predictors of chronic evolution 4011, semaine de Rhumatologie. Rhumatologie, 1994, (4§), (8) : and quality of life in patients with low back pain : a prospective study. Predicting subjective disability in chronic charge multidisciplinaire des lombalgiques chroniques. Le préalable psychiatrique à l’in sciences humaines « psychologie clinique », 2005, Université Lumière, dication d’arthrodèse lombaire. Perceived self-effcacy and outcome expectan back pain : predictive relationships among pain intensity, disability cies in coping with chronic low back pain. Br J Health screening questionnaire for predicting outcome in acute and subacute Psycho, 1998, 3 : 225-236. A review of psychological risk factors in back and neck in acute low back pain : relationships with current and future disability pain. A report from the Swedish impairment quantifcation after functional restauration, Part I, Lumbar Lumbar. A prospective investigation of biologic, psychological and in persons with chronic back pain : immediate assessment following social predictors of therapy outcome. Depressive symptoms and disability in acute and the mind and the spine –Which goes frst? Groupe de travail québecois sur les aspects cliniques des affections tauration versus 3 hours per week of physical therapy : a randomized vertébrales chez les travailleurs. Rôle de certains facteurs psychosociaux dans le profl naire – Revised : A multisample study. Working disability due to des lombalgies communes : Étude semi-prospective en psychologie de la occupational back pain: three-year follow of 2300 compensated santé. The thoracolumbar spine in young elite athletes, Current low back pain patients : relationship to patient characteristics and concepts on the effects of physical training. A prospective three-year follow-up study of subjects with beliefs infuence work loss due to low back trouble. Acute, Subacute and chronic low back pain : clinical surgery in patients with slipped disk operated upon for the frst time. Med Care, mediators of outcome in a multidisciplinary treatment of chronic low 1992, 2, 30, 473-483. Infuence of age and duration in the making of the initial medical diagnosis of work-related back injuries.

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Other diseases, even the longer ones and those accompanied by fever, proved neither serious nor fatal; these will be described later. There was fever, attended by shivering, of continuous, severe and usually non-remittent type. Thus one day the fever would be less severe, the next day the fever would be higher and so on, but in general becoming worse with time. The patients showed continuous sweating but the whole of the body was not involved. Their stomachs were disordered and the stools small, bilious, not homo­ geneous, fluid and pungent, causing the patient to get up frequently. The urine was either thin, colourless and un­ digested, or thick with a slight sediment which did not settle easily but was, as it were, raw and unripe. Cough was slight but frequent, and little was coughed up and that only with difficulty. In the most violent cases, there was no progress towards ripening of the sputum and the patients continued to cough it up raw. The patients rapidly became worse and wasted away, refusing to take food and having no thirst. While it was still summer and during the autumn there were also many cases of fever apart from consumption. These were continuous but not violent and, though those affected were ill for a long time, they suffered nothing in other respects for their stomachs generally remained in good order and they took no harm worth speaking of. Usually the urine was clear and of a good colour but thin, becoming ripened later about the time of the crisis. There was not too much coughing, nor did the patients have much trouble with the cough. Generally they were only slightly ill and showed none of the fevers attended with shivering suffered by con­ sumptive patients, and little sweating. The paroxysms of fever were irregular, being at different intervals in different cases. In the shortest illnesses, the crisis occurred at about the twentieth day, in most cases at about the fortieth and in a number at about the eightieth. In some cases the fever re­ solved at a time different from those given above without reaching a crisis. In most of these the fever returned after a short interval and the crisis was reached in one of the usual periods. The course of the remainder was smooth and no deaths occurred from the other fevers. There was unseasonably wintry weather in Thasos early in the autumn, and rainstorms suddenly burst to the accom­ paniment of northerly and southerly winds. The winter was northerly and there was much rain, with frequent heavy showers, as well as snow. However, immediately after the winter solstice when the west wind usually begins to blow, the great storms returned with gales from the north, and snow and rain fell continuously from a sky full of racing clouds. The spring was cold with northerly winds accompanied by cloudy skies and much rain. The summer was not too scorching for the etesian winds blew steadily, but heavy rain followed again soon after the rising of Arcturus. The winter was healthy for the most part but early in the spring a good few, in fact most people, fell sick. Ophthalmia was the first disease to make its appearance, being accompanied by pain, moist discharge and without suppuration. During the summer and the autumn there were cases of dysentery, tenesmus and diarrhoea. Further, there were cases of bilious diarrhoea in which the stools were copious, thin, raw and sometimes watery and painful to pass. There were also many cases of discharges accompanied by strangury and a painful, bilious, watery discharge containing particles and pus. Often there was no fever and the patients were not confined to bed, but in many other cases which will be described there was fever. Those who exhibited all the symptoms to be mentioned were consumptive and suffered pain. During the autumn and on into the winter there were cases of continued fever, in a few cases caitsus, diurnal and nocturnal fevers, roughly tertian and exact tertian fevers, quartans and fevers of no regular form. Causus was the least frequent of these fevers and those affected by it suffered the least. The crisis was regularly attained, usually on the seventeenth day including the days of intermission. I knew of no case of causus which was fatal or which was complicated by brain-fever. In all cases of this fever four periods regularly elapsed from the time the malady was contracted and the final crisis was reached after seven paroxysms. In not a few cases, however, they emerged as quartans only on the departure of other fevers and ailments. There were many cases of quotidian, nocturnal and irregular fever; they lasted a long time whether the patients were con­ fined to bed or not. In most cases the fever lasted through the season of the Pleiads until the winter. Often the disease was accompanied by convulsions, especially in the case of children when the fever was, at first, slight. Although these maladies were protracted, they were not usually serious unless the patient was already likely to die from some other cause. The worst, most protracted and most painful of all the diseases then occurring were the continued fevers. These showed no real intermissions although they did show paroxysms in the fashion of tertian fevers, one day remitting slightly and becoming worse the next. They began mildly but continually increased, each paroxysm carrying the disease a stage further. A slight remission would be followed by a worse paroxysm and the malady generally became worse on the critical days. Although all patients suffering from these various fevers showed shivering fits at irregular times, such fits were least frequent and most irregular in patients with these continued fevers. Again, the fevers generally were attended with many fits of sweating but in cases of continued fever they were infrequent and brought harm rather than relief. In the fevers generally, digestion was disturbed and difficult but this was most marked in these cases of continued fever. In them, too, the urine was either: (a) Thin, raw and colourless, becoming slightly more concocted at a crisis, (b) thick, but cloudy rather than forming sediment, or (c) of small quantity, bad and forming a raw sediment. Cough accompanied the fever, but I have no instance to record of a cough being either harmful or helpful. These various symptoms [in cases of continued fever] were usually long-lasting, distressing and occurred without any order or regularity. In the majority of cases there was no crisis, whether or not the case was desperate. In a few cases a crisis occurred not earlier than the eightieth day but in some of these there was a relapse so that the majority of cases lasted on into the winter. Generally the disease resolved without a crisis, and this absence of crisis was equally marked both in those who recovered and those who did not. These cases of [continued] fever, although they showed this characteristic of not reaching a crisis, were otherwise very varied. The most important and most ominous sign, which in the end was seen in most cases, was complete loss of appetite. This was specially marked in those whose condition was already desperate in other respects. Further, these febrile patients showed no greater desire for water than they would normally. Abscesses formed in those cases in which the illness was very prolonged and attended by much pain and loss of weight.

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Epithelial ovarian, fallopian tube and primary peritoneal cancer Front-line treatment: Avastin is administered in addition to carboplatin and paclitaxel for up to 6 cycles of treatment followed by continued use of Avastin as single agent until disease progression or for a maximum of 15 months or until unacceptable toxicity, whichever occurs earlier. The recommended dose of Avastin is 15 mg/kg of body weight given once every 3 weeks as an intravenous infusion. Treatment of platinum-sensitive recurrent disease: Avastin is administered in combination with either carboplatin and gemcitabine for 6 cycles and up to 10 cycles or in combination with carboplatin and paclitaxel for 6 cycles and up to 8 cycles, followed by continued use of Avastin as single agent until disease progression. Treatment of platinum-resistant recurrent disease: Avastin is administered in combination with one of the following agents – paclitaxel, topotecan (given weekly) or pegylated liposomal doxorubicin. The recommended dose of Avastin is 10 mg/kg of body weight given once every 2 weeks as an intravenous infusion. When Avastin is administered in combination with topotecan (given on days 1-5, every 3 weeks), the recommended dose of Avastin is 15 mg/kg of body weight given once every 3 weeks as an intravenous infusion. It is recommended that treatment be continued until disease progression or unacceptable toxicity (see section 5. Cervical Cancer Avastin is administered in combination with one of the following chemotherapy regimens: paclitaxel and cisplatin or paclitaxel and topotecan. It is recommended that treatment be continued until progression of the underlying disease or until unacceptable toxicity (see section 5. Special populations Elderly patients: No dose adjustment is required in the patients ≥ 65 years of age. Patients with renal impairment: the safety and efficacy have not been studied in patients with renal impairment (see section 5. Paediatric population the safety and efficacy of bevacizumab in children aged less than 18 years old have not been established. There is no relevant use of bevacizumab in the paediatric population in the indications for treatment of cancers of the colon, rectum, breast, lung, ovarian, fallopian tube, peritoneum, cervix and kidney. Method of administration the initial dose should be delivered over 90 minutes as an intravenous infusion. If the first infusion is well tolerated, the second infusion may be administered over 60 minutes. If the 60-minute infusion is well tolerated, all subsequent infusions may be administered over 30 minutes. If indicated, therapy should either be permanently discontinued or temporarily suspended as described in section 4. Precautions to be taken before handling or administering the medicinal product For instructions on dilution of the medicinal product before administration, see section 6. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6. Intra-abdominal inflammatory process may be a risk factor for gastrointestinal perforations in patients with metastatic carcinoma of the colon or rectum, therefore, caution should be exercised when treating these patients. Therapy should be permanently discontinued in patients who develop gastrointestinal perforation. Limited information is available on the continued use of Avastin in patients with other fistulae. In cases of internal fistula not arising in the gastrointestinal tract, discontinuation of Avastin should be considered. Serious wound healing complications, including anastomotic complications, with a fatal outcome have been reported. Therapy should not be initiated for at least 28 days following major surgery or until the surgical wound is fully healed. In patients who experienced wound healing complications during therapy, treatment should be withheld until the wound is fully healed. Necrotising fasciitis, including fatal cases, has rarely been reported in patients treated with Avastin. This condition is usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Avastin therapy should be discontinued in patients who develop necrotising fasciitis, and appropriate treatment should be promptly initiated. Clinical safety data suggest that the incidence of hypertension is likely to be dose-dependent. Pre-existing hypertension should be adequately controlled before starting Avastin treatment. There is no information on the effect of Avastin in patients with uncontrolled hypertension at the time of initiating therapy. In most cases hypertension was controlled adequately using standard antihypertensive treatment appropriate for the individual situation of the affected patient. The use of diuretics to manage hypertension is not advised in patients who receive a cisplatin-based chemotherapy regimen. Avastin should be permanently discontinued if medically significant hypertension cannot be adequately controlled with antihypertensive therapy, or if the patient develops hypertensive crisis or hypertensive encephalopathy. Monitoring of proteinuria by dipstick urinalysis is recommended prior to starting and during therapy. Patients receiving Avastin plus chemotherapy, with a history of arterial thromboembolism, diabetes or age greater than 65 years have an increased risk of developing arterial thromboembolic reactions during therapy. Therapy should be permanently discontinued in patients who develop arterial thromboembolic reactions. Patients treated for persistent, recurrent, or metastatic cervical cancer with Avastin in combination w ith paclitaxel and cisplatin may be at increased risk of venous thromboembolic events. Haemorrhage Patients treated with Avastin have an increased risk of haemorrhage, especially tumour-associated haemorrhage. There is no information on the safety profile of Avastin in patients with congenital bleeding diathesis, acquired coagulopathy or in patients receiving full dose of anticoagulants for the treatment of thromboembolism prior to starting Avastin treatment, as such patients were excluded from clinical trials. Therefore, caution should be exercised before initiating therapy in these patients. Pulmonary haemorrhage/haemoptysis Patients with non-small cell lung cancer treated with Avastin may be at risk of serious, and in some cases fatal, pulmonary haemorrhage/haemoptysis. Before initiating Avastin, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm. Caution should be exercised when treating patients with clinically significant cardiovascular disease such as pre-existing coronary artery disease, or congestive heart failure with Avastin. Close observation of the patient during and following the administration of bevacizumab is recommended as expected for any infusion of a therapeutic humanised monoclonal antibody. If a reaction occurs, the infusion should be discontinued and appropriate medical therapies should be administered. Caution should be exercised when Avastin and intravenous bisphosphonates are administered simultaneously or sequentially. A dental examination and appropriate preventive dentistry should be considered prior to starting the treatment with Avastin. In patients who have previously received or are receiving intravenous bisphosphonates invasive dental procedures should be avoided, if possible. Eye disorders Individual cases and clusters of serious ocular adverse reactions have been reported following unapproved intravitreal use of Avastin compounded from vials approved for intravenous administration in cancer patients. These reactions included infectious endophthalmitis, intraocular inflammation such as sterile endophthalmitis, uveitis and vitritis, retinal detachment, retinal pigment epithelial tear, intraocular pressure increased, intraocular haemorrhage such as vitreous haemorrhage or retinal haemorrhage and conjunctival haemorrhage. Some of these reactions have resulted in various degrees of visual loss, including permanent blindness. Therefore fertility preservation strategies should be discussed with women of child-bearing potential prior to starting treatment with Avastin. Conclusions on the impact of bevacizumab on gemcitabine pharmacokinetics cannot be drawn. In addition, hypertension (including hypertensive crisis), elevated creatinine, and neurological symptoms were observed in some of these patients. Radiotherapy the safety and efficacy of concomitant administration of radiotherapy and Avastin has not been established. Pregnancy There are no clinical trial data on the use of Avastin in pregnant women. Studies in animals have shown reproductive toxicity including malformations (see section 5. IgGs are known to cross the placenta, and Avastin is anticipated to inhibit angiogenesis in the foetus, and thus is suspected to cause serious birth defects when administered during pregnancy.

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Patients’ identify the most appropriate training program available compliance will also be poor because unless other pro to them in the region. The professionals involved in pa fessionals understand what you do, patients may be tient care should get such training as an essential first discouraged from following your treatment. Ideally such training should include all three do following scheme of action would be good for initial mains of knowledge, skill, and attitude. If the service is part professionals in the hospital and in the neighbor of a large department of anesthesiology that already hood should be offered the opportunity to attend has a considerable role in postoperative management, such a program. The more people are sensitized, it may be easiest to start a postoperative pain manage the better the response to your pain manage ment program. All the professionals involved in start with an outpatient facility for cancer pain manage some way with the pain management program, ment. A stand-alone service may find it easiest to start a including nurses, should be able to evaluate pain chronic pain service. Second, the professionals who deliver pain care teers, social workers, nurses, general practitioners, should all have at least a few weeks’ “hands-on” anesthetists, oncologists, neurologists, psychiatrists, training such as the certificate course described and other specialists all have their roles to play. It would of the team should, at the earliest opportunity, make better sense to have a system for consultations gain the level of expertise that can be obtained when necessary. Matters related to opioid availability, particularly regu latory issues, have been dealt with in detail in a sepa Quality of life as the objective: The goal of management rate chapter. Affordability of drugs is a matter of par should be improved quality of life rather than just treat ticular concern in developing countries. All the symptoms of the pa often, the most expensive medication would be avail tient must be treated. Given that anxiety and depression able in developing countries, while the inexpensive form part of the pain problem, there should be routine drugs tend to slowly fade away and go off the market. The nature of the problem and treatment options Such an effort, for example, has resulted in availability must be discussed with the patient and family and a of a week’s supply of oral morphine for the price of a joint plan arrived at. Professionals need What are the challenges regarding to remember that formal education and intelligence are not synonymous. If the service is successful, the demand is likely ble of making difficult decisions than a more sophisti to be enormous, and soon the service will be flooded cated, educated patient. The following points would be use treatment modality should be taken into consideration ful as guiding principles. Rajagopal Incorporation of principles of palliative care: Treatment at home: The majority of people in What is the objective of pain management? If pain is pain in developing countries may have little access to relieved, but other symptoms such as breathlessness transportation. Hospitals seldom have enough space to or intractable vomiting persist and hence quality of take in such patients, even if the patients could afford life does not improve, the purpose of treatment fails. Most patients Hence, the objective should be improvement of quality will need to stay in their homes. As in devel two parallel streams of care have evolved—one man oped countries, patients are opting to stay at home to be aging pain as a symptom and the other providing “to treated, especially when they are terminally ill. In many occa Pearls of wisdom sions, the involvement of a spiritual person close to the family would help decision making and make patient In conclusion, three foundation measures are necessary compliance easier. Governmental policy National or state policy emphasizing the need to alleviate chronic cancer pain through education, drug availability, and governmental support/endorsement. The policy can stand alone, be part of an overall national/state cancer control program, be part of an overall policy on care of the terminally ill, or be part of a policy on chronic intractable pain. Education Drug availability Public health-care professionals Changes in health care (doctors, nurses, pharmacists), regulations/legislation to others (health care improve drug availability policy makers/administrators, (especially opioids) drug regulators) Improvements in the area of prescribing, distributing, dispensing, and administering drugs Guide to Pain Management in Low-Resource Settings Chapter 43 Resources for Ensuring Opioid Availability David E. Joranson The purpose of this chapter is to provide perspective Case 1 and tools that you can use to make opioid analgesics A patient was initially given radiotherapy for her pain, more available and accessible for the treatment of your but it was not effective as the disease progressed. Finally, she returned to the system of drug control laws, regulations, and distribu doctor in excruciating pain requesting medication that tion in your country. She was given another weak pain distribute controlled medicines according to medical medication along with antidepressants and sent home. The an this chapter poses a number of questions that are nual requirement of morphine is approximately 10,000 relevant to a better understanding of how the system is tablets of 20 mg. But the Institute has not been able to supposed to function, and to identify and remove impedi procure a single tablet primarily due to the stringent ments to availability of opioids and patient access to pain state laws and multiplicity of licenses. This of tablets the [manufacturer] did not have tablets in does not imply that opioids are indicated for every type of stock and by the time the tablets could be arranged, the pain. The doctors at the Institute and the pain from noncancer conditions, but the choice of thera associated pain clinic have stopped prescribing morphine pies needs to be made on an individual basis, governed by tablets because they would not be available. Such situations normally arose as a result of critical importance of availability and access to opioid the difficulties encountered when trying to obtain the analgesics for the relief of pain. At other times, manufacturers of the Guide to Pain Management in Low-Resource Settings, edited by Andreas Kopf and Nilesh B. This material may be used for educational 321 and training purposes with proper citation of the source. Joranson drugs simply did not have any stock to sell a direct of pain and suffering and that they also have a potential result of low and unpredictable demand. The principle recognizes that efforts to pre times, morphine stocks would run out. In these emer vent illegal activities and abuse should not interfere with gencies, the clinic would resort to otherwise unethical the adequate availability of opioid analgesics to relieve and unacceptable cutback measures, implemented in pain and suffering. International agreements that are such a way so as to minimize the effect on patients and binding on governments have recognized for decades families. Such situations are tragic mia, and a range of other diseases that may include and never should be allowed to happen, but they do set severe pain. Clini resources that can be used by health professionals and cians understand only too well how unrelieved severe government in low-resource settings, or anywhere else, pain can destroy quality of life and sometimes even to improve availability and patient access to opioid anal the will to live. Some—but not all—of the wealthier countries this chapter is based on the international studies have fairly good opioid availability, and therefore pa and experience of the University of Wisconsin Pain and tients have access to opioid analgesics. A num used to improve availability and access to essential opi ber of organizations with an interest in pain, palliative oid pain medicines. Readers are en couraged to consult the resource materials referenced Why are controlled drugs such as in the text and at the end, refer to other chapters in oral morphine important? Pain is treated Efforts to improve opioid availability should be guided with a combination of drug and nondrug measures. Resources for Ensuring Opioid Availability 323 Opioids block the transmission of pain in the path national and provincial/state regulations are more re ways of the nervous system. Some opioids, such as strictive than is necessary and impede or completely fentanyl, morphine, hydromorphone, and oxycodo block access, hampering the ability of pain and pallia ne can relieve moderate to severe and escalating pain. Tese opioid agonists lack a “ceiling effect” so that the Although international agreements recognize that dose can be increased to relieve increasing pain, keep national governments may be more restrictive, regula ing in mind side effects. International health and regu tory controls over opioid analgesics are not balanced latory bodies do not recommend a maximum dose for if they interfere in legitimate medical treatment of pa opioid analgesics. Tools for assessing balance in national laws and analgesics do have a ceiling effect and, especially in the regulations and for bringing about change are discussed absence of opioid agonists, may be overused to try to later in this chapter. Tere is agreement that several opioid agonists How should prescription opioid in different dosage forms should be available to allow analgesics be handled safely? All those who handle con important pain relief medicines at an affordable cost, trolled opioid analgesics, including manufacturers, when and where needed by patients. Do opioids have a potential Controlled medicines should be used only by the per son for whom they are prescribed and according to the for abuse? Yes, opioids do have an abuse potential and therefore It is important to keep prescribed medicines in the are “controlled” under international, national, and state original container because the label has the prescription laws and regulations. Many controlled opioids are also information that establishes in the eyes of the law the designated as essential medicines; they are safe and ef patient’s right to possess a controlled drug. The label on fective—indeed indispensable—for the relief of severe the original container should have the instructions for pain. Controlled medi Tere is a legal tradition to classify opioids as “nar cines should always be stored out of sight to prevent cotic drugs,” “dangerous substances,” and even as “poi theft, and kept out of reach of children to avoid acciden sons. The movement of controlled substances is subject National requirements vary for returning or dispos to government regulatory controls such as licensing, se ing of unused or “leftover” medicines. Additional infor cure storage, inventory, recordkeeping, and reporting mation about requirements for secure disposal and ways of procurement, storage, distribution, and dispensing. The manner in which regulatory requirements are What should be done if pain administered differs greatly from country to country, medicines are diverted?

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And there is a quality control system for department-owned traditional medicine factories and a post market drug survey of all traditional medicine drugs around the country is ongoing. Research papers are presented at the Myanmar Health Research Congress and also at the annual Traditional Medicine Conference. A total of 150 kits were distributed to 44 villages in Nay Pyi Taw with a quota of one kit per 50 households. Kit holders selected from the villages were middle-aged middle-school graduates, preferably recommended by villagers, religious person, monk or school teacher and were given training on the use of medicines in the box for minor ailments. Seven standardized Myanmar traditional medicine drugs with cotton wool, spirit, bandage, plaster, thermometer, pamphlet, guidance manual and stickers on traditional medicine are put in the kit. Delivery is according to a distribution plan and kits are usually reordered when their supplies are low but not completely used up. The price has been made reasonable for medicines produced by department owned factories. Regular supervision on the use of the kit is made by the traditional medicine practitioner of the respective township traditional medicine clinic. With humanitarian assistance from Nippon Foundation, the traditional medicine kit distribution project is being expanded (since 2009). It has 150 beds, providing health services especially for monks and nuns, but also for the general public. Others are Sidagu Ayudana hospital (100 beds) and Wachet Jivitadana Sangha hospital (25 beds) situated in Sagaing, meant for monks and nuns but also for locals staying in the community especially poor people. Usually all township hospitals in the whole country have a separate Sangha ward for monks. For other prisons, medical care of prisoners has to be covered by the respective regions/state, district or township hospital. The first in the series of reforms implemented since the 1990s was on improved access to essential medicines and the introduction of different financing mechanisms to recover and replenish the costs. Revolving Drug Fund, hospital trust funds, community cost sharing including exemption for the poor, and community donations) in all public hospitals. Later the mechanisms were extended by introducing exemption for the poor and supporting them through other mechanisms like trust funds, to offer protection from financial risk. However, these interventions are not able to raise sufficient revenues to replenish the medicines, or to reduce the out of-pocket expenses and financial burden of the poor. Thus, those townships without any donor-supported programmes had to concentrate on their routine activities with little technical, financial or material support. With the low salary paid to health workers, the staff in these areas became off-hour private practitioners. Donor-coordination and fund-support mechanisms have evolved into integrated programme management with the principle of 135 Oneness in line with the Paris Declaration on Aid Effectiveness, but more effort is needed. This community-based policy had a great impact on health development, especially in the prevention and control of major communicable diseases, and reducing child and maternal mortality. Health development in Myanmar could also be judged from its success stories, such as eradication of smallpox, elimination of leprosy, trachoma, poliomyelitis, and iodine-deficiency disorders (Ko-Ko, Thaung & Soe-Aung, 2002). Myanmar received international recognition for its achievement in health development during the 1980s and 1990s. For example, the Ayadaw Township People’s Health Plan Committee received the Sasakawa Health Prize at the 39th World Health Assembly in May 1986 (Tin-U et al. The township has maintained its momentum of health and development (Than-Sein, 2012). Revolving Drug Fund, hospital trust funds, expanded public Community Cost Sharing with exemption for the poor, and community hospitals; donations) were developed in all public hospitals, initially aimed to expanded ensure replenishment of essential medicines by mobilizing resources private health from households and communities in the light of insufficient government system funding. Later the mechanism was extended by introducing exemption for the poor and using other mechanisms. Government Reforms in 2011: In his augural address to the Union Parliament in March 2011, of the health sector President U Thein Sein indicated that the people would have to work harder Republic of envisaged, than ever and the government would make amendments to financial and the Union but not yet tax policies as necessary for the evolution of the market economy and of Myanmar implemented improvement of the socioeconomic status of the people. March 2011) 2012: Social Security Act adopted, covering private-sector workers’ pension and unemployment benefits scheme; social health insurance; maternity and sick leave; and compensation for ill-health, disability and death. Source: Asia Pacific Observatory on Health Systems and Policies 137 the reforms might look like usual developmental work in the health sector and no major evaluation or impact study has been carried out so far specifically linked to these reforms. However, anecdotal evidence from various sources indicates the impacts of health system performance and health inequity. The following paragraphs discuss a few of these reforms, the experiences of which should provide policy-makers with lessons for present and future improvement of the health system. However, there are a few major impediments to the availability and effective use of essential medicines: (1) limitation of availability, procurement and distribution of essential medicines at the most distant health care facilities; (2) emergence of fake/counterfeit and low quality medicines and increasing prices; and (3) the different financing mechanisms for the purchase of these medicines by the consumers. Patients and their families initially accepted the idea of paying for the medicines, which they had otherwise to procure from outside markets, paying higher prices with no assurance of quality. Initially these mechanisms aimed to ensure replenishment of essential medicines by mobilizing resources from households and communities in the light of insufficient government funding. Later the mechanism was extended by introducing exemption for the poor and using other mechanisms, like trust funds for poor patients, to offer protection from financial burden. The issue of counterfeit, fake and spurious drugs has come up as major issue in Myanmar since the mid-1990s. In addition, many counterfeit drugs were imported through cross-border trade from neighbouring countries (via land and sea routes). Some 5–16% of the samples either contained substandard, low quantity active ingredients or failed laboratory tests (not containing the stated ingredients) – this applied mainly to antibiotics. While the local community had to pay higher prices for the purchase of essential medicines, the fake and counterfeit drugs made them sicker and poorer. These donor-supported programmes concentrated on selected townships and specific programme priorities. Thus, those townships without any national donor-supported programme being implemented in their area had to carry out their routine work with little technical, financial and material support. With the low salary paid to health workers, the staff in these areas became private practitioners. These staff had to take more time for private health care, charging for almost every service they delivered in public facilities. Tenders for purchase of medicines for health centres were devolved to the regional health departments. Private investors are yearning for this lucrative market of hundreds of millions of dollars worth of tenders. Analysis of this experience of purchasing mechanisms and of the utilization of medicines by the health care facilities in late 2013–early 2014 will help in future policy development. There are over 40 private hospitals and thousands of private health clinics in Yangon city, at least five private hospitals in the capital, Nay Pyi Taw, and thousands of such private health care institutions in the big cities (regional capitals and other cities), and even in rural villages. Myanmar amended the national laws relating to private health care, including private dental and oral health clinics and hospitals, in 2007. The law is supposed to control the quality of health care, including patient safety, and it also has provisions for control of physical location and zoning for establishing big hospitals with speciality services. With the establishment of peace agreements with some ethnic groups in north-eastern border areas around 1992, the government started to open new health care facilities and post staff in these areas where civil conflicts have made provision of basic social and health development services difficult for four or five decades. An incentive policy had been introduced by the socialist government in 1974 that all government staff who were assigned in these areas (about 70 townships) had been given double salary (routine salary plus living allowance equivalent to their salary) and also the promise of transfer to areas of their choice by end of one year of service. This policy aimed to legitimize the existence of the central government, by showing responsiveness to these difficult areas where the majority of the ethnic-minority populations live. Another policy in those days was to recruit secondary school students for professional and paramedic training from these areas without the application of conventional criteria such as high marks or selection exams. In this way, more doctors, nurses and midwives returned back to serve their home towns. The approach was reintroduced in 2013, but since there are more border-area townships (now about 110) there is room for further 142 improvement such as ensuring retention of health workforce, adequate supplies and basic equipment, and improved responsiveness of service provision especially in terms of language and cultural barriers. During the 1990s, the government established 12 new universities for graduate and postgraduate medical doctors, graduate and postgraduate nurses, and similar degree courses for paramedical technicians, health assistants, etc. While regular 3-year 9-month training for diploma nurses was continued, the universities of nursing (2 in Myanmar now) delivered a four-year Bachelor degree course.

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For patients with watery discharges, consisting of ‘phlegm’ abstaining from baths was deemed better, 619 unless their use was important for other reasons. Epilepsy was to be treated with, among other things, purges, followed by bathing; the patient, however, was advised to avoid frequent baths. In certain cases the patient ought to avoid drinking strong or undiluted wines after taking a bath and avoid 620 remaining in the bath for a long time. Epilepsy might deserve additional attention here, as this disease received a lot of attention in the ancient medical texts, especially in the Hippocratic corpus. The author complained about various charlatans who, discussing the so-called “sacred disease” (the name given to epilepsy and similar illnesses), would hide their ignorance of its nature and call the disease sacred, 621 attributing it to the gods, and forbid, among other things, bathing the patients. For all it was worth, the extra caution when it came to bathing patients suffering from epilepsy seems to have survived until at least Late Antiquity, if in a milder form. Strokes and losses of consciousness were among the afflictions for which the 622 timing of the patient’s bathing was important. Taking baths was advised in pleurisy (pleuritis), but only when the 623 symptomatic inflammation was already in decline. In the Hippocratic texts, bathing is always treated as part of a more complex regimen, which usually consists of proper diet, exercises, rest and purging. He adopts a regimen contrary to the one he would benefit from and, among other things, takes many hot baths. Bathing was also discouraged in typhus, during its early stages, though after 626 about three and half weeks, the patient was to start receiving more nourishing food and take baths to strengthen the body. A malignant disease, bearing some semblance to typhus, was described in another Hippocratic work – after the initial treatment, and only after fever and pain have disappeared, the patient was to be bathed in plentiful 627 hot water Post-operation treatment of an abscess of the womb included hip-baths, of warm oil, water, or decoction of mallows; the patient should be put into such a bath 628 on the third day after the operation. Before surgical removal of leg varices, Paul suggests, the patient should be washed, and after ligatures have been tied on to the legs, he should be made to walk, 629 so that the affected veins would become more prominent. Almost identical 630 treatment is given by Aetius, with a note on the possibility of the use of cautery. Paul notes that occasionally fractured bones will not grow together properly, and as one of the causes for this he gives overly frequent bathing of the limb, or various other disturbances; the treatment, which was also to counteract emaciation, involved nourishing food, warming of the affected limb and bathing of the whole 631 body. In some of these conditions, bathing in general was not otherwise forbidden; in others, it was to be limited to the affected area. I discuss such cases below, following the earlier separation of bathing in pure water and in mineral waters and water with added substances. In pure water For patients affected by catarrh with coryza, caused by hot intemperaments, the cure is the same as for headaches rising from the same humours – bathing and pouring large amounts of hot water over the head. An ailment described by Paul of Aegina as erysipelas in the brain was to be 633 treated by cold applications (and bloodletting). The protrusion of bowels ought to be treated with applications, which should be applied only after the intestine was reduced and washed in cold water; Paul notes that this condition occurs most often in children. Numerous possible applications are listed, one of them specifically for the adults, and they were to be used unless the disease had already lasted for a long period of time. A precaution is added that the 634 patients should abstain from frequent bathing, certain foods and significant effort. The following sections of both of their works, however, do mention washing the face, legs and hands in cold water when the patients have been too long in the sun. A Hippocratic text mentions that washing in warm water should help for 637 638 639 various pains in the head, ears, and the body. In a disease where one of the symptoms is ulcerated skin of the head, the treatment involves washing it in hot water and then avoiding bathing for the next three days. When the ulcers actually do appear on the head, hot baths and application of ointment 641 is advised. Ulcers that have not yet suppurated were to be helped by applications 642 and having tepid water poured over them. In another disease, attacking mainly ears, 643 hot baths are advised as well, but only when the fever and pain remit. Relating advice for getting rid of the parasite dracunculus (or Guinea worm, Dracunculus medinensis) taken from his sources, Paul lists washing skin with warm water as means of drawing the parasite to the surface of the body, from where it could 644 be pulled out over a longer time (the latter method is still the most common 645 treatment nowadays). Immersing the ulcer caused by the parasite in water, however, could cause contamination of the water with parasite larvae, although the ancient texts do not address this; it is difficult, however, to ascertain whether the suggested therapy would have contributed to spreading the disease further. Discussing treatment of rabies, Paul suggests washing the afflicted (bitten) body part; the sore resulting from applying escharotics, should also be washed in a decoction of camomile and the root of wild dock (most likely that of Rumex 646 crispus). For poisonous spider (ϕαλαγγίον) bites, frequent baths, are advised, as they relieve the pain. The bitten areas in particular should be washed with hot seawater; 647 various decoctions should be administered orally as well. This treatment is reminiscent of the Hippocratic case study, when bathing and sweating seem to have helped a girl suffering from mushroom poisoning: while she was taking a bath, she vomited the 649 mushroom and, subsequently, sweated before recovering. Discussing burning of the eyelids with medicines, Paul notes that it should be avoided, but in case it is necessary, the resulting eschar (slough) should be carefully 650 washed off. Similarly, in cases when separating the eyelid from the eye by incision 651 was necessary, the area should be washed after the incision is made. In a similar vein, describing the operation for cataract, Paul mentions washing the eye with water 652 right after the perforator is removed. Should complications, such as inflammation, arise, the arm should be gently rubbed 654 with oil and bathed in warm oil daily, until the problem subsides. In water with added ingredients or in other substances 655 One of the treatments for paleness, given by Oribasius and copied by 656 Paul is boiling almond fruit in water and washing with it. Sleeplessness caused by fevers was discussed separately from cases affecting patients without other symptoms, and the treatment was quite different: rather than using relaxing baths, washing the patient’s forehead with a decoction from black 657 poppies was advised, at the time when the paroxysms caused by the fever subsided. Describing how to deal with excessive sweating, Paul mentions a treatment proposed by Archigenes, that is, bathing the patient’s abdomen in the juice of plantain, coriander, purslane or cabbage, as they were believed to have antiperspirant 658 properties. Paul’s text characterizes phrenitis (possibly meningitis) as an inflammation of the membranes (of the brain), caused by the excess of blood, of yellow bile, or by the 660 yellow bile turning black (which was supposed to be the worst case). Phrenitis is accompanied by watchfulness, and the treatment should include anointing the head with oils, occasionally with hot fomentations, but the patient should not be given hot water to drink. Further treatment included binding the patient with ligatures after bathing and friction. If the body was squalid and hot, then the patient should be bathed in fresh water even if the fever remained, and he should be treated with anointing and given weak wine to drink. The general Hippocratic advice was to wash 661 patients suffering from phrenitis with warm water. Convulsions (spasms) were believed to arise either from plethora, or from depletion; the one caused by depletion was deemed more dangerous. If there were no reasons to prevent the patient from bathing, a tepid hip-bath with added oil was 662 suggested, along with gentle friction. Some of the notes on the treatment of tetanus include the following advice: if the attack continues for a long time, the patient needs to be put in a hip-bath of oil, twice a day, but for a short period of time, as of all the possible measures, oil baths 663 were considered to be the most weakening. Two case studies from Epidemics mention tetanus: first one describes how a man who suffered from a sprained thumb, after the inflammation ceased, went to work in the field. When he was going home, he felt pain in the lower back and then he bathed; his jaws became fixed together in the 664 evening and he died on the third day. The same case is described again in a later 665 book, and only here is the disease named: it was tetanus. In both cases bathing is merely mentioned among the actions of the ill person and the link between bathing and the worsening of health and death of the patient is uncertain. Adams notes that Alexander of Tralles favoured tepid baths for treating phrenitis. If the bathing causes flux, bread or sponges soaked in Ascalonian wine, or other astringents should be applied to abdomen, and the patient should take his baths with the 666 applications. One of the case studies in the Hippocratic Epidemics describes how bathing might have helped a man who was suffering from a long bout of dysentery; on the seventieth day from the start of his disease, he took a bath towards the night and sweated afterwards. Since the description of the case ends almost right after this remark, without the mention of either death or curing the patient, it seems plausible to assume that the patient lived. Sweating, most probably caused by the bath, should 667 then be seen in this case as positive and leading to health. Paul’s compendium contains a rather detailed course of treatment for colic afflictions: if the pain is persistent, the patient should be made to sit in a hip-bath of the decoction of fenugreek (Trigonella foenum-graecum), marshmallows (Althaea officinalis), chamomile, mugwort (Artemisia vulgaris), dill, bay and similar plants. If the pain still does not subside, natural baths should be employed, but bathing in drinking water should be avoided, unless the pain (and, presumably, the lack of nearby mineral springs) make using it necessary. Enemas should be followed by bathing; also, 668 fomentations should be made in the baths, because of their heat. Adams adds that Alexander of Tralles specified that if the illness was caused by cold humours, baths should only be taken in sulphurous water, or hip-baths of decoction of parsley, anise and oil; if it was caused by hot and bilious humour, ordinary baths should be used, but if the problems were caused by an inflammation, then baths should only be employed 669 after venesection.

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Degree of cal cifcation has also been correlated to daytime tiredness and sleep disturbance (Kunz et al. There is one remarkable study published by the British Medical Journal more than 20 years ago that indicates a correlation between pineal calcifcation in humans and a poor sense of direction (Bayliss et al. This report is intriguing when compared with studies on homing pigeons, whose pineal gland is paramount to survival, indicated by a brain weight of 10% (compared with 1% for humans). When homing pigeons have extensive calcifcation, they too lose their sense of direction. The Pineal Gland 347 Perhaps, researchers should begin to study the correlation between pineal calcifca tion and senility. In addition, the pineal gland’s major hormone, melatonin, is highly lipophilic, which means that it easily passes out of the pineal via cell membranes, including the epi thelial cells in the blood vessels, the lymph vessels, the serous cavities, and the cavities of the heart. The lack of a blood–brain barrier and the lipophilic quality of melatonin places the pineal gland in the optimal position for its responsibilities as the primary endocrine transducer and regulator of hormonal signals. In addition, a neural pathway has been established from the eye to the pineal gland (Figure 10. The pathway begins at the ganglion cells of the retina, which have axons that make up the retinohypothalamic tract. From the hypothalamus, long descending axons of hypothalamic neurons synapse on autonomic neurons of the intermediolateral cell column in the upper thoracic spinal cord. The signals continue via the paraventricular nuclei to the spinal cord, where preganglionic axons exit the spinal cord to terminate on neurons in the superior cervical ganglia. Postganglionic neurons from the superior cervical ganglia travel back up and terminate in the pineal gland. Unlike many invertebrates whose pineal glands are connected to the roof of the brain, in mammals these postganglionic neurons replace any direct nerve con nection to the brain. In the early 1960s, Richard Wurtman and his mentor Julius Axelrod determined that in periods of darkness, the postganglionic (sympathetic) fbers from the superior cervical ganglia release norepinephrine (the major hormonal input) into the synap tic cleft, activating the retinohypothalamic–pineal system (Wurtman et al. Pinealocytes secrete various peptides and neurotransmitters (see next section) in addition to melatonin (the major hormonal output). When norepinephrine stimulates β-adrenergic recep tor sites at night, melatonin is synthesized and secreted from the pinealocytes. Recall that in the chapter on the relaxation system (Chapter 4), we learned that mela tonin not only fts into its own receptor, but also into the benzodiazepine receptor (Marangos et al. A group of researchers from Buenos Aires frst showed that there are benzodiaz epine receptors in the bovine pineal, and then a few years later they located them in the human pineal (Lowenstein and Cardinali, 1982; Lowenstein et al. Both benzodiazepines and melatonin reduce anxiety, alleviate depression, and aid insom nia. Recall that diazepan can suppress melatonin-binding sites, an action reversed by exogenous melatonin, and that peripheral benzodiazepine receptors can reverse the antidepressant action of melatonin (Atsmon et al. Clearly, a portrait emerges of a reciprocal and interactive relationship between these two molecules. The pineal infuences the secretion of these hormones, potentially resulting in signifcant functional and physiological changes. It is possible that some of the hormones are synthesized in the pineal and others arrive there via the circulation, but their presence still appears to have an impact on system function. For the most part, the pineal has an inhibitory impact on hormones and body function. The extensive number of hormones found in the pineal, alone, is indicative of the broad infuence of the pineal gland (Table 6. In 1958, melatonin (N-acetyl-5-methyoxytryptamine) was frst isolated by Aaron Lerner, an American dermatologist (Lerner et al. Lerner isolated the mela tonin, which was known to lighten skin melanocytes of amphibians and fsh, from 350 the Scientifc Basis of Integrative Medicine 250,000 bovine pineal glands (Binkley, 1988). Curiously, melatonin also is found in plants, particularly of the rice family, and some researchers claim that it can enter the blood and bind to melatonin receptor cites when ingested (Hattori et al. It is, however, an intriguing line of research, which in my opinion, warrants further study. Endogenous circadian rhythms of not only melatonin, but also of core body temperature and cortisol, average 24. Daytime administration of small doses of melatonin increases fatigue, decreases oral temperature, and impairs vigilance tasks (Arendt et al. An 80-mg dose of melatonin can raise normal nighttime concentrations by 350 to 10,000 times (Waldhauser et al. As any new parent might guess, infants under three months of age secrete very little melatonin. Fortunately, this trend soon changes as humans reach peak con centration levels in the frst to third years of life (Brzezinski, 1997). As mentioned, melatonin production progressively declines throughout life, showing considerable depletion with age: 250 pg/ml at ages 1 to 3; 120 pg/ml at ages 8 to 15; and declining gradually to 20 pg/ml by age 50 to 70 (Utiger, 1992). Food and Drug Administration (it is categorized as a supplement because it is naturally found in foods), it is possible that there are detrimental effects that are not generally known. Important research shows that an optimal dose of melatonin for those individuals whose levels are subnormal seems to be 0. Melatonin synthesis occurs in the retina, Harderian gland, lymphocytes, monocytes, bone marrow cells, ovary, and the gut (Arendt, 1988; Reiter et al. Animal studies show that the increased level of pineal melatonin production during darkness is paralleled by an increased level of melatonin in the blood (Rollag et al. Although melatonin can be synthesized in areas other than the pineal, it is generally thought that the contribution of melatonin measured in blood plasma is the Pineal Gland 351 solely of pineal origin because pinealectomized animals had no detectable plasma melatonin (Cogburn et al. However, other research on animals shows that at least some of the plasma melatonin loss from pinealectomy is regained if the animal is retested several weeks later (Osol et al. A case study published in the New England Journal of Medicine reported that the removal of a cancerous pineal gland from a patient resulted in the disappearance of plasma melatonin, although the diseased gland had been capable of normal melatonin secretion and circadian rhythm (Neuwelt et al. The researchers concluded that the pineal is the sole source of plasma melatonin in humans. In support of this concept is the knowledge that pineal gland removal in humans is accompanied by chronic and severe insomnia, which can in turn be ameliorated by melatonin administration (Etzioni et al. While concentrations of urinary and salivary melatonin are not identical to plasma melatonin levels, there is a consistently parallel relationship. For example, levels of a major melatonin urinary metabolite closely correlate to plasma melatonin levels, and saliva concentrations of melatonin maintain a correlation that is approximately 70% lower than those in the blood (Arendt, 1988; Kennaway and Voultsios, 1998; Lynch et al. The Kennaway study found that there is a highly signifcant correlation between the ratio of free plasma to total plasma melatonin and in the saliva melatonin to total plasma melatonin ratio. These results were the frst solid confrmation of an association between salivary and circulating melatonin levels. When norepinephrine stimulates the β-adrenergic receptor sites in the pineal, melatonin is not directly secreted from the pinealocytes, but rather it trig gers a series of intracellular responses by which the pineal metabolizes the amino acid, tryptophan, into melatonin (Arendt, 1988; Wurtman and Moskowitz, 1977a). A great deal of research has been performed to determine the importance of the role of each of the precursors of melatonin. These fuctuations correspond to the research on melatonin phase shifts and light suppression, which are described in the following section. This phase-response curve may vary signifcantly even among healthy individuals (up to 30 ng per 8 h interval), but it maintains a fairly consistent pattern for any particular person, allowing for the gradual and steady changes that correlate to shifts in season (Wurtman and Moskowitz, 1977b). A “reset” of the phase-response curve or a “phase shift” occurs when an envi ronmental factor. A delayed response or phase shift takes place when the secretion of melatonin shifts to a later time, which could occur from exposure to bright light at night or β-adrenergic blocking agents. An advanced response or phase shift occurs when there is exposure to bright light in the latter part of the night or very early morning hours. This results in a phase shift that causes melatonin to secrete earlier in the night. Virtually all investigations into the function of melatonin utilized the experimen tal setup of determining whether a phase shift has occurred. Hundreds of studies that have been performed on plants, insects, and mammals, including humans, confrm the fact that exposure to bright light at night causes a phase delay, and exposure to bright light in the very early morning hours results in a phase advance (Czeisler et al.

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Trypsin activates other proteolytic enzymes—chymotrypsin and carboxypolypeptidases. These enzymes breakdown intact protein and with the help of peptidases continue the breakdown until small polypeptides and amino acids are formed. The last phase of protein digestion also occurs in brush border, in which peptidases hydrolyse di and tri-peptides into constituent amino acids. Absorbed amino acids and peptides are transported via the portal vein to the liver to be released into the general circulation. Some amino acids, which remain in the epithelial cells, are used in the synthesis of new cells and intestinal enzymes. The endogenous protein released internally (by breaking down of epithelial cells and intestinal secretions) is digested and absorbed from the small intestine along with that ingested in the diet. Lipids the stomach lipase does act on emulsified fats in milk, cream, butter and egg yolk, but most of the hydrolysis of fats takes place in the small intestine. As soon as the food enters the duodenum, the gall bladder releases some bile and the pancreas secrete enzyme-rich juices. Bile is a secretion composed of bile acids, bile pigments, cholesterol, lecithin and many other compounds. About a liter of bile is secreted daily due to the stimulus of food in the duodenum. Large sugar molecules are changed to simple sugars by action of amylase and lipase acts on glycerides and reduces these to fatty acid and glycerol. The digested meal must be removed from the duodenum over a period of time, to permit digestion to proceed. Micelles, a combination of free fatty acids, monoglycerides and bile salts, facilitate the passage of lipids through the aqueous environment of the intestinal lumen to the brush border. The bile salts are then released from the lipid complex and return 3 to 15 times to carry more lipids across the membrane, depending on the amount of food ingested. The fatty acids and monoglycerides are reassembled into new triglycerides in the mucosal cell. Chylomicrons are formed by surrounding a combination of triglycerides, cholesterol, and phospholipids with a beta-lipoprotein coat. Chylomicrons are transported by lymphatic vessels into the blood stream and further on to the liver. Cholesterol is hydrolysed by pancreatic cholesterol esterase from ester form and absorbed in the same manner as lipids. Some forms of the vitamins A, E and K and carotene do not need bile acids for their absorption. Fatty acids of 10 carbons or less, due to shorter length and increased solubility, do not need bile salts and micelle formation for their absorption and can be absorbed directly into the mucosal cell. From the mucosal cell these acids go directly via the portal vein to the liver, without esterification. Those patients, who cannot metabolise usual long-chain fatty acids in dietary fat, due to lack of bile salts or some other problem, can be fed triglycerides of medium-chain fatty acids (C8 and C10). The digestive process is also aided by friendly bacteria which live in the intestinal tract. Other Nutrients Vitamins and water pass unchanged from the small intestine into blood by passive diffusion. In the first stage, chemical reactions occur in the stomach and intestines, which are affected by the pH of the mix. In the second stage, these are carried across the membrane into intestinal mucosal cell. In the third stage, minerals are transported into the blood stream or are bound within the cell. Important interactions occur between minerals in the gastrointestinal tract, which affect the amount that is absorbed. There is simultaneous absorption of vitamins, minerals and fluids through the intestinal mucosa. About 8 liters of fluids move to and from across the membrane of the gut to keep the nutrients in solution. The current understanding of the sites and routes of absorption of nutrients is depicted in Figure 2. Psychological factors, which play an important role in food acceptance, ingestion and digestion. If one likes the sight, smell and taste of food, it increases secretions of saliva, stomach juices and motility of gastrointestinal tract. Sound teeth to bite, cut and tear food into smaller pieces helps digestion, absence of molars, incisors and/or canine teeth affects the person’s ability to grind the food adversely and hence digestion is poor. Sufficient supply of water to dilute the food, permits effective movement through the digestive tract and increases the surface area for efficient enzymatic breakdown. Normal secretion of enzymes, bile, hydrochloric acid aids the chemical splitting of food components to small absorbable units. Any psychological stress, which makes a person tense, interferes with the digestive process by upsetting the occurrence of the normal secretions mentioned above. Role of Large Intestine Large intestine consists of cecum, colon, rectum and the canal and is about 5 feet long. Since the colonic contents move forward very slowly, most of the nutritionally valuable matter is absorbed. The large amounts of mucus secretion by the mucosa of large intestine protects the intestinal walls from the adverse effects of bacterial and other action. The neutralisation of acidic products of bacterial action is ensured by the action of bicarbonate ions secreted in exchange for absorbed chloride ions. Absorption and Transportation Absorption is the process of sucking up the nutrients in the body. Absorption of food from the digestive tract into the blood and lymph takes place after the digested food is moved forward by peristaltic waves (muscular contraction and relaxation) into the small intestine. These peristaltic waves push the food against the absorbing surface of the intestinal wall. The intestinal wall is lined with four to five million tiny finger-like projections called villi (see Figure 2. The cells which cover villi permit the absorption of final products of digestion— small molecules of sugars, amino acids and fat products and water, into the vessels that carry away the blood and lymph. Ordinarily a great deal of time is permitted for the absorptive process because the digested material must traverse the entire length of the intestine a distance of about 20 ft. Besides the shape and size of intestinal wall, other factors affect absorption of the digested food. For example, bile favours absorption of fats, calcium can be absorbed in the presence of vitamin D and vitamin B12 can be absorbed only in the presence of an intrinsic factor in the gastric juice. The intestine, which is a semipermeable membrane, is highly selective and permits the passage of nutrients only under certain special conditions. A high concentration in the blood stream may allow less absorption of vitamins and minerals than would be permitted at a time when the blood level of these nutrients is low. The sugars, amino acids, water-soluble vitamins, minerals salts and possibly some of the fat products are absorbed directly into the blood stream through the intestinal wall and are carried to the liver. The remainder of the end products of fat digestion and the fat soluble vitamins enter into the lymph system. Digestion, Absorption and Utilisation of Nutrients 2121212121 Individuals in normal health may vary in their capacity to absorb even fully hydrolysed foods. The recommended daily dietary allowances and the daily food guide provide quantities of nutrients generally sufficient to cover the needs of individuals with normal variations in capacities to digest and absorb nutrients. Enlarged villi, showing “brush border” of microvilli Muscularis mucosae Mucosal folds (valvulae conniventes) Villi Circular muscle layer Longitudinal muscle Outer serosa Figure 2. Utilisation of Nutrients in the Body Metabolism of all nutrients occurs within the cells of our body. The final oxidation of nutrients into carbon dioxide and water occurs in the mitochondria. The individual cells die and are replaced by new cells formed as part of normal life processes.

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Another unique aspect of this discipline is that transplant surgeons initiate and manage the immunosuppressive drug regimens that patients require after re ceiving someone else’s organs. The transplant surgeon typically works as a part of an integrated team of professionals, including transplant coordinators, nurses, psy chiatrists, social workers, and medical subspecialists (nephrologists, endocrinol ogists, gastroenterologists, and hepatologists). Trauma Surgery and Critical Care Fast paced, intense, and unpredictable, trauma surgery gives you the chance to put your skills to work in the acute setting and save lives. Traumatic injuries range from motor vehicle accidents, gunshot and stab wounds, crush injuries, electri cal injuries, and much more. Trauma surgeons are true general surgeons who command a fund of knowledge about the entire human body. They serve as lead ers of the trauma team to stabilize and resuscitate acutely ill patients before tak ing them off to the operating room. Working at Level I trauma centers, these sur geons have to be available 24 hours a day, 7 days a week when they are on duty. Many trauma victims are critically ill for long periods of time, so this dual spe cialization of trauma surgery with surgical critical care is an ideal combination. If you enjoy complex physiology and a great deal of direct patient management, this invigorating field is for you. Vascular Surgery Vascular surgery involves the arteries and veins of the entire body, from the neck to the distal extremities. To help an older man with severe peripheral vascular disease in his leg, which could lead to gangrene, vascular surgeons perform a bypass operation to go around the diseased artery segment. Vascular surgeons, therefore, maintain a high level of technical skill and finesse. It is a subspecialty full of great variety: elective procedures such as arteriovenous fistulas for dialysis access to emergencies like repairing a ruptured aortic aneurysm. Most patients undergoing vascular surgery have multiple comorbidi ties, in particular heart disease and diabetes. This highlights the need to know a great deal about the medical management of these disorders. If you enjoy medi cine, surgery, and critical care, completing a 1-to 2-year fellowship in vascular surgery is the ideal combination for a gratifying career. Advances in endovascu lar surgery (stent-grafts for treatment of abdominal aortic aneurysm) are revolu tionizing the field and expanding the scope of vascular surgery. Surgery is the perfect field for those who want to see that their actions have an immediate and essential effect on their patient. It is an ideal career for those who want to heal, quite literally, with their hands. Consider the treatment of a teenager with appendicitis: a discussion with the patient, a dose of antibiotics, anesthesia, incision, resection of the appendix, and discharge the following day. Before the era of antibiotics and rapid surgical treatment, appendiceal perforation was much more common, often leading to death from overwhelming abdominal in fection. A survey of 59 surgeons currently in practice said that it brought them joy to “fix patients. If they see what sur geons do and how they love it, they will be bitten by the bug that has bitten so many—generation after generation. Noth ing is greater than the unbelievable surge of adrenaline that occurs while scrub bing in, stepping into the operating room, and gowning up. Surgeons combine the scientific nature of a technician with the passion of an artist and the empa thy of a physician. They demand nothing but the best for the patients, and they give nothing but the best in all of their efforts. Although challenging and de manding, surgery amply rewards all the effort you put into it. Danagra Georgia Ikossi is a resident in general surgery at Stanford Univer sity Medical Center. After growing up both here and in Cyprus, she earned her undergraduate degree from Bates College. Jonathan Long Le, is a resident in plastic surgery at the University of California—San Francisco. Many medical students, patients, public policy makers, and even physicians in other fields of medicine might find it difficult to define. In fact, nearly half of all patients confuse these physicians with family practice doctors, general practi tioners, or even interns (first-year residents). In a single day, they can act as a diagnostician, an educator, a director, an advocate, a motivator, a healer, and a comforter. They also come to their bedsides in the hospital and manage their inpa tient care. Some internists spend their time providing acute and chronic primary care; others become subspecialists in cardiology, gastroenterology, endocrinology, and more. Whether focusing on one organ system or taking care of the whole pa tient, internists approach everything with great intellectual curiosity. Sick patients with complex medical problems turn to internists for high quality care. In many ways, internists are similar in practice style to pediatricians—but the kids have grown up. There is less asthma and more emphysema, the neonatal inten 229 Copyright © 2004 by the McGraw-Hill Companies, Inc. Their primary responsibility is to diagnose and treat acute and chronic medical conditions. A number of illnesses invariably comprise the core of most internal medicine practices. These diseases can range from acute problems such as up per respiratory tract infections, influenza, viral gastroenteritis, and urinary tract infections to more chronic problems like diabetes mellitus, chronic obstructive pulmonary disease, hypercholesterolemia, and hypertension. In fact, a large pro portion of medical patients are elderly with complex, chronic comorbidities. Common illnesses treated in the young-adult and middle-aged populations in clude gastroesophageal reflux disease, peptic ulcer disease, hyper or hypothy roidism, depression, musculoskeletal injuries, sexually transmitted diseases, and the acute infections listed above. Despite the usual plethora of common com plaints and illnesses, internists also have many opportunities to diagnose and treat rare diseases like babesiosis or Still’s disease. This is why a general internist’s daily practice spans a number of medical disciplines. You receive the challenges (as well as the rewards) of treating a broader range of illnesses than in almost any other specialty. This specialty is all about diversity: a varied group of patients spanning late adolescence to the end of life, a number of practice settings from the clinic to the hospital, a broad range of illnesses from acute to chronic, and over a dozen subspecialties. For ex ample, a physician trained in general internal medicine will evaluate a 24-year old woman presenting with weight loss and night sweats while a colleague who specialized in cardiology treats a 70-year-old heart attack victim in the cardiac catheterization lab. On a given day, a general internist with a special interest in sports medicine will treat a 40-year-old male with a torn rotator cuff, while an other colleague gives preventive influenza vaccinations to the residents of a nurs ing home. No matter the subspecialty, all internists have a similar set of clinical re sponsibilities. Most important, they provide long-term medical care while diag nosing and treating acute and chronic problems, whether in the office or hospi tal. Internists are generally responsible for taking care of their own patients if they are admitted to the hospital (for problems such as congestive heart failure, pan creatitis, asthma, bacteremia, unstable angina, and pneumonia). All internists practice preventive medicine, which involves health maintenance and disease screening. General internists must be aware of their own limitations and know when to seek specialized help on a given organ system disease. In fact, they are often asked by surgeons and obstetricians to see patients who have difficult general medical conditions. Internists have highly detailed knowledge about how to manage the most complicated of medical problems found in the adult population. Family practitioners, on the other hand, care for people of all ages throughout their entire lives. Because they have broader train ing across other disciplines (obstetrics-gynecology, surgery, psychiatry), family practice doctors have less depth of training in internal medicine. Another distinguishing fea ture of internal medicine is the option to subspecialize in a vast array of fields af ter residency.

References:

  • https://www.aapm.org/meetings/05SS/program/eyeplaque072005_chiu.pdf
  • https://pubs.usgs.gov/fs/2017/3064/fs20173064.pdf
  • https://metronidazole.files.wordpress.com/2010/03/medical-surgical_nursing-10th-edition-by-brunner-suddarth.pdf
  • https://www.cancer.org/content/dam/CRC/PDF/Public/8605.00.pdf

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