By P. Stejnar. Gooding Institute of Nurse Anesthesia.

Others are statistically naive buy discount zantac 300 mg on line, and make dangerous and unnecessary concessions (such as fitting analyte concentration as a function of response discount 300 mg zantac overnight delivery, which reverses the conventional roles of the dependent and independent variables) generic zantac 300 mg with mastercard. Several comparisons of various plotting procedures have suggested that highly flexible methods such as manual plotting or splines were superior to other techniques (2,3,20,30,116). However, the criteria of comparison were innately biased in favor of methods which tend to pass through the individual standard points. When the deviation of the calibration curve from an intermediate standard is used to compare methods, techniques such as splines and manual plotting do not fare very well (4,6,9,17). Splines can be rather clumsy to use in practice if they require operator intervention to define the points at which the individual segments of the spline join up. If an interpolating spline is used, such intervention is unnecessary, but the spline translates any imprecision in the location of the standard points into a bias in interpolation. The numerous parameters of a spline are not amenable to the statistical tests which can be applied to simpler methods such as the logistic equation. These are a few of the considerations which prompted Finney to call the advantages of splines "illusory" (117). Almost aU of the comprehensive data processing packages for assay utilize a four-or five-parameter logistic equation to fit the calibration data. Som e workers seem to confuse this technique with the older and much less flexible two-parameter logistic method, also known as the logit-log technique. The four-and five-parameter logistic equations have been successfully used for a wide variety of types of binder-ligand assay (66,100,118). Just as important as having an appropriate equation to fit, is using the proper technique to fit it. The most general curve-fitting method in general use is that of maximum-likelihood. Finney has compared this method to the more commonly encountered technique of least squares and found the latter satisfactory for routine use (101). S o m e of the simpler calibration methods use linear least squares, but the more advanced methods require the more complex non-linear least square technique. In either case, it is vitally important to weight the fit to take into account the heteroscedasticity (non-uniformity of variance) almost invariably found in the response (121). Methods of assessing the quality of fit include analysis of variance (which are exact only in the case of linear least squares models) and the plotting of residuals. A very clear graphic technique embodied in the programs of Dudley (79) and Malan (4) plots the difference between the known and predicted analyte concentrations of the standards, with the predicted values being bracketed by their confidence limits. This allows a rapid check to see if the irregularity in the fit is much smaller than the random error present, which would normally be expected if the selected calibration method is appropriate for the assay at hand. If a device is being selected especially for the purpose of assay data analysis, there is a huge choice, from inexpensive hand-held calculators to large computers. Factors in the decision should include not only the price of the device, but also ease of use, maintainability, and reliability. The flexbility of the device is greatly extended if it can be attached to other computing devices and to laboratory equipment. It is important to select a program which is written using good modular structured programming techniques so that it will be easy to correct and to improve. The program should also extract the maximal amount of information possible from the data, in accordance with accepted practice. The majority of the programs indexed in Table 1 do not perform the basic set of procedures outlined in section 2. Rather than review the entire list of available programs, it seems more useful to put forward several examples of carefully executed and comprehensively conceived programs which run on a variety of computing devices. For computers capable of handling a moderately large F O R T R A N program, the package of Raab, McKenzie, and Thompson would seem to be the most flexible and powerful program currently available (73,74). Also well suited are the pioneering programs of Rodbard (48), and the program of Peters (75). The F O R T R A N programs of Finney (68) and Healy (53) are well executed but evidently not intended for routine laboratory use. It is attractive and easy to use, but Finney has expressed some mild misgivings about certain statistical aspects of the multi-binding site model it uses to fit the calibration curve (117). These seem relatively minor but still have not been discussed in print by the developers of the program. One advantage of this and the larger F O R T R A N programs is that data entry is relatively easily done by use of punched paper tape output taken directly from the final measurement device of the assay. This program goes well beyond previous calculator programs, which are essentially simply calibration and interpolation programs (54,78), and offers a very comprehensive analysis of results. Nevertheless, this program establishes a new minimum level of acceptable statistical capability for assay programs in general. The use of any of these programs may require that additional programming be done at the local level. The language of alphanumeric prompts m ay need to be modified to suit the local workers. Interfacing the assay program with pre-existing laboratory data management programs m a y be necessary. Finney has outlined the characteristics of an ideal assay program (117); the requirements make it clear that writing a complete package is not a trivial task. It is to the benefit of both individual laboratories and the assay community as a whole to concentrate upon the dissemination and continued improvement of several good programs rather than the continued development of many local programs. This will probably lead to increased use of disseminated processing in laboratories, in which small special- purpose computing devices are attached to assay machinery and used strictly for assay calculations. These small machines will communicate with a hierarchy of other larger machines to pass on results to a data archive.

All reactions are handled in this manner either by the resident or attending physician discount zantac 300mg without prescription. Training in the Unique Computer Needs of a Transfusion Service: During the blood bank laboratory orientation and training cheap zantac 300mg with amex, the resident learns how laboratory staff use computers to acquire components from the blood supplier (Community Blood Center) discount 150 mg zantac mastercard, enter test results, track the unit, and release the unit to the patient care unit. The resident also learns the principles behind the electronic cross-match using a computer. The resident frequently uses the blood bank computer for retrieving patient and blood bank data. The resident has computer continuous access in the resident/fellow office for patient care and for Medline literature searches. Pathology Resident Manual Page 122 Training in Immunologic/Serologic Aspects of Blood Product Screening: The resident is trained regarding blood donor testing at the Community Blood Center, including red blood cell serology and infectious disease serologic testing. In addition, they spend time learning neutrophil serology and platelet serology & cross-matches. During this period, the residents will on average have one out of every seven days free of hospital duties. While on-call, residents are supervised by a Faculty Member, who is available at all times, either via their office phone, pager, or home phone. No on call duties outside of regular laboratory working hours are assigned to the resident involving coverage at these sites. The resident who is assigned to Transfusion Medicine for the month, is responsible for Clinical Pathology Call from Monday to Friday 8 a. The remainder of the call time is divided between all residents who are on a Clinical pathology rotation, who have previously rotated through Transfusion Medicine. The Chief Residents will make out the clinical pathology call schedule and make sure no resident is on call for more than 6 days in a row. At all times, a supervising faculty member is on call for evening and weekend questions. In addition, the resident usually has an informal lunch meeting with the blood bank medical director at least once a week and often three times a week (case discussions, mentoring). Education in Blood Bank Management Blood supply inventory management is discussed both at regular Transfusion Committee meetings. Scholarly Activities/Research Because of this the resident evaluates and discusses research findings in the literature and receives feedback from faculty. The resident is urged to write up and publish interesting or unique transfusion problems Pathology Resident Manual Page 123 encountered during the rotation. Blood Bank faculty eagerly offers to mentor the resident through the process leading to a publication. If a resident is interested in a research project and has sufficient time, the blood bank faculty will arrange this in one of the Transfusion Medicine research labs. Resident Evaluation If problems with not meeting expected knowledge and skills are observed during the rotation, the lead faculty member meets with the resident to evaluate the problem and develop a corrective action plan. Residents will be evaluated on performance of daily activities (described previously), participation in required meetings and conferences, and presentations to the staff on assigned cases. The residents are provided with continuous feedback on their performance during the rotation. Residents are evaluated on their demonstrated ability to provide informative consultation to the clinical service teams, their medical knowledge, their application of this knowledge to efficient/quality patient care, and their diagnostic, technical and observational skills. Residents are also evaluated on their interpersonal skills, professional attitudes, reliability, and ethics with members of the teaching faculty, peers, laboratory staff, and clinicians. They are further evaluated on their initiative in fostering quality patient care and use of the medical literature, as it relates to their assigned cases. Their timely completion of assigned interpretive reports is another component of the evaluation. While designed for residents, clinical chemistry post-doctoral fellows and incoming chemical pathology fellows may also take this rotation either together with or separate from the residents. In either case the residents and fellows equally share the daily duties and are considered peers. Interaction with faculty located at these institutions is intended to provide a perspective on laboratory organization/design and the practice of clinical chemistry as seen in a variety of different settings. The clinical chemistry rotation is organized to both teach the fundamental principles of clinical chemistry and to provide extensive experience with the day-to-day clinical application of those fundamentals. The fundamental principles are taught through a structured list of teaching objectives that are arranged into three separate Units. Each Unit Coordinator is responsible for arranging the day-to-day scheduling of their Unit, how and when the laboratory exercises will be performed, and when the resident will meet with the faculty members. Depending on the faculty and the Unit, this interaction will includes the following: • Didactic sessions on specific topics with the faculty members. At least one week prior to the start date of each unit, the resident(s) should review the section of this manual that describes the requirements for the next scheduled Unit. They then should contact the Coordinator to receive information regarding appointments for the didactic sessions and to complete any necessary arrangements for laboratory demonstrations and exercises. Prior to each Unit, the resident should review the Specific Learning Objectives and review the Required Reading Assignment listed in each Unit. If they are familiar with the material, they need not read the reading assignment word-for-word. However, if the material is not familiar to them, they should make every attempt to master it before meeting with the faculty for the didactic sessions.

Retroviral transduced hepatocytes were shown to become stably engrafted into the animal’s liver with a subsequent lowered serum cholesterol level cheap zantac 300 mg mastercard. The results of these early experiments provided support for the efficacy of this treatment and paved the way for human clinical trials order zantac 150mg online. A 28-year-old French Canadian woman was the first recipient of liver-directed gene therapy purchase 150mg zantac. After suffering a myocardial infarction at the age of 16, she had a coronary artery bypass at the age of 26. The left lateral segment of the patient’s liver, comprising about 15% of total mass, was removed and the parenchymal liver cells were isolated. Only genetically altered hepatocytes were reinfused into the portal circulation (Fig. The patient also responded to the drug lovastatin, which prior to gene therapy had no effect. The recombinant receptor gene had no transcriptional elements that could respond to cholesterol-mediated regulation. This indicates that the response to lovastatin was related to posttranscriptional regula- tion, a mechanism demonstrated in previous studies. The patient’s sera contained no antibodies to the recombinant receptor when a western blot analysis was performed. Engraftment of suc- cessfully transduced hepatocytes as well as transgene expression was shown for all patients, without significant side effects. None of the patients developed an immune response to the transgene or to retroviral proteins. Although gene transfer was demonstrated in all patients, the clinical impact on the disease was low with serum cholesterol levels still exceedingly above the normal range. Only genetically altered hepatocytes are reinfused into the portal circulation of the patient. The animals experienced an immediate, but transient, decrease in total serum cholesterol by 153 ± 53mg/dl. However, the low levels and short duration of recombinant gene expression were disappointing. However, the expression of the recombinant receptor as well as the effect on the lipid profile has been only tran- sient. This was due to the immune response that the host mounted against a low- level expression of viral proteins, with the subsequent destruction of the genetically altered cells. The latter is due to loss of transduced cells or inactivation of the expression vectors. There is a well-characterized canine model that has been used in preclinical trials for hemophilia B. After undergoing gene therapy this time was reduced more than 50% with times in the range of 18 to 22min. Also, encouraging is the fact that this effect remained stable for over 9 months (Fig. While repeated administrations could be considered, it is possible that an immune response could develop with subse- quent treatment. They simply injected the mice in a tail vein with the recombinant vector after g-irradiation was applied to the liver. As pre- viously discussed, this treatment probably stimulates cells to divide, thereby improv- ing the efficacy of adenoassociated viral gene therapy. It is a protease inhibitor whose function is essential in protecting the alveolar surface of the lung from destructive protease activity. This is manifested in a high risk for the early develop- ment of pulmonary emphysema, due to proteolysis of the pulmonary extracellular matrix. The most common mutants, called Z and S occur with an allelic frequency of 1 to 2% and 2 to 4%, respectively, in this population. Attempts to correct this disorder have been studied on dogs where the introduc- tion of the correct gene was performed in an ex vivo manner. Another group of investigators attempted an in vivo approach using small lipo- somes as the method of gene delivery. A plasmid containing the full-length human a1-antitrypsin gene was encapsulated in small liposomes and was intravenously injected into mice. Interestingly, there was no additive effect when additional doses of the liposome complex were delivered. It is unclear why the repetitive application did not further increase the gene expression. Also, it is not completely understood why the stimulation of cell proliferation by partial hepatectomy increased gene expression. Patients with this recessively inherited disease are characterized by high serum levels of unconjugated bilirubin, with little or no conjugated pigment in the bile. At present, the only defin- itive treatment for this disorder is liver transplantation. These rats exhibit lifelong hyperbilirubinemia and develop biliru- bin encephalopathy. They provide a model system for studies on the efficacy of gene therapy for Crigler–Najjar syndrome type I. As a strategy to prolong the duration of targeted gene expression, advantage was taken of the fact that the translocation of endosomes to lysosomes as part of the endocyto- tic degradative pathway requires an intact microtubular network. Biliru- bin glucuronides were excreted in the bile and serum bilirubin levels decreased by 25 to 35% in 2 to 4 weeks and remained reduced for a period of 8 weeks. There are other drugs that could produce the same effect yet are safe for applica- tion in clinical human trials. Alternatively, to avoid side effects and broad biodis- tribution, colchicine could be delivered in a liver-specific manner.

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