Amy H. Sheehan, PharmD

• Associate Professor of Pharmacy Practice, Purdue University College of Pharmacy
• Drug Information Specialist, Indiana University Health, Indianapolis, Indiana

https://www.pharmacy.purdue.edu/directory/hecka

Together with oxides and fine particulate matter menstruation 7 weeks post partum buy 5 mg aygestin amex, ozone forms the smog (derived from the words smoke and fog) womens health clinic buy 5mg aygestin visa. Its toxicity is due to production of free radicals menstrual belt generic aygestin 5 mg otc, which damage the lining cells of the respiratory tract and the alveoli (produces cough and dyspnea) on acute exposure pregnancy jeans aygestin 5 mg cheap. Though low levels of ozone can be tolerated by healthy individuals pregnancy insurance buy aygestin with paypal, they are harmful to lung function womens health worcester 5 mg aygestin otc, especially in patients suffering from asthma or emphysema. Chronic exposure to ozone in smog can cause deterioration in pulmonary function and is associated with a slight but significant increase in mortality. Particles of size <10 m in diameter are particularly harmful, because they can reach all the way to the alveoli. In the alveoli, they are phagocytosed by macrophages and neutrophils, release mediators and produce an inflammatory reaction. In contrast, larger particles are less dangerous because they are removed in the nose or are trapped by the mucociliary action in the upper respiratory tract. Acute exposure produces bronchoconstriction and inflammation of respiratory tract. They are also generated from burning fossil fuels, especially in generating electricity. It is produced by the incomplete combustion (oxidation) of organic substances (carbonaceous materials). However, individuals working in confined environments with high exposure to fumes. Carboxyhemoglobin concentrations under 10% are common in smokers and usually do not produce symptoms. The oxygen from carboxyhemoglobin does not dissociate as readily as in oxyhemoglobin. Indoor Air Pollution In the modern world there is increased potential for pollution of the indoor air. Smoke from burning of organic materials: They contain various oxides of nitrogen and carbon particulates which are irritants that predisposes to lung infections and also may contain carcinogenic polycyclic aromatic hydrocarbons. It is produced by burning carbon-containing material, such as wood, dung, or charcoal in homes for cooking, heating, and light. However, low-level chronic exposures in nonsmokers home are less likely to increase the risk of lung cancer. They may also contain allergens derived from pet dander, dust mites, and fungi and molds that can cause rhinitis, eye irritation, and even asthma. Metals as Environmental Pollutants the various heavy metals that can produce harmful effects in humans include lead, mercury, arsenic, and cadmium. Lead is a heavy metal commonly found in the environment of industrialized countries. The use of lead-based paints and leaded gas has been greatly decreased and the main sources of lead in the environment includes mines, foundries, batteries, and spray paints, all of which are occupational hazards. The flaking lead paint in older houses, lead pipes and soil contamination also contains lead. In adults: Occupational exposure in individuals engaged in lead smelting (releases metal fumes and deposits lead oxide dust). Lead oxide is a constituent of battery grids and an occupational exposure occurs in individuals working in the manufacture and recycling of automobile batteries. In children: Lead poisoning was related to pica-the habit of chewing on cribs, toys, furniture and woodwork-and eating painted plaster and fallen paint flakes. Pathophysiology: Lead is easily absorbed through the lungs or, less often, the gastrointestinal tract. In these sites, lead competes with calcium, binds phosphates, and has a half-life of 20 to 30 years. Lead can easily cross the blood-brain barrier and concentrations in the brain, liver, kidneys and bone marrow. Lead binds to sulfhydryl groups in proteins and interferes activities of zinc (Zn)-dependent enzymes and also calcium metabolism (lead competes with calcium). In bones, teeth, nails and hair, it forms a tightly bound pool of lead which is harmful. Effects of chronic exposure to low lead levels: Presently, the level of exposure to lead is markedly reduced due to the several measures taken to prevent exposure to lead. The chronic and cumulative exposure to lead is best measured in bone, rather than blood. The chronic lead exposure in children may produce mild dysfunction, or may be massive and lethal. In young children, it may produce sensory, motor, intellectual, and psychologic impairments. Lead-induced peripheral neuropathies in adults generally subside with the elimination of exposure. Excess lead interferes with the normal remodeling of calcified cartilage and primary bone trabeculae in the epiphyses. This can be detected radiographically as radiodense "lead lines" and is simple method of detecting increased body stores of lead in children. Lead also inhibits the healing of fractures by increasing chondrogenesis and delaying mineralization of cartilage. Lead binds to sulfhydryl groups and interferes with two enzymes involved in heme synthesis in bone marrow erythroblasts. The enzymes inhibited are (i) aminolevulinic acid dehydratase and (ii) delta ferrochelatase. Inability to produce heme adequately causes a microcytic and hypochromic anemia like that seen in iron deficiency (refer Chapter 11). This may increase the fragility of red cells causing hemolysis (reduced life span). In adults, peripheral neuropathies are common whereas central nervous tissue is more commonly affected in children. Lead encephalopathy is observed in severe cases and the brain shows edema, flattening of gyri and compression of ventricles. Microscopically the changes include edema, congestion, petechial hemorrhages, demyelination of the cerebral and cerebellar white matter, and necrosis of cortical neurons accompanied by diffuse astrocytic proliferation in both the gray and white matter. They may develop convulsions or display altered states of consciousness (drowsiness to frank coma). The most common manifestation of lead neurotoxicity in the adults is peripheral demyelinating neuropathy. It typically involving motor neurons (radial and peroneal nerves) innervating the most commonly used muscles. Thus, the extensor muscles of the wrist and fingers are often the first to be affected, followed by paralysis of the peroneal muscles (wrist drop and foot drop). Lead-induced neuropathy may be responsible for the paroxysms of extremely severe, poorly localized abdominal pain known as lead colic. Kidney: Excretion of lead occurs through kidneys, and acute exposures may cause damage to proximal tubules. Lead nephropathy is due to the toxic effect of the lead on the proximal tubular cells of the kidney. It is characterized by aminoaciduria, glycosuria and hyperphosphaturia (Fanconi syndrome). Microscopically, characteristic intranuclear lead inclusions are seen in the nuclei of the proximal tubular cells in lead nephropathy. Chronic renal damage may result in fibrosis in the interstitium and renal failure. Laboratory diagnosis: For definitive diagnosis of lead poisoning, intoxication, elevated blood lead and red cell free protoporphyrin levels (>50 g/dL) or, alternatively, raised blood levels of zinc-protoporphyrin levels or its product are required. Mercury Mercury binds to sulfhydryl groups (like lead) in certain proteins with high affinity. Source: Humans have used inorganic mercury since prehistoric times and it has been known to be an occupation-related hazard. It was used as a pigment in cave paintings, a cosmetic, a remedy for syphilis, and a component of diuretics. In recent years, the main sources of exposure are organic (derived from living matter) mercury present in contaminated fish and dental amalgams that release mercury vapors. In some areas mercury used in gold mining, or from fertilizer and plastics factory, is discharged into and contaminate the rivers. Inorganic mercury from industrial wastes can be converted to highly neurotoxic organic compounds, such as methyl mercury by bacteria in bays and oceans. Nephrotoxicity: In the kidneys, mercury can produce acute tubular necrosis (proximal tubular necrosis) and renal failure. Arsenic compounds have been used as insecticides, herbicides, weed killers, other agricultural products and wood preservatives. Arsenicals may also be found naturally in soil and ground water (in countries, such as Bangladesh, Chile, and China) as a result of naturally occurring arsenic-rich rock formations, from coal burning or from use of arsenical pesticides. Toxic effects: these include: v v Acute arsenic poisoning is almost always due to accidental or homicidal ingestion. Ingested of large quantities of arsenic causes severe abdominal pain, diarrhea; cardiac arrhythmias, shock and respiratory distress syndrome; and acute encephalopathy. These effects may be due to the interference with mitochondrial oxidative phosphorylation. Chronic exposure to arsenic: Chronic arsenic intoxication affects many organ systems. Cancers of the skin, respiratory tract (lung carcinoma) and gastrointestinal tract may develop due to industrial and agricultural exposure. This may be followed by the development of basal and squamous cell carcinomas (but not melanomas). Arsenic can cause encephalopathy and peripheral neuropathy (paresthesias, motor palsies and painful neuritis). Cadmium Sources: Cadmium is a plasticizer and a pigment and is relatively a modern toxic agent. It is used in manufacturing alloys, producing rechargeable nickel-cadmium batteries and electroplating other metals. Cadmium oxide fumes are released during welding of steel parts previously plated with a cadmium anticorrosive. Cadmium can contaminate soil and plants directly or through fertilizers and irrigation water. Both plant- and animal-derived foodstuffs may contain substantial amount of cadmium. In the kidney, initially it produces proteinuria due to tubular damage (rather than glomerular damage) that may progress to end-stage renal disease. Chromium Chromium (Cr) is used in several industries, such as metal plating and some types of manufacturing. Chronic exposure is highly genotoxic and increases the risk of lung cancer and other tumors. Nickel Nickel is used in electronics, coins, steel alloys, batteries and food processing. The most frequent effect of exposure to nickel is contact dermatitis ("nickel itch") and can develop due to contact with metals containing nickel, such as coins and costume jewelery. Exposure to nickel increases the risk of lung cancer and cancer of the nasal cavities. Tobacco is the most common exogenous cause of human cancers and is responsible for about 90% of lung cancers. Apart from death due to various types of cancers, tobacco can cause deaths from cardiovascular and metabolic diseases, deaths from nonmalignant lung diseases and perinatal deaths. Life expectancy is reduced by cigarette smoking and overall mortality is proportional to the amount (dose dependent) and duration of smoking commonly quantitated as "pack-years. Betel quid/pan is a type of tobacco chewing that contains several ingredients, such as areca nut, slaked lime, and tobacco which are wrapped in a betel leaf. Oral cancers are found on the buccal and gingival surfaces in the sites where tobacco products are held in contact with the mucosa for long periods. Constituents of Tobacco Smoke Tobacco contains more than 2,000 substances (potentially noxious) and more than 60 have been identified as carcinogens and few of them along with the type of injury produced by these agents are listed in Table 9. It does not directly cause tobacco-related diseases, but is strongly addictive and is responsible for tobacco addiction. Nicotine binds to nicotinic acetylcholine receptors in the brain, and release catecholamines from sympathetic neurons. This is responsible for the acute ill effects of smoking namely increase in heart rate, blood pressure, cardiac contractility and output. Respiratory System the most common diseases caused by cigarette smoking involve the respiratory system mainly lung. The risk of developing lung cancer depends on the intensity of exposure and is usually expressed in terms of number of "pack years". In nonsmokers, passive environmental smoke inhalation is also associated with risk of lung cancer than those who are not exposed to passive smoke. Chronic bronchitis, emphysema and chronic obstructive pulmonary disease: Contents in tobacco smoke directly irritate the tracheobronchial mucosa, producing inflammation and increased production of mucus (bronchitis). Cigarette smoke also recruits leukocytes to the lung, and increases the local production of elastase. Children living along with adult smokers are susceptible to increased respiratory illnesses and asthma.

Diseases

• Annuloaortic ectasia
• Trigger finger
• Otospondylomegaepiphyseal dysplasia
• Macroglobulinemia
• Carotid artery dissection
• Kleine Levin syndrome

Hypocalcemic Tetany Calcium is required for normal neural excitation and the relaxation of muscles menstruation gas bloating order aygestin toronto. Hypocalcemic tetany is a convulsive state caused by an insufficient extracellular concentration of ionized calcium menstrual sea sponge order generic aygestin online. Nonskeletal Effects of Vitamin D Vitamin D receptor is also present in various cells and tissues that are not involved in calcium and phosphorus homeostasis pregnancy 9 weeks 5 days buy aygestin online now. Many cells women's health center vcu safe aygestin 5mg, such as macrophages menstruation 6 days early cheap 5mg aygestin with visa, keratinocytes diagnosis women's health issues order 5mg aygestin, and tissues, such as breast, prostate and colon can produce 1,25-dihydroxyvitamin D. It is involved in the hydroxylation of proline and lysine in procollagen to hydroxyproline and hydroxylysine in mature collagen. Antioxidant properties: Ascorbic acid is the most active powerful reducing agent controlling the redox potential within cells. Vitamin C can scavenge free radicals directly and can act indirectly by regenerating the antioxidant form of vitamin E. Rarely, it may occur as a secondary deficiency, particularly among older persons who live alone, and chronic alcoholics. Vitamin E Vitamin E is a collective name for 8 stereoisomers of tocopherols and tocotrienols. Anti-inflammatory: Vitamin E also inhibits prostaglandin synthesis and the activities of protein kinase C and phospholipase A2. Vitamin E deficiency is seen only in premature infants and in severe and prolonged malabsorption diseases, such as celiac disease, or after smallintestinal resection. Vitamin K Forms of vitamin K: There are two natural forms: Vitamin K1 (phylloquinone) derived from vegetable (green leafy vegetables, such as kale and spinach) and animal sources (liver), and vitamin K2 (menaquinone) which is synthesized by bacterial flora in the colon and in hepatic tissue. Others: Other important gla proteins include osteocalcin (in bone) and matrix gla protein (vascular smooth muscle) that are important in mineralization of bone. However, the importance of vitamin K for mineralization of bone and prevention of vascular calcification is unknown. Deficiency in newborn: It is because of (1) low-fat stores, (2) low breast milk levels of vitamin K, (3) sterility of the infantile intestinal tract, (4) liver immaturity and (5) poor placental transport. Inadequate thiamin results in inadequate adenosine triphosphate synthesis and abnormal carbohydrate metabolism, respectively. Alcoholism, chronic renal dialysis and chronic illnesses, such as cancer are common precipitant factors. Alcohol interferes with the absorption of thiamine and with the synthesis of thiamine pyrophosphate. Maternal thiamine deficiency can lead to infantile beriberi in breastfed children. It is the classic deficiency syndrome observed in individuals consuming polished rice diet. It shows combinations of peripheral neuropathy, cardiovascular dysfunction and cerebral dysfunction. The neuropathy affects the legs most markedly, and these patients have difficulty rising from a squatting position. However, if untreated, they may be followed by a prolonged and largely irreversible condition, called Korsakoff syndrome. The syndrome is common in chronic alcoholics but may also be seen with thiamine deficiency resulting from gastric disorders including carcinoma, chronic gastritis, or persistent vomiting. Dry beriberi presents with a symmetric peripheral neuropathy of the motor and sensory systems with diminished reflexes. It also plays a role in drug and steroid metabolism including detoxification reactions. Serves as a coenzyme for a diverse array of biochemical reactions and as an electron donor. Deficiency Causes: Almost always is due to dietary deficiency and is usually seen in conjunction with deficiencies of other B vitamins. Effects of Deficiency Nonspecific and mainly manifests as lesions of the mucocutaneous surfaces of the mouth and skin. These include hyperemia and edema of nasopharyngeal mucosa, cheilosis, angular stomatitis, glossitis and seborrheic dermatitis. Other lesions include corneal vascularization, normochromic-normocytic anemia and personality changes. It is found mostly in populations in which corn is the major source of energy in parts of China, Africa and India. Early symptoms: Loss of appetite, generalized weakness and irritability, abdominal pain, and vomiting. Early signs: Bright red glossitis, stomatitis, vaginitis, esophagitis, vertigo and burning dysesthesias. Advanced stages: Characteristic skin rash develops that is pigmented and scaling that develops in skin areas exposed to sunlight. Four Ds: Diarrhea (in part due to proctitis and in part due to malabsorption), depression, seizures and dementia (or associated symptoms of anxiety or insomnia) leading to death and dermatitis are part of the pellagra syndrome. Certain medications, such as isoniazid, cycloserine, penicillamine, l-dopa, ethanol and theophylline can inhibit B6 metabolism. Because vitamin B6 interferes with the action of l-dopa, it should not be given with this drug. Microcytic hypochromic anemia is due to diminished hemoglobin synthesis, since it is the first enzyme involved in heme biosynthesis. Severe vitamin B6 deficiency: Peripheral neuropathy and abnormal electroencephalograms. These include pernicious anemia, pancreatic insufficiency, atrophic gastritis, small bowel bacterial overgrowth, or ileal disease. Neurologic complications: Demyelination of peripheral nerves, posterior and lateral columns of spinal cord, and nerves within the brain. The fully oxidized form is called folic acid which is not found in nature but is the pharmacologic form of the vitamin. Cytology is a branch of science which deals with study of cells and/or tissue fragments and cytopathology is a branch of pathology that deals with study and diagnosis of disease at the cellular level. During 1920, Dr George N Papanicolaou introduced cytology as a method of diagnosis by obtaining cells naturally shed off (exfoliated) into cervical and vaginal secretion. Subsequently use of cytological examination was extended to cells which shed off into other body cavities. Diagnostic cytology consists of the interpretation of cells from the human body that either exfoliate (desquamate) spontaneously from epithelial surfaces (Exfoliative Cytology), or are obtained from various organs/tissues by different clinical procedures (Interventional Cytology). In contrast to surgical pathology, cytopathology deals primarily with morphology observed in single cells or small groups of cells without regard to stroma. Pathologist who deals with and reports cytological material is called cytopathologist. It is usually used for screening, diagnosing and management of lesions that may represent cancer or its precursors. Advantages include cost-effectiveness, rapid turnaround time, and a diagnosis with minimal patient risk. Diagnosis and management of cancer: In oncology, diagnosis is essential for proper management of a cancer patient. For diagnosis: t Cytopathology is a valuable adjunct to histopathology for the diagnosis of benign, dysplastic and malignant lesions. For example, detection of malignant cells in ascitic fluid in a patient with ovarian tumor. Management of cancer: t Cytopathology may help in assessing response to therapy. Diagnosis of benign neoplasms: Cytopathology helps to distinguish between benign and malignant neoplasms. Intraoperative consultation: Intraoperative cytology is the procedure by which the cells are obtained during operation. Touch (imprint) cytology: Smears are prepared by forcefully pressing the clean glass slide to the cut surface of the organ. Scrape cytology: Smears are prepared from material obtained by scraping the cut surface of the biopsy specimen with clean scalpel. Crush preparation (crush cytology): Small fragments of fresh unfixed surgical tissue are crushed between two slides. Diagnosis of specific infections: A variety of bacterial, viral, protozoal and fungal infections can be diagnosed by cytopathology. For example, tubercle bacilli in lymph node aspirates, herpetic inclusions and trichomonas in cervico-vaginal smears, fungal hyphae in touch preparations from draining sinuses. Diagnosis of non-neoplastic and inflammatory lesions: It helps in diagnosis of conditions which do not routinely require surgical intervention. Cytogenetics: Cytological specimens can be used for chromosomal studies including leukocyte and tissue cultures and for demonstrating sex-chromatin. Hormonal assessment in females: Vaginal smears reflect changes in female sex hormonal levels. Identification of cell of origin: the cytoplasmic characteristics may help in identifying the cell of origin in malignant tumors. Two categories of methods are involved in diagnostic cytology to obtain cells for microscopic examination namely-exfoliative and interventional. Exfoliative cytology is the study of spontaneously/naturally exfoliated (shed) cells from the epithelial lining of an organ into a body cavity or body fluids such as urine, sputum, etc. Rate of exfoliation is increased in disease-states and yields a larger number of cells for study. Abrasive cytology: Apart from exfoliation, cells for study may also be obtained by scraping, brushing, or washing various mucosal surfaces. In abrasive cytology viable cells are artificially obtained by abrasive techniques from the surface of an organ. The instrument used to obtain the cells includes scraper or spatula (cervical, oral cavity-buccal smear for sex chromatin) and cytological brush (bronchial, gastrointestinal tract). The cells may also be obtained by washing or lavage (peritoneal, bronchoalveolar), where small amount of saline or similar solution is instilled into the target organ and aspirated. The cells obtained by abrasive technique do not show degenerative changes or necrosis, in contrast to that of exfoliative cytology. When the cells are collected with an instrument, the cells are either rinsed into a preservative solution, or simply directly spread onto slides. There are different methods of obtaining exfoliated cells and smears are prepared from the material obtained. Surface of mucosal or epithelial lining Cells may be shed naturally or obtained by artificial exfoliation 1. Urinary tract Urinary sediment (in voided urine) Bladder washings Retrograde catheterization Prostatic massage (secretions) 4. They are recommended for routine population screening for cervical cancers and endometrial cancers. Though they are v recommended for routine screening and help in localization of lesions (if present) but are difficult to prepare. Endocervical and endometrial smears: They are prepared by aspirating the contents of the endocervical canal and endometrial cavity respectively. Applications of Pap Smear Pap smears in gynecological sites may be used for hormonal evaluation, and identification of non-neoplastic, benign, and malignant tumors. Hormonal evaluation Assessment of hormonal status is carried out on smears from lateral vaginal wall. Non-specific inflammatory changes are commonly observed in gynecological smears and these changes may reflect acute or chronic inflammatory process. Specific inflammatory changes: They may be seen with a variety of infectious agents and their detection helps to identify these agents as cause of the disease. In the smears, Candida (refer page 98) may appear in two forms namely-the yeast form (unicellular) appears as round to oval budding organisms within conspicuous capsules, and the fungal form (pseudohyphae) as thin, elongated, pseudo septate, bamboo-like filaments. Neoplastic epithelial cell abnormalities Detection of carcinoma of the uterine cervix and its precursor lesions is considered as the most important application of exfoliative cytology in female genital tract. These include: v Pre-invasive and invasive squamous cell abnormalities: Pre-invasive intraepithelial neoplastic process of uterine cervix usually precedes the fully-developed invasive squamous cell carcinoma and can be detected by cytologic examination. Classification of cervical precancerous lesions and cervical cancer screening are discussed on pages 739-41, and page 743 respectively. Automation in Cervical Cytology Presently, automated devices such as PapNet for primary screening are available in the market. Automation can perform routine pre-screening of many Pap smears, reduces the workload of cytopathologists and also provides quality assurance. Non-gynecologic Exfoliative Cytology Respiratory Tract Cellular material from the respiratory tract may be obtained by different techniques. Sputum (sampling of exfoliated cells) Sputum contains mucus admixed with exfoliated cells from the entire respiratory tract. By examining the morphology of these cells, it is possible to identify the underlying pathological process. Sputum is the most commonly examined sample from respiratory system and is easy to collect and examine. Sputum is collected in the early morning produced by a spontaneous deep cough to bring up material from small airways and alveoli. If the patient is not able to produce sputum then expectoration (cough reflex) can be artificially induced by 20 minutes aerosol-inhalation of coughstimulating substances [e. Sputum should be collected in a clean container and should be kept in a petri dish on white background.

Stresses may accelerate aging probably by increased production of glucocorticoids pregnancy 26 weeks best purchase for aygestin. Thus menstrual 3 times a month purchase aygestin 5mg fast delivery, aging can be delayed by either by reducing the metabolic damage or by increasing the repair response to that damage women's health tips now generic aygestin 5mg without prescription. Factors that Increases Longevity Caloric Restriction It has been found that caloric restriction alters signaling pathways that influence aging and can slow down aging and prolong life women's health center lattimore road purchase aygestin 5mg. Note: Hormesis is a biological phenomenon whereby a beneficial effect (improved health menstruation every 20 days buy aygestin 5 mg with visa, stress tolerance womens health zone abortion buy aygestin 5 mg mastercard, growth or longevity) results from exposure to low doses of an agent that is otherwise toxic or lethal when given at higher doses. Definition: Inflammation is a complex local response of the living vascularized tissues to injury (infections and tissue damage). It brings cells (phagocytic leukocytes) and molecules which are necessary for host defense (antibodies, and complement proteins) from the circulation to the site of injury (where they are required), to eliminate the offending injurious agents. Inflammation is largely confined to the site of infection or damage but can develop some systemic manifestations. Sometimes, the term subacute inflammation is used to describe the inflammation between acute and chronic. A fifth clinical sign, loss of function (functio laesa), was later added by Rudolf Virchow. Cardinal sign Rubor (redness) Calor (heat) Tumor (edema/swelling) Dolor (pain) Mechanism Increased blood flow and stasis Increased blood flow Increased vascular permeability causing escape of a protein-rich fluid from blood vessels Chemical mediators: Prostaglandins and kinins Causes of (Stimuli for) Inflammation (Box 3. Julius Cohnheim first described emigration of leukocytes through microvasculature walls in inflammation. This recognition is done by receptors on cell surface (cellular receptors) and circulating proteins. Cellular Receptors for Microbes the presence of infectious pathogens (microbes) is recognized through receptors present on cells. These cells include phagocytes, dendritic cells (cells in epithelia and all tissues which are involved in capturing microbes), and many other cells. There are many cellular receptors for microbes which detect pathogens or the damage induced by them (refer page 142). These proteins include cytokines that induce inflammation, anti-viral cytokines (interferons), and cytokines and membrane proteins that promote lymphocyte activation and immune responses. Sensors of Cell Damage All cells contain cytosolic receptors which recognize molecules that are liberated or altered due to cell damage. The cytosolic receptors activate a multiprotein cytosolic complex called the inflammasome. Gain-of-function mutations in the cytosolic receptors produce rare diseases known as autoinflammatory syndromes which are characterized by spontaneous inflammation. Circulating Proteins Many plasma proteins recognize microbes and function to destroy bloodborne microbes and stimulate inflammation at the site of tissue infection. Explain the sequential vascular changes/reactions of blood vessels/hemodynamic changes in acute inflammation. Sequence of events in acute inflammation: Acute inflammation has two major components namely: (1) reactions of blood vessels (vascular changes) and (2) reactions of leukocytes (cellular events). Purpose: To deliver the circulating cells, fluids and plasma proteins from the circulation to sites of infection or tissue injury. Increased permeability of the microvasculature: It leads to escape of protein-rich fluid from the circulation into the extravascular tissues. Write short essay on mechanism of increased vascular permeability (vascular leakage) in inflammation. Exudation is defined as the process of escape of fluid, proteins and circulating blood cells from the vessels into the interstitial tissue or body cavities. Escape of a protein-rich fluid causes edema and is one of the cardinal signs of inflammation. Leukocyte-mediated vascular injury: the leukocyte (mainly neutrophils) which adheres to the endothelium during inflammation may themselves injure the endothelial cells. Characteristics Characteristics Cause Mechanism Transudate Noninflammatory process Ultrafiltrate of plasma, due to increased hydrostatic pressure with normal vascular permeability Clear, serous Straw yellow <1. Increased transcytosis: Process of transport of fluids and proteins through the channels called vesiculo-vacuolar organelle is increased in number during inflammation. Leakage from new blood vessels: During repair new blood vessels are formed (angiogenesis). Increased vascular permeability and chemotaxis: Occurs predominantly in venules (except in lungs, where it occurs in capillaries). This process delivers leukocytes capable of phagocytosis (neutrophils and macrophages) to the site of injury. Leukocyte events can be divided into: leukocyte recruitment and leukocyte activation. Leukocyte Recruitment/Extravasation Normally, leukocytes move rapidly in the blood, and during inflammation, they slow down and escape to the site of injury/causative agent in the extravascular space. Definition: Leukocyte recruitment to sites of inflammation (extravasation) is the process of migration of leukocytes from the lumen of the vessel to the site of injury in the extravascular tissues. The extravasated leukocytes perform the main function of eliminating the causative agents. In the Vascular Lumen Normally, leukocytes move rapidly in the flowing blood which prevents them from attaching to the vascular endothelium. In inflammation, they should be stopped and then brought to the offending agent or the site of tissue damage, outside the vessels. Margination: During inflammation when the blood flow slows down (stasis), leukocytes (mainly neutrophils) move towards the peripheral column and accumulate along on the endothelial surface of vessels. Rolling: Marginated leukocytes are able to detect and react to changes in the endothelium. Initially, they attach weakly to the endothelium, detach and bind again with a mild jumping movement. Molecules involved: Selectin family of adhesive molecules and its complementary ligands (Table 3. Selectins mediate the initial weak interactions between leukocytes and endothelium. Cytokines are secreted by cells in tissues, in response to microbes and other injurious stimulus. The endothelial selectins (E-selectins) are activated after stimulation by cytokines and other mediators. Adhesion of leukocyte to endothelium: Endothelium gets activated and leukocytes bind more firmly and finally come to rest at some point. They resemble as pebbles over the endothelium (pavementing) and a bloodstream runs without disturbing them. Transmigration or diapedesis: Leukocytes migrate through the vessel wall by squeezing through the intercellular junctions between the endothelial cells. Migration across the basement membrane: Leukocytes penetrate the basement membrane of the vessel by secreting collagenases. Definition: Chemotaxis is defined as process of migration of leukocytes toward the inflammatory stimulus in the direction of the gradient of locally produced chemoattractants. Chemoattractants: these are produced by microbes and by host cells in response to infections and tissue damage and during immunologic reactions. Characterized by the inability of neutrophils to exit the circulation to sites of infection, leading to leukocytosis and increased susceptibility to infection. Process of loose binding and detachment of leukocytes to endothelial cells is termed rolling. During inflammation, the endothelial cells at the site of inflammation gets activated and express high-levels of selectins. Acute inflammation: Neutrophils predominate in early stage and are replaced by monocytes after 24 hours. Genetic deficiencies of leukocyte adhesion molecules cause recurrent bacterial infections. The most important functional responses of leukocyte activation is phagocytosis and intracellular killing. Definition: Many leukocytes recognize, internalize, and digest foreign material, microorganisms, or cellular debris by a process termed phagocytosis. Recognition and Attachment Receptors on the surface of phagocytic cells recognize components of microbes and necrotic cells. The major opsonins are IgG antibodies, the C3b breakdown product of complement, and certain plasma lectins (notably mannose-binding lectin) called collectins (Table 3. Clinical significance of opsonins: After exposure to antigen, B cells get activated and mature into plasma cells, which produces immunoglobulins (IgG). Bruton disease: Defect in maturation of the B-cells leading to absence of immunoglobulin production. Engulfment Next step in phagocytosis is engulfment and formation of a phagocytic vacuole. Phagocytosis is dependent on polymerization of actin filaments present in the phagocytic cell. Killing and Degradation Killing and degradation of ingested microbial agents/particles occurs within neutrophils and macrophages. In neutrophils, this oxidative reaction occurs during phagocytosis 2 and is called as respiratory burst. Oxygen-derived radicals may be released extracellularly from leukocytes and may produce tissue damage during inflammation. Serum, tissue fluids, and host cells have antioxidant mechanisms which can protect tissue damage caused by these potentially harmful oxygen-derived radicals (refer pages 179). Granule enzymes and other proteins: Neutrophils and monocytes have granules containing enzymes and antimicrobial proteins. These granules are actively secreted and are thus different from classical lysosomes. Phagocytic vesicles containing engulfed material (or microbial) may fuse with granules of leukocytes and also with lysosomes. If the initial leukocytic infiltration goes unchecked, the enzymes in these granules can damage the normal tissues. Normally, these harmful enzymes (especially proteases) are controlled by a system of antiproteases in the serum and tissue fluids. One of important anti-protease is 1-anti-trypsin, which is the major inhibitor of neutrophil elastase. A deficiency of 1-anti-trypsin may lead to sustained action of leukocyte proteases, and damage the tissue. These collections of activated macrophages try to wall off the microbes, forming aggregates called granulomas. Termination of the AcuteInflammatory Response Inflammation is terminated after the elimination of the offending agent. This is because of the following properties of the chemical mediators of inflammation chemical mediators: i. Are degraded after their release Neutrophils also have short life span and die by apoptosis within hours to a day or two after leaving the bloodstream. A switch in the type of metabolite produced from arachidonic acid namely proinflammatory leukotrienes to anti-inflammatory lipoxins (refer page 61). General Features of Chemical Mediators v Source of mediators: Mediators are derived either from cells or from plasma proteins (Table 3. Plasma-derived mediators: Produced mainly in the liver and present in the circulation as inactive precursors, which require activation. They can act on one or few or many diverse targets, or may have different effects on different types of cells. Vasoactive Amines: Histamine and Serotonin Histamine and serotonin are the first mediators to be released during inflammation, which are stored as preformed molecules in cells. Actions: (1) Dilation of arterioles and (2) increase of the vascular permeability. These are cyclooxygenase pathway (produce prostaglandins) and lipoxygenase pathway (produces leukotrienes and lipoxins). Systemic effects: t Prostaglandins are responsible for pain and fever in inflammation. Source: Platelets, basophils, mast cells, neutrophils, macrophages, and endothelial cells. Action: Multiple inflammatory effects: v Vascular reactions: Vasoconstriction and bronchoconstriction, and at low concentrations it induces vasodilation and increased vascular permeability. Pathological actions: n Endothelial cell damage, which causes increased vascular permeability. Source: Many cells such as endothelial cells, macrophages and neurons in the brain. These are polypeptides which function as mediators in immune responses and in inflammation (acute and chronic). Source: Cytokines are secreted by many types of cell (activated lymphocytes and macrophages, endothelial, epithelial, and connective tissue cells). Tumor Necrosis Factor and Interleukin-1 these are the two major cytokines involved in inflammation. Chemokines Chemotactic cytokines or chemokines are small proteins, which selectively attracts various leukocytes to the site of inflammation.

Individual Participant Data Meta-Analyses As traditional meta-analyses are easier to conduct since they are based on published data and methodologies are widely available menstruation in the bible buy cheap aygestin 5mg line, the question arises as to whether they provide valid estimates of the comparative effectiveness of different interventions pregnancy acne buy aygestin pills in toronto, simply because there may be differences between primary studies regarding outcome breast cancer xeloda generic aygestin 5 mg with mastercard, subgroup definitions menstruation running buy generic aygestin 5mg, and methods of analysis pregnancy mood swings order aygestin. The annual birth rate is about 80 000 women's health big book of exercises app aygestin 5 mg generic, with onethird of births contributed by visitors from mainland China. Data from networks of the following countries were used: Finland, France, the Netherlands, and Sweden [33]. Use of cervical pessary to prevent preterm birth when compared with no intervention, progesterone, and cerclage. The need for making progress in the development and implementation of core outcome sets is well recognized, and has resulted in a significant change in the quality and relevance of research in, for example, rheumatoid arthritis trials in the 1990s. Successful implementation of this field has enriched clinical practice by identifying relevant outcomes that are now routinely monitored by healthcare professionals around the world [38]. At the time of writing there was a core outcome set for studies on prevention of preterm birth [40], epilepsy in pregnancy [41], and induction of labor [42]. Other core outcome sets for studies in for example preeclampsia/pregnancy hypertension, stillbirth, and intrauterine growth retardation are in development. First, the collected baseline characteristics and outcomes (and their definitions) can be aligned before the start of the studies. Some of the initiators of such trials have already set up international collaborations, resulting in studies that have recruited their patients in different countries spread over all continents. An example is the dissemination of the preterm birth core outcome set in 12 ongoing preterm birth trials within 2 years of publication of the core outcome set [43]. Future collaboration could also result in studies on rare diseases, which need recruitment around the globe, or where sample sizes are too large to be funded by a single funding body. Funding bodies may get to work together to encourage funding bodies to support part of a trial. Choice of primary outcomes in randomised trials and systematic reviews evaluating interventions for preterm birth prevention: a systematic review. Patient perspective: fatigue as a recommended patient centred outcome measure in rheumatoid arthritis. Multicentre randomised controlled trials in obstetrics and gynaecology: an analysis of trends over three decades. Methodology and analytic techniques used in clinical research: associations with journal impact factor. The management of Myelomeningocele Study: full cohort 30-month pediatric outcomes. Pharmacogenomics of 17-alpha hydroxyprogesterone caproate for recurrent preterm birth: a casecontrol study. Randomised double blind placebo controlled trial of rofecoxib (a cox-2 specific prostaglandin inhibitor) for the prevention of preterm delivery in women at high risk. Effectiveness of progestogens to improve perinatal outcome in twin pregnancies: an individual participant data meta-analysis. Effect of diet and physical activity based interventions in pregnancy on gestational weight gain and pregnancy outcomes: meta-analysis of inividual participant data from randomised trials. Outcome measures in rheumatoid arthritis randomised trials over the last 50 years. Development of a core outcome set for trials on induction of labour: an international multistakeholder Delphi study. Conclusion: In unselected women with an uncomplicated twin gestation, treatment with progestogens (intramuscular 17Pc or vaginal natural progesterone) does not improve perinatal outcome. Vaginal progesterone may be effective in the reduction of adverse perinatal outcome in women with a cervical length of 25 mm; however, further research is warranted to confirm this finding. There were no significant between-group differences in perinatal mortality rate, randomization-to-delivery interval, or other specified outcomes. Conclusion: Prophylactic 17Pc given to mothers with triplet pregnancies had no significant impact on perinatal outcome or pregnancy duration. Although summary effect estimates favored the intervention, the reductions in maternal (odds ratio 0. No evidence was found of differential intervention effects across subgroups, for either gestational weight gain or composite outcomes. There was strong evidence that interventions reduced the odds of cesarean section (0. Conclusion: Diet- and physical activity-based interventions during pregnancy reduce gestational weight gain and lower the odds of cesarean section. Recurrence increased with decreasing gestational age at delivery in the index pregnancy. Normotensive women experienced chronic hypertension after pregnancy more often after experiencing recurrence (odds ratio, 3. Conclusion: Among women that experience hypertension in pregnancy, the recurrence rate in a next pregnancy is relatively low, and the course of disease is milder for most women with recurrent disease. These reassuring data should be used for shared decision-making in women who consider a new pregnancy after a pregnancy that was complicated by hypertension. Intrapartum Fetal Monitoring [33] Results: We analyzed data from 12 987 women and their newborn infants. Risk of Stillbirth in Twins [34] Results: Data were obtained from 32 studies (29 685 dichorionic, 5486 monochorionic pregnancies). In monochorionic pregnancies beyond 34 weeks (13 studies, 2149 pregnancies), there was a trend towards an increase in stillbirths compared with neonatal deaths after 36 weeks, with an additional 2. The actual risk of stillbirth near term might be higher than reported estimates because of the policy of planned delivery in twin pregnancies. There is a long history of the establishment of disease registers and this is also the case for congenital anomaly registers. This article provides an overview of 2 congenital anomaly register networks, focusing on factors that lead to the successful operating of a register and the main uses of their data. From the perspective of patient care, information held by disease registers can be used to monitor high-risk groups, manage demand for care, identify the correct patient care pathways, and identify delays in diagnosis. Disease registers provide important information to clinicians to support their clinical practice and enable prevalences to be compared. In public health terms, disease registers undertake surveillance of a particular disease or health condition in the population, help inform the planning of healthcare provision for that disease/condition, and can monitor health burden and the impact of healthcare interventions. Disease registers also contribute to advancing medical knowledge through research into the patterns and causes of a disease/ health condition. A disease register is a documentation of all cases of a certain disease or health condition that occur within a defined population. As well as sociodemographic information such as maternal age, address/location and parental occupation, routinely collected clinical data is notified, usually prospectively. Hospital- and clinic-based registers contain data on all patients with the specific disease/health condition treated in a particular hospital or clinic. The denominator for the background population is often unknown, and ascertainment may be biased due to different characteristics or behaviors of cases that are or are not registered or treated at the included hospital/clinic. For population-based registers, registration is dependent on place of residence and these registers are notified of data on cases occurring within a geographically defined area. Denominator data is available for population-based registers and they tend to have a high ascertainment of cases regardless of case characteristics. Congenital Anomaly Registers Following the identification of thalidomide and rubella as teratogens, an agent or factor that can cause malformation of the embryo, congenital anomaly registries were established for the surveillance of environmental causes and for the early warning of new teratogenic exposures. Most congenital anomalies are rare (for example spina bifida, one of the more common congenital anomalies, only affects 1 baby in every 2000 births), and therefore it is necessary to collect information on these anomalies across a large population. When comparing prevalence between registers, it is essential to know whether all cases occurring in all pregnancy outcomes are included and what the restrictions are on case inclusion, so that accurate comparisons can be made. Included cases are those occurring in pregnancies to mothers resident in that region, even if they were delivered outside the region. Data are collected in a standardized format and subjected to rigorous validation checks to ensure high quality. Malta, Norway, and Wales, all births are covered by a registry, and in others only a small proportion of the birth population of that country is covered. Pleven, Bulgaria) can participate in meetings and projects but do not submit data [5]. If, after further investigation at the local level, a cluster persists, local registers inform the local public health authorities of the cluster for appropriate action to be taken. Register data are also used for genetic studies and to understand the interaction of genetic and environmental factors in causing congenital anomalies. For example, by combining data the registers can produce accurate prevalence figures for rare anomalies, consider trends over time and, through linkage studies, provide information on survival and predictors of survival that can inform healthcare planning and contribute to etiological research. Registration of congenital anomalies is not only an important activity in its own right but also as an indicator of other adverse pregnancy outcomes linked to teratogenic exposures, such as miscarriages and neurobehavioral outcomes. This voluntary system involved the passive collection of notifications of congenital anomalies occurring in live births and stillbirths. Initially, cases were notified within 7 days of birth but this cut-off was subsequently lifted. British Isles Network of Congenital Anomaly Registers Seven regional congenital anomaly registers were established in England between 1985 and 2003, and 1 to cover all of Wales in 1998, to meet local needs and for audit and research projects, including audits of prenatal diagnosis and research into the causes of specific anomalies within their locality. The objectives were to: undertake surveillance and analysis of congenital anomalies; monitor and audit health provision, detection and outcomes for congenital anomalies; provide information to support planning and administration of the provision made for health and social care for pregnancies and infants affected by congenital anomalies; conduct medical research, approved by research ethics committees, into the causes and consequences of congenital anomalies; and provide information to clinicians to support their clinical practice. Data were collected on all suspected and confirmed congenital anomalies identified in utero, at birth, or in childhood. Some identifiable information was collected on the mother and baby but only enough to enable regional registers to avoid duplicate registrations and for the validation of cases, ensuring accurate matching between antenatally diagnosed anomalies and postnatal notifications. The regional registers shared a standardized minimum dataset, methodology, multiple source notification and confidentiality, and information technology security protocols. They were proactive in their method of data collection and regularly reviewed the completeness of the notification of congenital anomaly groups, facilitated by their close links with collaborating clinicians. These registers provided comprehensive and accurate data of high quality, having been subjected to rigorous quality control in terms of case ascertainment, use of multiple sources, and adoption of internationally approved methods of coding, recording, and analysis. The data were used to: monitor the Down syndrome prenatal screening and diagnostic services, and the impact on the diagnosis of Edwards and Patau syndromes; provide data on annual numbers of affected births to help healthcare planning; and provide information for research into Down, Edwards and Patau syndromes. In 2013, there were 1872 diagnoses of Down syndrome, 65% made prenatally, a rate of 2. Registers have many important functions, including the monitoring of healthcare interventions. This in turn will provide a resource for clinicians to support high-quality clinical practice; support and empower patients and their carers through the provision of information relevant to their disease or disorder; provide epidemiology and monitoring of the frequency, nature, cause and outcomes of these disorders; support research into congenital anomalies, rare diseases and precision medicine, including basic science, cause, prevention, diagnostics, treatment and management; inform the planning and commissioning of public health and health and social care provisions; and provide a resource to monitor, evaluate and audit health and social care services, including the efficiency and outcomes of screening programs [15, 16]. This new national system has been built on the existing knowledge and expertise of the regional congenital anomaly registers as of April 2018. A single data management system has been developed and notifications are made electronically. Data are collected on all suspected and confirmed congenital anomalies identified in utero, at birth, or at any point in childhood. In Uses of Data Held by Congenital Anomaly Registers Data from congenital anomaly registers have many and varied uses. Statistical monitoring is undertaken on an annual basis, and the results are fed back to registers and can result in further investigations at the local registry level [6]. The two most common prevalence measures used in congenital anomaly epidemiology are total and live birth prevalence. Live birth prevalence refers to the number of congenital anomaly-affected pregnancies resulting in a live birth divided by the total number of live births. In this comparison, the registers showed similar rates of cardiac defects that can be diagnosed antenatally. This variation in reporting is likely to be reflected in the relationship the register has with the Pediatric Cardiology Departments that facilitate the notification of postneonatal diagnosis of cardiac anomalies. The increasing trends in microcephaly and congenital hydronephrosis could not be explained by discrepancies in diagnostic criteria. Disappointingly, this recent analysis did not find a decrease in neural tube defects, despite the efforts at prevention through folic acid supplementation [18]. There are a number of underlying factors that may explain variations in prevalence between registers and over time: case ascertainment methods including data collection methods; sources of information; demographics. Other sources of ascertainment variation include ascertainment of less severe forms of a congenital anomaly. However, not all variation in prevalence can be readily explained and may reflect true differences in prevalence. For example, higher prevalence rates for gastroschisis, an abdominal wall defect, have consistently been reported in the northern region of England [20, 21], and a geographical gradient in prevalence from the north to the south of England has been reported [17]. It is important that the underlying prevalence of congenital anomalies in a particular locality is understood and taken into account in the design of research studies that aim to investigate the contribution of exposures to congenital anomaly risk so that incorrect interpretations are avoided. Rare Diseases Within the European Union, a disease is considered to be rare if it affects not more than 5 per 10 000 persons. Rare diseases include genetic diseases, congenital anomalies, rare cancers, autoimmune diseases, toxic, and infectious diseases.

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