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By K. Musan. Central Bible College. 2018.

The number of biotechnology-based therapeutics introduced in medical practice is increasing along with their use in a personalized manner (Jain 2012) discount 150 mg bupron sr mastercard. Recombinant Human Proteins There are a large number of therapeutic proteins approved for clinical use and many more are undergoing preclinical studies and clinical trials in humans discount bupron sr 150 mg otc. Virtually all therapeutic proteins elicit some level of antibody response order 150mg bupron sr amex, which can lead to potentially serious side effects in some cases. Therefore, immunogenicity of therapeutic proteins is a con- cern for clinicians, manufacturers and regulatory agencies. In order to assess immu- nogenicity of these molecules, appropriate detection, quantitation and characterization of antibody responses are necessary. Immune response to therapeu- tic proteins in conventional animal models has not been, except in rare cases, pre- dictive of the response in humans. In recent years there has been a considerable progress in development of computational methods for prediction of epitopes in protein molecules that have the potential to induce an immune response in a recipi- ent. It is expected that computer driven prediction followed by in vitro and/or in vivo testing of any potentially immunogenic epitopes will help in avoiding, or at least minimizing, immune responses to therapeutic proteins. Another approach to protein therapy is in vivo production of proteins by geneti- cally engineered cells where the delivery of proteins can be matched to the needs of the patient and in vivo production and controlled delivery might reduce adverse effects. Therapeutic Monoclonal Antibodies Compared with small-molecule drugs, antibodies are very specific and are less likely to cause toxicity based on factors other than the mechanism of action. Orally available small molecules have many targets but they may also hepatotoxic and are involved in drug-drug interactions. From the point of view of a clean safety profile, antibodies are extremely attractive. Antibodies have for many decades been viewed as ideal molecules for cancer therapy. These will be described in more detail in the section on personal- ized cancer therapy in Chap. Many molecular biological and immunological studies have revealed the targeting properties of the host immune system and the biological mechanisms of cancer cells for a more specific anticancer effect. The accumulating results from many basic, clinical and translational studies may lead to more individualized therapeutic strategies using these agents directed at specific genetic and immunologic targets. Cell Therapy Cell therapy is the prevention or treatment of human disease by the administration of cells that have been selected, multiplied and pharmacologically treated or altered outside the body (ex vivo). The aim of cell therapy is to replace, repair or enhance the function of damaged tissues or organs. The cells used can originate from the patient or from a donor or from another species. Other sources include cell lines and cells from patients’ tumors to make cancer vaccines. Cells can be encapsulated in selectively permeable membranes that block entry of immune mediators but allow outward diffusion of active molecules produced by the cells. Genetic engineering of Universal Free E-Book Store Cell Therapy 191 cells is part of ex vivo gene therapy. The cells may be introduced by various routes into the body and selectively implanted at the site of action. Autologous Tissue and Cell Transplants The term transplantation, used mostly for organ transplants in the past, is now also used for cells transplanted from one individual to another. Problems associated with transplantation include organ rejection requiring immu- nosuppressive therapy. Problems of rejection of grafted cells can be solved by using the patient’s own cells (autologous) and encapsulating cells from other sources. Stem Cells Stem cells are cells in the embryo and the adult human body that retain the capabil- ity of making a range of other cell types. In the embryo, these cells are the starting point for the development of the complete human being. In the adult, stem cells are one of the resources for repair and renewal of cells/tissues and may be used for personalized therapy. Adult stem cells of the individual patient are more suitable for personalized therapy. In addition, stem cells derived from unfertilized oocytes could also be selected for homozygosity of a drug response gene, a disease gene, or a cancer gene from a female carrier and, therefore, could provide a model and business rationale for drug testing and drug discovery. For example, a collection of stem cells homozygous for different drug metabolizing gene variants could be used to prescreen a drug for its pro- spective toxicity and efficacy in the population. A cancer progression model can be established by differentiating stem cells homozygous for a cancer gene to the cancer tissue types, leading to the identification of biomarkers of cancer pro- gression and drugs for cancer prevention. Cloning and Personalized Cell Therapy Cloning is the procedure used to create a cell or organism that is genetically identi- cal to an existing cell or organism. The underlying biological mechanism of cloning is the reprogramming of the nuclei of specialized adult cells to become the nuclei of new embryonic cells. Cloning cells in the laboratory is a routine procedure used to produce life-saving therapeutic proteins such as human insulin for the treatment of diabetes. Potential further applications of cloning can improve treatments for ill- nesses stroke, Parkinson’s disease and heart disease. Human therapeutic cloning provides a potentially limitless source of cells for cell therapy and tissue engineer- ing. Cloning helps to overcome the problem with transplants of either cells or organs as the immune system recognizes them as foreign. But a patient’s body will not reject cells if they are genetically identical to him or her. The promise of cloning is that it could be used to create stem cells that are essen- tially the patient’s own. An embryo would be cloned from one of the patient’s own cells, and destroyed when it was a few days old to produce stem cells.

We obtain these data: One Eye Two Eyes 10 2 12 4 9 6 8 Enter the data: In the Data Editor buy 150mg bupron sr with mastercard, create two variables generic 150 mg bupron sr, each the name of a condi- tion of the independent variable (for example bupron sr 150mg otc, One and Two). Then in each row of the Data Editor, enter the two dependent scores from the same participant; for example, in row 1, enter 10 under One and 2 under Two. Select the variables: In the area under “Paired Variables,” drag and drop each of your variables into the highlighted row labeled “1. The output also includes the “Paired Samples Statistics” table, containing the X and sX in each condition. In the “Paired Samples Correlations” table is the Pearson r between the scores in the two conditions. We have these data: Condition 1: Condition 2: Condition 3: Blue Green Yellow 10 20 24 12 24 25 14 28 26 17 19 21 16 21 23 Enter the data: Enter the data as we did in the independent-samples t-test: Name one variable for the independent variable (for example, Color) and one for the depend- ent variable (Desire). Again identify a participant’s condition by entering the condi- tion’s number in the Color column (either a 1, 2, or 3). Label the output: Use words to label each level, as we did in the independent- samples t-test. Select Descriptive: Click Options and, in the “Options” box, checkmark Descrip- tive to get the X and sX of each level. In the “Descriptives” table, the first three rows give the X, sX and confidence interval for in each level. Under “(I) color” is first Blue, and in the rows here are the comparisons between Blue and the other conditions. Thus, the first row compares the mean of Blue to the mean of Green and the difference is 28. The confidence interval is for the difference between the s represented by these two level means. Under “(I) color” at Green are the comparisons involving the mean of Green, including again comparing it with Blue. Note in your output the line graph of the means, which may be exported to a report you are writing. Name the variables: In the Data Editor, name three variables: one for factor A (Volume), one for factor B (Gender), and one for the dependent variable (Persuasion). Let’s use 1, 2, and 3 for soft, medium, and loud, and 1 and 2 for male and female, respectively. Label the output: Enter word labels for each factor as described in the independent- samples t-test (B. In the Data Editor, enter a participant’s level of A in the Volume column and, in the same row, enter that participant’s level of B in the Gender column. While still in the same row, enter that participant’s dependent score in the Persuasion column. Thus, in the male-soft cell is the score of 9, so we enter 1 under Volume, 1 under Gender, and 9 under Persuasion. In row 4 of the Data Editor, for the first male-medium score, enter 2 under Volume, 1 under Gender, and 8 under Persuasion, and so on. Select the variables: Move your dependent variable (Persuasion) to “Dependent variable. Select Descriptives: Click Options and, in the box that appears, checkmark Descrip- tive Statistics. In the box that appears, to plot the main effect means, move a factor to “Horizontal Axis” and click Add. To plot the interaction, click the factor with the most levels (Volume) and move it to “Horizontal Axis. The row labeled “Total” has the X and sX for the main effect of soft volume, after collapsing across gender. In the next group of rows labeled “Medium” are the male-medium cell, the female-medium cell, and the main effect for medium volume, and so on. If the Gender factor had involved more than two levels, a separate “Mul- tiple Comparisons” table for it would appear. Likewise, compute effect size—using our formula for 2—for each significant effect. The One-Way Chi Square In Chapter 15, we discussed a study involving the frequency of left- or right-handed geniuses. Participant Handedness 1 2 3 4 5 6 7 8 9 10 2 11 1 12 2 Enter the data: In the Data Editor, name one variable (for example, Handedness). Select Chi Square: On the Menu Bar, select Analyze, Nonparametric Tests, and Chi- Square. Then type in the expected frequency for the lowest labeling score: We’d enter the fe for the number of 1s. For example, let’s examine the study comparing Type A or B personalities and the incidence of heart attacks from Chapter 15. Select the Chi Square: On the Menu Bar, select Analyze, Descriptive Statistics, and Crosstabs. In a survey, Foofy finds that three people prefer country music, nine prefer hip- hop, and two prefer classical. In another survey, Foofy asks if people like (1) or dislike (2) country music and if they like (1) or dislike (2) classical music. You can compute descriptive statistics for these raw interval/ratio scores by selecting Options and then checking Descriptive. The Mann–Whitney U Test Enter the data: Create the Data Editor as in the independent-samples t-test (B. Select the nonparametric test: On the Menu Bar, select Analyze, Nonparametric Tests, and 2 Independent Samples. Select the nonparametric test: On the Menu Bar, select Analyze, Nonparametric Tests, and 2 Related Samples.

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Colorectal Anastomotic Leakage Risk Factors bupron sr 150mg discount, Prevalence cheap bupron sr 150mg without a prescription, and Long-Term Sequelae Approximately 3% to 6% of large-bowel surgical anastomoses constructed by experienced surgeons may leak generic 150 mg bupron sr otc. Anastomotic breakdown is the most common cause of stricture formation and also predisposes to increased local recurrence of cancer, a lower cancer-specific survival, and poor colorectal function. Risk factors for anastomotic leakage include male gender, obesity, malnutrition, cardiovascular disease and other underlying chronic disease states, steroid use, alcohol abuse, smoking, inflammatory bowel disease, and preoperative pelvic irradiation. Specific operations that predispose to the development of a leak include emergency indications for surgery, low anterior resection, colorectal anastomoses, particularly difficult or long surgeries lasting over two hours, intraoperative septic conditions, and perioperative blood transfusions (26). Diagnosis The diagnosis of an anastomotic leak in the postoperative patient is relatively straightforward. A typical triad indicative of infection includes fever, leukocytosis, and pelvic pain. Given these signs and symptoms, together with the appropriate surgical history, anastomotic leakage should be high on the differential diagnosis. Other clues that might prompt clinical suspicion include absence of bowel sounds on postoperative day 4 or diarrhea before day 7, greater than 400 mL of fluid from an abdominal drain by day 3, and renal failure by day 3. Intra-abdominal Surgical Infections and Their Mimics in Critical Care 265 Treatment Following intravenous fluid resuscitation and antibiotic therapy to cover gut flora, laparotomy to lavage the abdominal cavity and either place a protecting stoma or an end colostomy is generally indicated for the more severe anastomotic leak. Risk Factors Perforated ulcer represents yet another potential source of abdominal infection in the postop- erative patient. Curling’s ulcers, or stress ulcers, affect in particular burn patients with septic complications; Cushing’s ulcers develop in patients with central nervous system pathology involving midbrain damage, such as occurs after head trauma. Risk factors predicting ulcer perforation include smoking, exposure to nonsteroidal anti-inflammatory drugs, cocaine abuse, and Helicobacter pylori infection (27,28). Presentation and Diagnosis Perforation most typically presents as an acute abdomen with sudden onset of pain, occasionally accompanied by nausea and vomiting, diffuse abdominal tenderness, rigidity of the abdominal wall, and ileus. Plain abdominal and upright chest films exhibiting signs of free air may detect 85% of free perforations (30) and is often the radiologic modality of first choice. Treatment Although there has been debate in recent years with regard to a 12-hour period of observation and supportive treatment before proceeding to surgical intervention for perforation, the poor prognosis associated with delay in definitive treatment and the relatively straightforward surgical procedure has persuaded many surgeons against this approach (28). Currently, direct suture repair, often with omental patch reinforcement, is the usual treatment of choice. From there, 266 Wilson impaired opsonization and phagocytosis in these patients allows bacteria to colonize the ascitic fluid and generate an inflammatory reaction. Complications develop secondary to this inflammation, as intravascular blood volume drops and hepatorenal failure predictably ensues. Renal failure is, in fact, the most sensitive predictor of in-hospital mortality (33). Atypical presentations may consist of acute prerenal renal failure or sudden-onset new hepatic encephalopathy with rapidly declining hepatic function. Secondary peritonitis is bacterial peritonitis secondary to a viscus perforation, surgery, abdominal wall infection, or any other acute inflammation of intra-abdominal organs. These indicators are all very sensitive but nonspecific for a diagnosis of secondary peritonitis, and their presence must be weighed against the remaining clinical picture before any firm diagnoses are reached (32). Low dose, short course cefotaxime—2 g twice a day for five days—is generally considered the first-line therapy, but other cephalosporins such as cefonicid, ceftriaxone, ceftizoxime, and ceftazidime are equally effective, and even oral, lower cost antibiotics such as amoxicillin with clavulanic acid will achieve similar results. For patients with penicillin allergy, oral fluoroquinolones such as ofloxacin are yet another suitable option, except in those with a history of failed quinolone prophylaxis implying probable resistance. The addition of albumin to an antibiotic regimen has been shown to decrease in-hospital mortality almost two-thirds from 28% to 10%. It is considered especially beneficial for patients with already impaired renal function and a creatinine >91 mmol/L, or advanced liver disease as evidenced by serum bilirubin >68 mmol/L (33). Fluoroquinolones, such as norfloxacin and ciprofloxacin, are the antimicrobials recommended for prophylactic purposes (33). Among this subset, infected pancreatic necrosis is the leading cause of death (39). Presentation and Diagnosis In addition to the typical signs and symptoms of pancreatitis, such as moderate epigastric pain radiating to the back, vomiting, tachycardia, fever, leukocytosis, and elevated amylase and lipase, patients with severe acute pancreatitis present with relatively greater abdominal tenderness, distension, and even symptoms of accompanying multiorgan failure (38). In these patients, the intensivist must maintain a high level of clinical suspicion for necrosis and possibly infection as well. Infection is estimated to develop in 30% to 70% of patients with necrotic pancreatitis (40). However, necrosis both with and without infection often manifest with similar clinical presentations because necrosis alone causes a systemic inflammatory response, and additional diagnostic data is generally needed to differentiate these (41). Enterococcus species are the organisms most frequently isolated, although many different pathogens including Candida spp. Treatment and Prophylaxis The distinction between sterile and infected necrotic pancreatitis is crucial, as the former may be handled medically when necrosis affects less than 30% of the organ, whereas the latter often demands surgical debridement (38). Recently, several studies have explored the potential of laparoscopy for infectious pancreatic necrosis, but this approach is rarely feasible in instances of extensive necrosis, and data is not yet sufficient to compare the safety and efficacy of 268 Wilson laparoscopic surgery versus laparotomy for this indication (43). Percutaneous drainage has a low success rate of just 32% and is generally insufficient management except in the case of a well-defined abscess, or one remote from the pancreas (41). Abdominal compartment syndrome has been noted in severe acute pancreatitis and decompression has been suggested for patients whose transvesical intra-abdominal pressure reaches 10 to 12 mm Hg (43). An appropriate antibiotic regimen for infected pancreatic necrosis is the second arm of a successful treatment plan: given the wide range of possible offending organisms, a Gram stain is recommended to tailor specific initial therapies prior to culture results. For gram-negative organisms, a single-agent carbapenem is effective; for gram-positives b-lactamase–resistant drugs, vancomycin, and even linezolid must considered. When yeast is identified, high-dose fluconazole or caspofungin should be sufficient.

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Individual responder analyses are proposed for use in clinical trials to better detect analgesic activity across patient groups and within sub-groups bupron sr 150 mg low price, and to identify molecular-genetic mechanisms that contribute to individual variation purchase bupron sr 150 mg with amex. Studies have shown that people with red hair need 20 % more general anesthesia than blonds and brunettes cheap 150 mg bupron sr otc. Redheads are also more sensitive to thermal pain and are more resistant to the effects of local anesthesia. While blond, brown and black-haired people produce melanin, those with red hair have a mutation of this receptor that produces a different coloring called pheomelanin, which results in freckles, fair skin and red hair. In conclusion, a number of genetic variants that prevent pain by decreasing nociception or increas- ing analgesia have been identified. Given the complex biological and psychological nature of pain, the interindividual variance in pain and analgesia due to identifiable genetic causes, should be taken into consideration in personalizing pain therapy. Pharmacogenetics/Pharmacogenomics of Pain More recently, there has been a growing body of evidence demonstrating differ- ences in analgesic response to various pharmacotherapies, although the source of this variability largely remains to be explained. To this end, basic science research is beginning to identify the allelic variants that underlie such antinociceptive vari- ability using a multiplicity of animal models, and powerful genetic approaches are being exploited to accelerate this process. There is already a growing body of evi- dence demonstrating differences in analgesic response to various pharmacothera- pies, although the source of this variability largely remains to be explained. P450 isoforms involved in the metabolism of some drugs used in the management of pain are shown in Table 12. In addition, analogous studies have been undertaken in humans, as a small but grow- ing number of clinical trials have begun to evaluate prospectively the existence, if often not the origin, of interindividual differences in analgesic drug response. Presentation of the spectrum of individual responses and associated prediction Universal Free E-Book Store Personalized Management of Pain 449 Table 12. Individual responder analyses in clinical trials can improve detection of analgesic activity across patient groups and within sub-groups, and identify molecular-genetic mechanisms that contribute to individual variation. Millennium Laboratories’ Pharmacogenetic Testing is saliva-based testing to detect genetic variations in enzymes associated with the metabolism of medications commonly prescribed to patients suffering from debilitating chronic pain and pain- related effects. This testing will help clinicians identify patients who may benefit from modifying the drug selection or dosing of certain prescribed analgesics. Proove Biosciences’ Drug Metabolism test offers a proprietary Medication Metabolism Metric to evaluate patients who are slow or fast metabolizers of a drug. Proove Narcotic Risk is a genetic test to identify patients at increased risk for chem- ical imbalances in the brain that lead to tolerance, dependence, or abuse of prescrip- tion pain medications. These tests help select the appropriate analgesic for a patient and reduce the risk of adverse effects and addiction thus facilitating personalized management of pain. Pharmacogenetics of Opioids Although morphine is the analgesic of choice for moderate to severe cancer pain, 10–30 % of patients do not tolerate morphine. Variations in genes involved in mu- opioid receptor signaling influence clinical response to morphine. Clinically relevant genetic as well as nongenetic factors influencing analgesic responses and side effects of opioids. Although available evidence on individual genotype associations with pain, anal- gesia and opioid adverse outcome are promising, conflicting data in the literature indicates that there is a need for larger and more robust studies with appropriate popu- lation stratification and consideration of nongenetic and other genetic risk factors. This study sug- gests that application of genotyping can improve surgical pain management in children. Therefore, small changes, be they splice variants or mutations, may produce dramatic effects. No definite studies have been done on this topic but the phenomenon appears to be widespread as products from approximately one-third of human genes undergo alternative splicing. Also, polymorphisms Universal Free E-Book Store Personalized Management of Pain 451 that alter splice variant expression could predispose patients to differences in disease progression. Genetically defined variations might account for differences of the intensity of inflammatory disease progression. Mechanism-Specific Management of Pain The is a need for the development of diagnostic tools that will allow us to identify the mechanisms of pain in an individual patient and pharmacologic tools that act specifically on these mechanisms. This strategy will enable a rational rather than an empirical trial-and-error approach to controlling pain. Treatment with antiinflam- matory drugs would be helpful in pain associated with inflammatory conditions but these drugs may not benefit patients whose pain is due mainly due to excitability caused by abnormal sodium channel activity after nerve injury as in painful diabetic peripheral neuropathy. Preoperative Testing to Tailor Postoperative Analgesic Requirements Patients vary a great deal in requirement for analgesics after surgery. Determining the best dose for each patient can be difficult because of individual differences in pain tolerance. If patients are undertreated and have severe pain, it can lead to ongo- ing, chronic pain. On the other hand, over treatment with pain medicine is associ- ated with bothersome side effects. About 2 weeks before surgery, the women answered questionnaires to measure anxiety, their expectations about pain and the levels of pain they were hav- ing during pregnancy. In addition, a small heat element was applied to their arms and backs and the women were asked to rate the intensity and unpleasantness. The heat was not applied long enough to cause skin damage and could be stopped by the patient at any time. After surgery, the women reported on their pain severity levels and researchers measured their requirements for pain medication. The researchers found that six groups of predictive factors accounted for 90 % of the total variances in patients’ postsurgical pain severity and medication requirements. The best pre- dictor of the total amount of pain medication required was a validated questionnaire that measured anxiety. The best predictors of overall postsurgical pain were blood pressure readings shortly before surgery and patients’ responses to the heat element that was performed before surgery.

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