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In one study discount 100 mg doxycycline free shipping, these three foods were implicated in 81% of all cases of childhood eczema purchase doxycycline 200mg with visa,6 while in another study 60% of children with severe eczema had a positive food challenge to one or two of the following: eggs cheap 200 mg doxycycline otc, cow’s milk buy generic doxycycline 100 mg on-line, peanuts, fish, wheat, or soybeans. One randomized, controlled trial found that in individuals with a positive reaction to eggs on a radioallergosorbent test, an egg-free diet was associated with improvement in the severity of eczema, with the greatest effect seen in those most severely affected. Elimination of milk products, eggs, peanuts, tomatoes, and artificial colors and preservatives results in significant improvement in at least 75% of cases. After one year, 26% of patients with eczema were no longer allergic to the five major allergens (egg, milk, wheat, soy, and peanut), and 66% were no longer allergic to other food allergens. Elevated levels of antibodies against candida are common in atopic individuals, indicating an active infection. Furthermore, the severity of lesions tends to correlate with the level of antibodies to candidal antigens. The bottom line is that elimination of candida results in significant clinical improvement of eczema in some patients. Probiotics Because the intestinal flora plays a major role in the health of the host, especially regarding eczema, probiotic therapy is particularly indicated. Studies show that administration of the probiotic Lactobacillus rhamnosus alone or in conjunction with Lactobacillus reuteri to infants with eczema and cow’s milk allergy demonstrates significant reduction of the severity of eczema. In fact, several double-blind studies with evening primrose oil (typically using dosages of at least 3,000 mg daily, providing 270 mg of gamma-linolenic acid) did show benefit. Several studies with evening primrose oil failed to demonstrate any therapeutic benefit over a placebo. In the largest of these studies and the one with the highest- quality methods, no benefit could be demonstrated for evening primrose oil. One is that fish oils contain primarily long-chain omega-3 fatty acids, which are further down the anti-inflammatory pathway, while evening primrose oil contains both omega-6 and omega-3 fatty acids and gamma-linolenic acid is at the beginning of the omega-3 anti-inflammatory chain. Some people, such as those with atopic disease, have poorer-functioning enzymes for the conversion to the anti-inflammatory prostaglandins. Botanical Medicines The use of botanical medicines in eczema can be generally divided into two categories: internal and external. Internally, licorice preparations can exert significant anti-inflammatory and anti-allergic effects. These benefits are perhaps best exemplified in several double-blind studies featuring a licorice-containing Chinese herbal formula. In one study, 40 adult patients with long-standing, refractory, widespread eczema were randomized to receive two months’ treatment consisting of either the active formula or a placebo decoction, followed by a crossover to the other treatment after a four-week washout period. In addition, of the 31 patients completing the study, 20 preferred the active formula, while only 4 preferred the placebo. There was also a subjective improvement in itching and sleep during the active treatment phase. No side effects were reported, although many subjects complained about the poor palatability of the decoction. A family history of allergic disease such as eczema and asthma is a major risk factor. With regard to using licorice topically, the best results are likely to be obtained by using commercial preparations featuring pure glycyrrhetinic acid. Several studies have shown glycyrrhetinic acid to exert an effect similar to that of topical hydrocortisone in the treatment of eczema, contact and allergic dermatitis, and psoriasis. In one study, 9 of 12 patients with eczema unresponsive to other treatments noted marked improvement, and two noted mild improvement when an ointment containing glycyrrhetinic acid was applied topically. In another study, 93% of the patients with eczema who applied glycyrrhetinic acid demonstrated improvement compared with 83% using cortisone. It is also considered a risk factor for breast cancer, though not as significant as the classic breast cancer risk factors: family history, early onset of menstruation, and late first pregnancy or no pregnancy. Noninvasive procedures, such as ultrasound, can help in differentiation, but at this time definitive diagnosis depends upon biopsy. Those who continued with little change in their methylxanthine consumption showed little improvement. Fiber A comparison between the diets of 354 women with benign proliferative epithelial disorders of the breast and those of 354 matched controls and 189 unmatched controls found an inverse association between dietary fiber and the risk of such disorders. There is an association between abnormal cell structure in nipple aspirates of breast fluid and the frequency of bowel movements. The cause of this association is probably that the bacterial flora in the large intestine transform estrogen into various toxic metabolites, including carcinogens and mutagens. Fecal microorganisms are capable of synthesizing estrogens as well as breaking the bond between excreted estrogen and glucuronate, resulting in absorption of bacteria-derived estrogens and reabsorption of previously excreted estrogen as free estrogen. Diet plays a major role in colon microflora, transit time, and concentration of absorbable metabolites. Vegetarian Diet Women on a vegetarian diet excrete two to three times more conjugated estrogens than women on an omnivorous diet. Bacterial beta-glucuronidase is a bacterially produced enzyme that breaks the bond between excreted estrogen and glucuronic acid. Probiotic supplementation has been shown to lower fecal beta-glucuronidase and may help improve bowel function as well. Reducing the total fat intake to 15% of total calories while increasing consumption of high-fiber foods has been shown to reduce the severity of premenstrual breast tenderness and swelling, as well as reducing the actual breast swelling and nodules in some women. Historically, naturopaths have used lipotropic factors such as inositol and choline to support the excretion of estrogen. Lipotropic supplements usually are a combination vitamin-and-herbal formulation designed to support the liver’s functions of removing fat, detoxifying the body’s wastes, detoxifying external toxins, and metabolizing and excreting estrogens. These lipotropic products vary in formulation depending on the manufacturer, but they are all similar. Evening Primrose Oil The only essential fatty acid to be studied in relation to fibrocystic breasts is evening primrose oil. When 291 women with cyclic and noncyclic breast pain were given 3,000 mg evening primrose oil for six months, almost half of the 92 women with cyclic breast pain experienced improvement, compared with one-fifth of the patients who received the placebo. For those women who experienced breast pain throughout the month, 27% (of 33 women) improved with evening primrose oil, compared with 9% on the placebo. After three months, pain and tenderness were significantly reduced in both the women with cyclic breast pain and those with noncyclic pain. When larger numbers of women were studied, vitamin E did not fare so well, showing no significant effects either subjectively or objectively. This hypersensitivity can produce excessive amounts of secretions, distending the breast ducts and producing small cysts and later fibrosis (hardening of the tissue due to the deposition of fibrin, similar to the formation of scar tissue). Results from these studies indicate that although treatment with high doses of iodides was effective in about 70% of subjects, it was associated with a high rate of side effects (altered thyroid function in 4%, iodinism in 3%, and acne in 15%). We recommend that patients take iodine only under strict medical supervision, as taking too much iodine can lead to altered levels of thyroid hormone. In addition to iodine, there is research showing that thyroid hormone replacement therapy may result in clinical improvement. For more information on subclinical hypothyroidism, see the chapter “Hypothyroidism. The improvement in breast pain was greater in the chasteberry group (52%) compared with the placebo group (24%). Food Allergy • Significant improvement in symptoms and signs of a disease linked to food allergy while on an allergy-elimination diet • Positive test result from an acceptable food allergy test • Typical signs of allergy: Dark circles under the eyes (allergic shiners) Puffiness under the eyes Horizontal creases in the lower eyelid Chronic (noncyclic) fluid retention Chronic swollen glands A food allergy occurs when there is an adverse reaction to the ingestion of a food. The reaction may or may not be mediated (controlled and influenced) by the immune system. The reaction may be caused by a protein, a starch, or another food component, or by a contaminant found in the food (a coloring, a preservative, etc. A classic food allergy occurs when an ingested food molecule acts as an antigen—a substance that can be bound by an antibody. Antibodies are the protein molecules made by white blood cells that bind to foreign substances, in this case various components of foods. The food antigen is bound by antibodies known as IgE (immunoglobulin E) for immediate reactions and IgG and IgM for delayed reactions. The IgE antibodies are specialized immunoglobulins (proteins) that bind to specialized white blood cells known as mast cells and basophils. When the IgE and food antigen bind to a mast cell or basophil, the binding causes a release of histamines, substances that in turn cause swelling and inflammation.

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Not surprisingly 100 mg doxycycline with amex, the natural measures used to achieve these goals are also similar to those used in the treatment of angina generic doxycycline 200mg fast delivery. Diet The guidelines given in the chapter “A Health-Promoting Diet” are appropriate here discount generic doxycycline canada. Since green leafy vegetables and green teas contain high levels of vitamin K 200mg doxycycline sale, you should avoid increasing your intake of these foods while taking Coumadin. You can eat the same levels you’re accustomed to—just don’t increase your consumption. In addition to high-vitamin-K foods, other natural remedies may interact with warfarin. For example, coenzyme Q10 and Saint-John’swort ( Hypericum perforatum) may reduce the efficacy of Coumadin, while proteolytic enzymes and several herbs, including Chinese ginseng (Panax ginseng), devil’s claw (Harpagophytum procumbens), and dong quai (Angelica sinensis), can increase its effects. It’s likely that you can continue using these products, but don’t change the dosage from what your body is accustomed to. Garlic (Allium sativum) and ginkgo (Ginkgo biloba) extracts may reduce the ability of platelets to stick together, increasing the likelihood of bleeding. We generally tell people taking Coumadin to avoid these products at higher dosages (more than the equivalent of one clove of garlic per day or more than 240 mg per day of ginkgo extract) but not to worry if they are just on the typical support dose. Iron, magnesium, and zinc may bind with Coumadin, potentially decreasing its absorption and activity. Take Coumadin at least two hours before or after any product that contains iron, magnesium, or zinc. Nutritional Supplements Magnesium The level of magnesium in the blood correlates with the ability of the heart muscle to manufacture enough energy to beat properly. Not surprisingly, many disorders of heart rhythm are related to an insufficient level of magnesium in the heart muscle. Magnesium was first shown to be of value in the treatment of cardiac arrhythmias in 1935. More than 75 years later, there are now many clinical studies that show magnesium supplementation to be of benefit in treating many types of arrhythmias, including atrial fibrillation, ventricular premature contractions, ventricular tachycardia, and severe ventricular arrhythmias. Given the importance of these two electrolytes for proper nerve and muscle firing, it is little wonder that low levels of these substances can produce arrhythmias. According to the results from one double-blind, placebo-controlled study, magnesium supplementation may offer significant benefit in the treatment of new-onset atrial fibrillation. Because of the benefits noted in several studies of patients with atrial fibrillation who were taking magnesium, researchers decided to conduct a study to determine if magnesium and digoxin were better than digoxin alone in controlling ventricular response. Eighteen people with atrial fibrillation of less than seven days’ duration received either digoxin plus a placebo or digoxin plus magnesium, both intravenously. Those who received magnesium were given 20% of a magnesium solution during the initial 15 minutes, with the rest infused over the next six hours. The benefit of magnesium was obvious within the first 15 minutes, as heart rate decreased immediately from an average of 130 to 120 beats per minute. After 24 hours, the group that received the magnesium had an average heart rate of roughly 80, while the group that received only digoxin had an average heart rate of 105. In the magnesium group, 6 of 10 patients (60%) converted to normal rhythm, whereas just 3 of 8 in the digoxin-only group (37. The recommended intake for oral magnesium in arrhythmia appears to be approximately 6 to 10 mg/kg per day. Be sure to use a form that is easily absorbed, such as citrate, as other forms can cause diarrhea at these dosages. Coenzyme Q10 (CoQ10) Coenzyme Q10 plays a critical role in the cellular production of energy. As the heart is among the most metabolically active tissues in the body, a CoQ10 deficiency can lead to serious problems there. A good analogy is that the role of CoQ10 is similar to the role of a spark plug in a car engine. Just as the car cannot function without that initial spark, the human body cannot function without CoQ10. Because of its safety and possible benefit, CoQ10 supplementation is indicated in any condition affecting the heart. Botanical Medicines Hawthorn Hawthorn (Crataegus species) preparations have a long history of use in minor arrhythmias. The benefits in congestive heart failure have been repeatedly demonstrated in double-blind studies (see the chapter “Congestive Heart Failure”). Follow the general guidelines on diet and lifestyle in the chapter “Heart and Cardiovascular Health. Estimates have indicated that 50% of those over 50 years of age have symptomatic hemorrhoidal disease, and up to one-third of the total U. Although most individuals may begin to develop hemorrhoids in their 20s, hemorrhoidal symptoms usually do not become evident until the 30s. Causes The causes of hemorrhoids are similar to the causes of varicose veins (see the chapter “Varicose Veins”): genetic weakness of the veins and/or excessive pressure on the veins. Because the venous system that supplies the rectal area contains no valves, factors that increase venous congestion in the region can lead to hemorrhoid formation. These factors include increased intra-abdominal pressure (caused by defecation, pregnancy, coughing, sneezing, vomiting, physical exertion, or portal hypertension due to cirrhosis); an increase in straining during defecation due to a low-fiber diet; diarrhea; and standing or sitting for prolonged periods of time. Classification of Hemorrhoids Hemorrhoids are typically classified according to location and degree of severity. External hemorrhoids occur below the anorectal line—the point in the 3-cm-long anal canal where the skin lining changes to mucous membrane. They may be full of either blood clots (thrombotic hemorrhoids) or connective tissue (cutaneous hemorrhoids). A thrombotic hemorrhoid is produced when a hemorrhoidal vessel has ruptured and formed a blood clot (thrombus), while a cutaneous hemorrhoid consists of fibrous connective tissue covered by anal skin. Cutaneous hemorrhoids can be located at any point on the circumference of the anus. Typically, they are caused by the resolution of a thrombotic hemorrhoid: that is, the thrombus becomes organized and replaced by connective tissue. Occasionally, an internal hemorrhoid enlarges to such a degree that it prolapses and descends below the anal sphincter. The following types of mixed hemorrhoids can occur: • Without prolapse: Bleeding may be present, but there is no pain. Diagnostic Considerations The symptoms most often associated with hemorrhoids include itching, burning, pain, inflammation, irritation, swelling, bleeding, and seepage. Itching is caused when there is mucous discharge from prolapsing internal hemorrhoids; tissue trauma resulting from excessive use of harsh toilet paper; Candida albicans; parasitic infections; and food allergies. However, as there are no sensory nerve endings above the anorectal line, uncomplicated internal hemorrhoids rarely cause pain. Bleeding is almost always associated with internal hemorrhoids and may occur before, during, or after defecation. When bleeding occurs from an external hemorrhoid, it is due to rupture of an acute thrombotic hemorrhoid. Therapeutic Considerations Conventional Medical Treatment Conventional medical treatment of acute hemorrhoids may be appropriate. It is used only in severe cases because it is associated with significant postoperative pain and usually requires two to four weeks for recovery. Diet Hemorrhoids are rarely seen in parts of the world where diets rich in high-fiber, unrefined foods are consumed. A low-fiber diet, high in refined foods, like that common in the United States, contributes greatly to the development of hemorrhoids. This straining increases the pressure in the abdomen, which obstructs venous blood flow. The intensified pressure increases pelvic congestion and may significantly weaken the veins, causing hemorrhoids to form. Hemorrhoids A high-fiber diet is perhaps the most important component in the prevention of hemorrhoids. A diet rich in vegetables, fruits, legumes, and grains promotes rapid transit of the feces through the intestine. Furthermore, many fiber components attract water and form a gelatinous mass that keeps the feces soft, bulky, and easy to pass.

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Lateral view of rhinogram indicating that contrast medium moved ventrally through the nasal cavity (open arrow) and stopped abruptly at the level of the palate (closed arrow) proven doxycycline 200 mg. Rostrocaudal radiograph following infusion of contrast medium into the right nostril showing communication between the infraorbital sinuses buy doxycycline master card. Note that the contrast medium does not properly pass into the oral cavity in this bird purchase 100mg doxycycline with amex. Other structures of interest include the palatine bone (p) buy cheap doxycycline 200 mg online, zygomatic arch (z), mandible (m), quadrate (q) and the periorbital diverticulum of the infraorbital sinus (s) (courtesy of Elizabeth Watson). A lateral rhinogram indicated that contrast medium moved through the nasal cavity (open arrows) and stopped abruptly at the level of the palatine (closed arrows) (courtesy of Elizabeth Watson). Radiographs indicate gaseous distension of the gastrointestinal tract (arrows) causing cranial displacement of other abdominal organs. Increased densities were noted in the syringeal area (open arrows), and the spleen (s) was enlarged. Necropsy findings included pericarditis and granulomatous pneumonia and tracheitis. A lateral radiograph showed a large, lobular, soft-tissue mass surrounding the distal trachea (arrows) that extended into the lung (lu) and displaced the trachea (t) ventrally. The liver (l) is also enlarged and is displacing the gas-filled proventriculus (p) dorsally. The histologic diagnosis was thyroid adenocarcinoma (courtesy of Marjorie McMillan). Initial radiographs showed a large, soft-tissue mass (arrows) ventral to the trachea and syrinx. Radiograph taken 11 months after treatment with antifungal agents demonstrates resolution of the mass (courtesy of Marjorie McMillan). Abnormal findings included increased parabron- chial densities (ring shadows -r), hyperinflation of the air sacs and thickening of the contiguous wall of the cranial and caudal thoracic air sacs (open arrow). The ventral separation of the contiguous wall of these air sacs forms a distinguishable fork (f) with the cranial thoracic air sac coursing cranially and the caudal thoracic air sac coursing caudoventrally. The medium is passing dorsally across an intratracheal mass (arrows) (courtesy of Marjorie McMillan). The increased parabronchial densities (open arrows) in the mid and caudal portions of the lung are suggestive of pneumonia. The intestines (i) are filled with gas secondary to aerophagia caused by severe dyspnea. The right abdominal (ra) and left abdominal (la) air sac areas are clearly visible. There is a uniform increase in the parabronchial pattern (arrows) and obliteration of the abdominal air sac space due to bulging of the abdominal wall (open arrow). The homogenous appearance of the abdomen is due to a combination of effusion and a mass. The pulmonary pattern is consistent with edema, which responded to diuretic therapy (courtesy of Marjorie McMillan). Radiographs indicated parabronchial ring shadows (arrow)consistent with pneumonia. Hyperinflation of the thoracic and abdominal air sacs and thickening of the air sac membranes are characteristic of air sacculitis (open arrows). Radiographs one month after the initiation of antibiotic therapy indicate a decrease in the soft tissue opacity of the air sacs. However, the presence of residual thickening (arrow) would warrant continuation of therapy. Spleen (s), proventriculus (p), ventriculus (v), heart (h), liver (l) (courtesy of Marjorie McMillan). The diminished serosal detail in the coelomic cavity was caused by hemorrhage from the dis- eased kidney. The pathologic diagnosis was glomeru- lonephropathy, infarction and arteritis (courtesy of Mar- jorie McMillan). Other structures that are easy to identify include the heart (h), syrinx (s), lung (lu), proventriculus (p), ventriculus (v) and intestines (i) (courtesy of Marjorie McMillan). It is common for the liver to be smaller than expected in macaws and some larger cockatoos. Heart (h), liver (l), spleen (s), syrinx (s), proventriculus (p), ventriculus (v), gonad (g). Note that the normal air sac triangle above the proven- triculus is obliterated and the proventriculus (par- tially gas-filled) is being displaced cranially (courtesy of Marjorie McMillan). Radiographs indicated massive hepatomegaly (l) with cranial displacement of the heart (h), dorsal displacement of the proventriculus (p) and caudodorsal displacement of the ventriculus (v). Histopathology indicated severe, chronic active hepatitis and cirrhosis (courtesy of Marjorie McMillan). Radiographs indicated hepa- tomegaly (l) with dorsal displacement of the proventriculus (p). Radiographs indicated a massive splenomegaly (arrow) and nephromegaly (curved arrow) caused by Chlamydia sp. The enlarged spleen is displacing the proventriculus (p) and ventriculus (v) ventrally and the liver (l) cranially (courtesy of Marjorie McMillan, reprinted with permission of Comp Cont Ed 8:1986). Note the “grape-like” cluster of follicles cranioventral to the kidneys (k) (courtesy of Marjorie McMillan). Herniation and polyostotic hyperostosis are characteristic of hyperestrogenism (courtesy of Marjorie McMillan). Radiographs indicated a fluid-filled abdomen with cranial displacement of the ventriculus (v) and proventriculus (p), both of which are impacted with grit. Abdominocentesis was consistent with an exudative effusion, and the diagnosis was egg-related peritonitis. The cranial displacement of theabdominal viscera indicates that the fluid is present in the intestinal peritoneal cavity (courtesy of Marjorie McMillan). The mass was visible as a soft tissue opacity at the caudal edge of the sternum (open arrow). Radiographic changes included gaseous distension of the intestines (i), thickening of the contiguous membrane of the caudal thoracic and abdominal air sac (open arrow). The client was a heavy smoker, and the lesions resolved over a three-month period when the client quit smoking and the bird received daily exposure to fresh air and sunlight. Crop (c), thoracic esophagus (ar- row), proventriculus with filling defects (p), ventriculus (v), duodenum (d), ilium and jejunum (open arrow). Barium contrast radiography indicated that the mass was associated with the thoracic esophagus. Radiographa) was taken 45 minutes and radiograph b) was taken 2 hours after barium administration. Contrast medium can be seen in the ventriculus (v), ascending and descending colon (d), jejunum and ileum (i), colon (open arrow) and cloaca (c). The gastrointestinal tract of neonates stays distended with food, making the deline- ation of abdominal structures difficult. Radiographs indicated joint enlargement, subchondral bone lysis and erosion of the intercondylar space. The bird had been equipped with a radiotransmitter and released from a hack tower several weeks before presentation. The bird was not being monitored and was found hanging upside down from a tree limb with the transmitter entangling the legs. Ultrasound can be used to differentiate nal effusion or organomegaly, ultrasound may be between soft-shelled eggs and egg-related peritonitis. With Patients may be held or secured with a plexiglass egg-related peritonitis, there is a heterogeneous hy- restraining device. Many birds that are minimally perechoic appearance to the coelomic cavity (Figure restrained in an upright position are extremely toler- 12. Ultrasound-guided biopsy can be used to collect diag- Higher frequency scanners provide less tissue pene- nostic samples from the liver. The patient must be tration but finer resolution and are most useful in sedated or anesthetized. In larger species a 22 ga Westcott used, but because of their shape, they do not conform needle is used to obtain specimens for cytology, his- well to the patient’s body. Spinal needles and 25 ga hypoder- mic needles may be used, but may be difficult to If the patient is in dorsal recumbency, the transducer localize with the ultrasound beam and often yield is placed just caudal to the sternum and the beam is only enough material for cytology.

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Unusual requirements for gene product processing needed for activity of the expressed gene must be considered when choosing a target disease cheap doxycycline amex. Many genes can be expressed in cell types other than the normally expressing cell types and still be therapeutic purchase doxycycline paypal. However order doxycycline on line amex, other gene products require special processing in a particu- lar cell type or in a particular organelle cheap doxycycline 100mg overnight delivery. Still other proteins may have cofactors (proteins) that are essential for activity and must be made in close proximity (same cell or organelle) as the cofactor. The commercial development process is faster when maximal information is known about a targeted gene (regulation, sequence, etc. The development of a commercial gene therapy product is also facilitated by the availability of an animal model of the genetic disease being targeted. Although not all human genetic diseases currently have animal models of disease, the number of transgenic and knock-out mouse strains (see Chapter 3), as well as larger animal models, has increased exponentially in the last few years. These animal models prove valuable in developing effective gene therapy treatment approaches for many single-factor genetic disorders and possibly some multifactor diseases as well. As for any commercial venture, patent and licensing issues for a particular gene will necessarily be important factors in choosing a target. The size of the potential patient population and the accessibility of patients for a particular product are also crucial. There are numerous genes that could be targeted for gene therapy, however, many of the single-factor genetic diseases are relatively rare (see Chapter 1). Dis- eases currently treated with recombinant proteins (severe immune deficiency, hemo- philia A and B) provide larger markets where gene therapy could have an impact. As with any new therapy, gene therapy approach for a disease state would need to have advantages over treatments currently in use. Assurance of purity must be provided to investigators who purchase or contract for reagents to be used in basic or clinical research. As can be seen from the recent events, poor quality control of reagents can lead to the cessation of clinical trails of gene therapy protocols (see Chapter 13). Within the typical research laboratory, plasmids continue to be routinely obtained by the standard method of CsCl–ethidium bromide density gradient ultracentrifugation. CsCl–ethidium bromide gradients are popular since large numbers of different plasmid prepara- tions can be processed simultaneously. For the researcher at the lab bench, it is time con- suming, labor intensive, and expensive. For the biotechnology company, how- ever, this method is completely unacceptable for the production of clinical-grade materials because of its use of mutagenic reagents and its inherent inability to be a process of scale. These modified “mini-prep” kits, make use of the alkaline lysis method for cell disruption followed by a chromatographic cartridge purification. Some kits use a silica-based stationary phase, while others are based on an agarose stationary phase. These kits are aimed at a particular market niche: the production of small quantities (milligram or less) of research-grade material for molecular biology applications. The common thread linking these processes is the basis of well-documented research. This basis allows for the final product to meet defined quality standards supported by validated analytical methods and controlled unit operations. All com- ponents of the process must be generally recognized as safe and must meet all applicable regulatory standards. Quality control is con- cerned with sampling, specifications, testing, and with documentation and release procedures ensuring satisfactory quality of the final product. Thorough vector characterization has been carried out, including a detailed history on the construction of the vector, com- plete nucleic acid sequence determination, and plasmid stability within the host strain. Several commercial media have been designed for plasmid produc- tion, but a defined medium that has been empirically developed for a specific strain plasmid is preferable. Bacterial strains should be compatible with high copy number plasmids, high biomass fermentations, and the selection system cannot be ampicillin based. Documented reproducible removal of key host-cell-derived impurities is essential for setting accurate limits and specifications on the bulk drug product. A functional in vivo or in vitro bioassay that measures the biological activity of the expressed gene product, not merely its presence, should be developed. This data is critical in eventually deter- mining product shelf life for the approved drug. Use of these reagents in any manufacturing process for a drug substance raises regulatory concerns about residuals in the final product. Disregarding such purity issues would increase the difficulty in process validation and ultimately putting final regulatory approval at risk. The final product must be free of contaminating nucleic acids, endotoxins, and host-derived proteins. Fermentation is generally considered the starting point in designing the purifi- cation process. By careful selection and control of the variables associated with the fermentation process, the subsequent purification may be greatly simplified. Various fermentation feed strategies (batch, fed-batch, continuous) should be explored. While somewhat more difficult to optimize, as well as document, continuous fer- mentations may offer several advantages in terms of production cycle times. Nor- mally, fed-batch fermentations allow quicker process development times, simpler process control and sufficiently high biomass. The growth stage at which the fer- mentation is harvested must also be tightly controlled since it will greatly impact on the final yield of purified plasmid. Harvesting too late in the fermentation cycle will not only result in low yields but also plasmid of poor quality. The monitoring of fermentation process parameters including temperature, glucose addition, dissolved oxygen, and carbon dioxide evolution are critical for the development of a reproducible process. By manipulation of these parameters or through the use of an inducible plasmid system, the growth characteristics of a strain can be effectively changed, resulting in an increase in the plasmid-to-biomass ratio. The host cell and plasmid are the most important starting materials in the pro- duction fermentation. The key parameters in choosing a host strain are a low endogenous endotoxin, the capability of growing to high biomass, and relevant genotypic markers. The plasmid should be structurally as well as segregationally stable and have a high copy number origin of replication. Chromatogra- phy is the tool that has enabled the biotechnology industry to achieve the purity levels required for today’s biotherapeutics, diagnostics, and other biologicals. These are based on the physical characteristics of the biomolecule as well as the intrinsic impurities derived from the host cell of choice, Escherichia coli. Plasmids are as large or larger than the pores of almost all chro- matographic resins. They include gel filtration chromatography, hydroxyapaptite chromatography, acridine yellow affin- ity chromatography, anion exchange chromatography, reversed phase chromatog- raphy, silica membrane binding, and binding to glass powder. Large-scale tangential flow systems, which are rou- tinely used for the processing of recombinant proteins, can easily nick the super- coiled form of the plasmid. Cross flow rates, pump design, as well as the mixer’s impeller design must all be carefully scrutinized. These contaminants and trace host protein contamination may be removed by a combination of selective precipitation, anion exchange chromatography, and a final polishing step. Given the lim- itations of currently available commercial matrices and the similar structure and charge profile of biomolecule species passing over the column, anion exchange chro- matography is best used as a primary capture and initial purification step. A second polishing step, which is orthogonal to the principles of anion exchange, is prudent and ensures rigorous process control. Historically, gel filtration has been used in the biotechnology industry as a pol- ishing step. This is a simple and reproducible method that also offers the advantage of simultaneously incorporating a buffer exchange step within the chro- matographic process. Contaminating salts and/or residual metals can thus be removed allowing for the careful control of the counter ion in the final drug product. However, the main drawback in using gel filtration is that it is a very slow and volume-dependent method. It is not a high throughput method and often becomes the bottleneck within a given process. It is commonly the method of choice for the purification of small pharmaceutical compounds.