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If the assumption of normality of residuals is not met order 40mg zocor mastercard, the direction of bias is not always clear purchase zocor 10mg without prescription. This may not be too important if the P value is large and clearly non-signiﬁcant or if the P value is small and clearly signiﬁcant order zocor 10mg visa. However purchase 40mg zocor free shipping, bias is a major problem if the P value is close to the margin of signiﬁcance or the sample size is small. Outliers can have an important effect on the perceived differences between groups by making the groups seem more different or more alike. The direction of bias caused by outliers is usually to artiﬁcially skew the mean value of a group in the direction of the outlier. Inﬂuential outliers can be recoded with a nominal value to remove their inﬂuence – a value that is commonly used is one that is marginally outside the range of the remainder of the data. An advantage of this method is that the results are readily understood and easily communicated. However, a disadvantage is that no allowance is made for measurements taken closer together in time to be more correlated than measurements taken further apart. The within-subject factor, which is related to time, is generally of most interest as the outcome variable. However, differences in between-subject ﬁxed fac- tors such as gender or treatment group can also be tested. However, sometimes the results of the univariate and multivariate repeated measures tests will disagree. The multivariate test statistics are based on transformed variables, not the original variables. In addition, the presence of Analyses of longitudinal data 165 outliers, sample size and violations of the test assumption may inﬂuence the test results. Sphericity requires that the variances of the differences for all pairs of repeated measures are constant. Sphericity should be checked for when there are three or more repeated measures conditions. The assumption of sphericity can be tested using Mauchly’s test which gives an estimate of epsilon ( ), a measure of sphericity. This statistic has a value of 1 when sphericity is met and values less than 1 indicate further deviation from sphericity. However, the Mauchly’s test is inﬂuenced by the sample size, in that, in small samples this test often fails to detect departures from sphericity and in large samples over detects sphericity. Another assumption is that the variances of the repeated measures are the same in each group, that is, there is homogeneity. The F test of the univariate model is robust to some violations of the assumption of normality of residuals but not to the sphericity assumption. When sphericity is not met, the F value is inﬂated and the P value is biased towards signiﬁcance. In this situation, the estimate of sphericity is adjusted using the Greenhouse-Geisser or the less conservative Huynh–Feldt methods. With these methods, the degrees of freedom are multiplied by the estimate of sphericity, consequently the degrees of freedom are decreased, making the F ratio more conservative. Thus, the original outcome values across time are trans- formed to contrast values and the model is applied only to these variables. This method of transforming the data bypasses the problem of dealing with covariance between time points rather than addressing it directly as in a linear mixed model. Interactions that are statistically signiﬁ- cant indicate that the pattern of change over time is different between groups. Thus missing values reduce the effective sample size, compromise statistical power and affect the generalizability of the results. If the number of missing values is small and the values are randomly missing, they can be replaced with a nominal value such as a mean value or the last value carried forward for each participant. The time point at which the increase is no longer signiﬁcant indicates where the plateau begins. Analyses of longitudinal data 167 • Polynomial, which tests for a trend across the time points. Tests of signiﬁcance for a linear trend through the data and for orders such as quadratic effects are included. For pairwise post hoc comparisons, the Tukey’s test is powerful when sphericity is met. When sphericity is violated, the Bonferroni is recommended since it maintains the type I error rate. The outlying values are few and are not extreme and therefore the values are left unchanged in the analyses. Between-Subjects Factors Value label N Group 1 Control 21 2 Intervention 26 Box’s Test of Equality of Covariance Matricesa Box’s M 22. A signiﬁcant interaction indicates that effect of 172 Chapter 6 one variable depends on the level of another variable. As an estimate of effect size the multivariate partial eta-squared was requested, which is the ratio of variance accounted by a factor to the variance accounted by a factor and its associated error. In this, it is important to note that partial eta-squared cannot be interpreted as explaining or accounting for the total variance. However, both eta-squared and partial eta-squared can be biased and have a number of limitations. However, the Greenhouse-Geisser and Huynh–Feldt epsilon values are high and greater than 0. Therefore, the Huynh–Feldt estimates shown in the Tests of Within-Subjects Effects table are the appropriate statistics to report for this model. Since the interaction is signiﬁcant, interpreting the main effects will not lead to an accurate understanding of the results. In general, a signiﬁcant main effect should not be interpreted when there is a signiﬁcant interaction that involves that main effect. Although the P values for the quadratic trends are also signiﬁcant, the partial eta-squared is lower indicating that the linear trend is a better ﬁt. The results of the trend contrasts should be interpreted with caution and the plots of the data should also be examined. This is a violation of the model assumptions and the results should be interpreted with caution. In reporting the results of the model, the violation of homo- geneity should be reported. Alternatively, transformation of all data can be undertaken to stabilize the variances between the groups. These means are predicted means, not observed means, and are based on the speciﬁed linear model.
Optimization of the time parameter with respect to reaction times and purification procedures is thus essential discount 10mg zocor free shipping. Furthermore zocor 10mg with amex, the search for techniques and methods supporting one-pot or flow-reactor systems in miniaturized versions is also very important purchase zocor 20 mg online. From the radiation safety point of view discount zocor 20 mg free shipping, the development of remote handling techniques using automation, e. The tomographic technique allows imaging of the radiotracer disposition in slices of the body of the object and measurements of the change of radioactivity in the tissue with time. The method gives accurate quantitative measurements of parameters relat ing to physiological processes in the tissue, such as blood flow, pH, energy metabolism, protein synthesis rate and cell proliferation. Furthermore, radiolabel ling of enzyme substrates will give information on the function of enzymes, such as neurotransmitter synthesis via decarboxylation of the appropriate amino acid to get information on the synthesis rate of neurotransmitters. The labelled drugs permit quantitation of the receptor number, as well as bind ing kinetics, together with information on selectivity for different receptor popula tions. Combined with observations of the clinical outcome, radiolabelled tracers can give new information of how a given pharmaceutical can affect several processes that take place in the tissue. Multitracer studies using differ ent ligands or single tracer studies in various protocols to enlighten various aspects of the observed system will become most valuable in the near future. For example, deuterium labelled L-deprenyl was utilized in developing a new method for interictal determination of epileptic focus [28, 29]. In this controlled blind study of a total of 16 healthy volunteers, 4 were given a placebo, 4 an established and registered drug and, finally, 8 were given the new neuroleptic, all for 7 days. The data from three groups are seen in the graph and show that the new drug penetrates and acts on the central nervous system, as measured by the change in n C-harmine binding . The patients included in this study were all relatively early in their development of Alzheimer’s disease with a Minimentens scoring of around 20-28. The study was set up to evaluate nicotine deposition and disposition by using 1^-nicotine, which had been applied in a new smoke cessation device containing cold nicotine [32, 33]. Using the tracer concept, we were able to show the relative deposition of nicotine as a function of time and region. An early example in our laboratory was the treatment of patients with pituitary prolaktinoma by bromocriptine. We showed, using n C-raclopride, how dopamine agonist treatment changed the receptor occu pancy as a function of time of treatment. Using another tracer, n C-L-methionine, we also showed that the uptake of the labelled amino acids was significantly reduced for even a very short time of treatment. A significant change in uptake was seen only a few hours after the start of treatment. Further, by the use of labelled bromocriptine we demonstrated that the action of the drug was at the site of the tumour . An important factor in further progress is the development of synthetic methods considering chemo, ‘regio’ and stereoselective synthetic reactions and their incorporation in rapid labelling procedures. The importance of designing appropriate tracer molecules will probably be seen in many applications in the future as a means to unravel biochemical processes with respect to stereo selectivity, transport mechanisms, specific binding and metabolism. Biodistribution studies in rat brain by dissection studies and in rhesus monkey by use of positron emission tomography, Appl. Generally speaking, the different inclination and orientation of the longitudinal axes of both kidneys in patients results in a high level of variability in the detection of the various types of complaint and can lead to an ambiguous diagnosis. In order to avoid this, some software has been developed at the Centro de Investigaciones Clínicas to automate the processing of renal tomography studies with a view to making it as independent of the observer as possible. It is based on an algorithm which performs a series of reorientations of each kidney separately yielding a final image. This facilitates greater objectivity and convenience in the analysis of each case. In this way, a standardization of the procedure is achieved, which means that serial developmental studies of patients can be performed with greater consistency. En general, la diferente inclinación y orientación de los ejes longitudinales de ambos riñones de los pacientes conduce a una alta variabilidad en la detección de los diferentes tipos de defectos y a un posile diag nóstico equívoco. Para evitarlo, se desarrolló en el Centro de Investigaciones Clínicas un “ software” para la automatización del procesamiento de los estudios tomográficos renales que fuera lo más independiente posible del observador. Este se basa en un algoritmo que realiza una serie de reorientaciones de cada riñón por separado que culminan en la obtención de una imagen final, facilitando así el análisis de cada caso con mayor objetividad y comodidad. De esta forma se logra una estandarización del procedimiento que permite realizar estudios evolu tivos de los pacientes con mayor rigor. En la evaluación de este tipo de lesiones generalmente se pueden determinar dos tipos de defectos: los de tipo inflamatorio, que se reflejan en las imágenes como una o varias zonas de hipofijación sin alteración del contorno externo, y los de tipo cicatriciales, que provocan deformaciones en el parénquima renal de carácter irreversible. Debido a que cada tipo de lesión lleva aparejado un pronóstico diferente, es importante determinar lo más exactamente posible la presencia de uno u otro tipo de defecto. Algunos autores han trabajado en el análisis de los cortes tomográficos teniendo en cuenta la reorientación de cada riñón . Debido a todo lo anterior, nos dimos a la tarea de obtener un algoritmo que reorientara de forma automática las imágenes de cada unidad renal por separado hasta una posición estándar a partir de la cual se pudiesen analizar los defectos existentes y posteriormente crear una imagen plana que reuniera la información con tenida en los diferentes cortes tomográficos. E tapas del algoritm o El procedimiento se realizó para cada riñón por separado —primero se procesaba el izquierdo y después el derecho— y está basado en la siguiente secuencia de pasos: En la primera parte, se creó una máscara tridimensional que envuelve al riñón y permite trabajar con los valores de éste. Los imágenes se centraron tomando en cuenta el centro geométrico de todo el volumen del órgano en cuestión. Posterior mente se pasó a analizar la inclinación inherente al eje longitudinal de la unidad renal en estudio; se tomaron los valores del contorno de las imágenes y, a partir de una regresión por el método de mínimos cuadrados, se ajustaron éstos a una recta que coincide con el eje antes mencionado; se calcularon los ángulos de inclinación de la recta con respecto a la vertical para posteriormente rotar todo el volumen a una inclinación estándar. Después se analizaron los cortes de la zona media del riñón para el cálculo del ángulo en que se encuentra ubicada la pelvis renal, donde se regis traron los menores valores de captación; finalmente se rotó el riñón hasta coincidir con el ángulo calculado. En una segunda etapa, se realizaron búsquedas radiales siguiendo las manecillas del reloj a partir de la localización de la pelvis renal. En estas búsquedas se localizó el máximo de captación en cada dirección hasta un radio medio que fue determinado por condiciones de isocontorno. Cada valor así obtenido fue recogién dose teniendo en cuenta el número de corte en una matriz de 64 X 64, correpon- diendo cada columna a un ángulo determinado y cada fila a un número de corte específico. De esta forma se obtuvo una imagen desenvuelta cilindrica de la super ficie del riñón (Fig. En este diagrama se representa la localización de las diferentes zonas renales en la imagen desenvuelta. Si en lugar de realizar la búsqueda de los máximos de forma radial se realiza de forma lineal, a partir de un piano central que pase por el medio de la pelvis renal, se obtiene otro tipo de imagen que correspondería a “ abrir” el riñón por la mitad o, lo que es lo mismo, obtener una imagen desenvuelta “ lineal” de la superficie renal. Después de obtener ambas imágenes para el riñón izquierdo, se procedió a aplicar la misma secuencia de pasos al riñón contralateral. Al finalizar todo el procesamiento, se muestran en pantalla las cuatro imágenes obtenidas para su evalua ción (dos para cada unidad renal). La adquisición de las imágenes planas se realizó en formato de 128 X 128 pixeles con 1 min de duración y aproxima damente 300 x 103 cuentas en cada imagen, en proyecciones posterior y oblicuas posteriores a 45°. La adquisición de las imágenes tomográficas se hizo en una matriz de 128 x 128 pixeles a 10 s por vista, con un total de 128 proyecciones.
Although the ﬁgures are given in percentages cheap 40 mg zocor with visa, diag- nostic statistics are more commonly reported as proportions purchase 10mg zocor visa, that is purchase zocor 10mg with amex, in decimal form cheap zocor 10mg otc. If the conﬁdence interval around a proportion contains a value less than zero, exact conﬁdence intervals based on the 334 Chapter 11 Table 11. These can be calculated at StatPages on the web (see Useful Websites) rather than asymptotic statistics based on a normal distribution. Thus, these statistics can only be applied to the study sam- ple or to a sample with the same proportion of disease-positive and disease-negative patients. In this sense, these two statistics describe the proportion of patients in each disease category who are test positive or negative. The false negative group is the proportion of patients who have the disease and who have a negative test result, that is, c/(a + c). The false positive group is the proportion of patients who do not have the disease and who have a positive test result, that is, b/(b + d). However, this is not possible since there is a trade-off between sensitivity and speciﬁcity. A test that is used to diagnose an illness in patients with symptoms of the illness needs to have a low false positive rate because it will then identify most of the peo- ple who do not have the disease. Although speciﬁcity needs to be high for a diagnostic test to rule the disease in, it is calculated solely from the group of patients without the disease. A test that is used to screen a population in which many people will not have the disease needs to have high sensitivity because it will then identify most of the people with the disease. Although sensitivity needs to be high in a screening test to rule the disease out, it is calculated solely from the group of patients with the disease. Diagnostic statistics 337 X-ray results (test)* Fracture detected by surgery (disease) Crosstabulation Fracture detected by surgery (disease) Total Present Absent X-ray results (test) Positive Count 36 24 60 % within fracture 81. Again, if the conﬁdence interval of a proportion contains a value less than zero, exact conﬁdence intervals should be used (e. Because each 95% conﬁdence interval is based only on a subset of the sample rather Table 11. The interpretation of the intervals for sensitivity is that with 95% conﬁdence between 70. Similarly, the interpretation for speciﬁcity is that with 95% conﬁdence between 69. It is not always understood that to show that a test can rule a disease out, a large number of people with the disease present must be enrolled and that to show that a test is useful in ruling a disease in, a large number of people without the disease must be enrolled. For most tests, a large number of people with the disease present and with the disease absent must be enrolled to provide tighter conﬁdence intervals, that is, more precision around both sensitivity and speciﬁcity. In studies when both the new diagnostic test and the gold standard result in a binary variable (e. Also, sensitivity and speciﬁcity should not be used in isolation because each is calculated from separate parts of the data. To be useful in clinical practice, these statistics need to be converted to a likelihood ratio that uses data from the total sample to estimate the relative predictive value of the test. A positive likelihood ratio greater than 1 indicates that a positive test result is associated with the presence of the disease, whereas a positive likelihood ratio of less than 1 indicates that a positive test result is associated with the absence of a disease. The pre-test probability is the probability of the disease in the clinic setting where the test is being used. The post-test probability is the probability that the disease is present when the test is positive. Although the scatter plots are useful for understanding the discriminatory value of each continuous variable, they would not be reported in a journal article. With complete overlap such as this, there will never be a cut-off point that effectively delineates between the two groups. In the data set, disease positive is coded as 1 and this value is entered into the State Variable box. BiochemA lies close to this line conﬁrming that the test is poor at discriminating between disease-positive and disease-negative patients. A curve that falls substantially below the diagonal line indicates that the test is useful for predicting patients who do not have the disease. Both BiochemB and BiochemC have an area under the curve that is signiﬁcantly greater than 0. The very small amount of overlap of conﬁdence intervals between BiochemB and BiochemC suggests that BiochemC is a signiﬁcantly better diagnostic test than BiochemB, even though the P values are identical. In diagnosing a disease, the gold standard test may be a biopsy or surgery, which is invasive, expensive and carries a degree of risk, for example the risk of undergoing an anaesthetic. Tests that are markers of the presence or absence of disease are often used to reduce the number of patients who require such invasive interventions. The exact points on the curve that are selected as cut-off points will vary according to each situation and are best selected using expert clinical opinion. Three different cut-off points on the curve are used for a diagnostic test, a general optimal test and a screening test. The cut-off point for a screening test is chosen to maximize the sensitivity of the test and for a diagnostic test is chosen to maximize the speciﬁcity of the test. This is the point at which the true positive rate is optimized and the false positive rate is minimized. In the table, the Excel function option has been used to also calculate Speciﬁcity and 1 − sensitivity for each point. To ﬁnd the coordinates of the optimal diagnostic point, a simple method is to use a ruler to calculate the coordinate value for 1 − speciﬁcity of the optimal cut-off point. The value for 1 − speciﬁcity is then calculated as the ratio of the distance of the point from the y-axis to the total length of the x-axis. Thus, of the three points, the ﬁrst point optimizes sensitivity, while 1 − speciﬁcity remains constant at 0. An alternative method to identify the cut-off point from the Excel spreadsheet is to use the following arithmetic expression, which uses Pythagoras’ theorem, to identify the distance of each point from the top of the y-axis. In this calculation, the ‘distance’ has no units but is a relative measure: Distance =(1 − sensitivity)2 +(1 − speciﬁcity)2 This value was calculated for all points in Table 11. For a diagnostic test, it is important to maximize speciﬁcity while optimizing sensitivity. For a screening test, it is important 348 Chapter 11 to maximize sensitivity while optimizing speciﬁcity. In this, the decision needs to be made about how important it is to minimize the occurrence of false negative or false positive results. The pos- itive likelihood ratio is computed for each cut-off point as sensitivity/1 − speciﬁcity. A high positive likelihood ratio is more important for a diagnostic test than for a screening test. The 95% conﬁdence intervals for sensitivity and speciﬁcity are calculated using the Excel spreadsheet in Table 11.
The most com- Childhood kidney cancer is different from adult kid- mon symptom is abnormal bleeding zocor 10 mg without prescription. The most common type of childhood cervix can be diagnosed by using a Pap test or other kidney cancer is Wilms tumor buy 10 mg zocor fast delivery. The diagno- Women who begin having sexual intercourse before sis of kidney cancer is supported by findings of the age 18 and have many sexual partners are at medical history and examination buy zocor 40mg with amex, blood 40 mg zocor, urine, and increased risk. Kidney ners begin having sexual intercourse at a young age cancer is treated with surgery, embolization, radia- and have many sexual partners, especially one who tion therapy, hormone therapy, biological therapy, had cervical cancer, are at increased risk. Cancer of the larynx occurs most often in people over the age of 55, especially cancer, colon A malignant tumor arising from those who have been heavy smokers. The larynx can be examined with for cancer of the colon and rectum (colorectal can- a viewing tube called a laryngoscope. Cancer of the cer) include colon polyps, long-standing ulcerative larynx is usually treated with radiation therapy or colitis, and genetic family history. Persistent cough and blocks the common bile duct, and bile cannot pass bloody sputum can be symptoms of lung cancer. A physician should be consulted for cancer, melanoma A skin cancer that begins in growths or sores on the penis, any unusual dis- cells called melanocytes, which normally grow charge from the penis, or bleeding. If cancer is found, more tests change in size, shape, or color of a mole can be a are done to find out whether the cancer has spread sign of melanoma. If it is not detected early, however, it options include surgery, radiation therapy, may spread to other areas of the body, and that can chemotherapy, and biological therapy. Diagnosis is confirmed with a biopsy of of recovery and choice of treatment depend on the the abnormal skin. Sun exposure can cause skin stage of the cancer and the patient’s general state of damage, which can in turn lead to melanoma. It is often first detected as a hard nodule found during a rou- cancer, non-Hodgkin’s lymphoma See lym- tine rectal examination. Diagnosis of prostate cancer is established when cancer cells are cancer, oral A malignant tumor of the mouth identified in prostate tissue obtained via biopsy. A sore in the mouth that does not heal can be some patients, prostate cancer is life threatening. A biopsy is the only many others, prostate cancer can exist for years way to determine whether an abnormal area in the without causing any health problems. Oral cancer is almost options for prostate cancer include observation, always caused by tobacco (smoking and chewing) radiation therapy, surgery, hormone therapy, and or alcohol use. Hereditary ovarian can- include heredity, colon polyps, and long-standing cer makes up a small percentage of all cases of ulcerative colitis. Removal of these polyps can identified: ovarian cancer alone, ovarian and breast prevent cancer. Ovarian cer can have no symptoms, so regular screening is cancer is difficult to detect early because there usu- important. Diagnosis can be made by barium enema ally are no symptoms and the symptoms that do or by colonoscopy, with biopsy confirmation of can- occur tend to be vague. There are many types of skin can- bladder habits, a sore that does not heal, unusual cer; the three most common types are basal cell bleeding or discharge, thickening or a lump in the carcinoma, squamous cell carcinoma, and the most breast or any other part of the body, indigestion or deadly, melanoma. The main cause of skin cancer is difficulty swallowing, obvious change in a wart or ultraviolet light from sunlight. Unexplained changes in the symptoms are not always signs of cancer; they can appearance of the skin that last longer than 2 weeks result from less serious conditions. The cure rate cancer cause little or no discomfort until the disease for skin cancer could be 100 percent if all skin can- is far advanced, so it is important to see a physician cers were brought to a physician’s attention before for regular checkups rather than wait for problems they had a chance to spread. Candida albicans A yeast-like fungal organism cancer, stomach See cancer, gastric. Normally kept in check by the body’s own cancer, testicular A malignant tumor of the male helpful bacteria, C. It is one of the most common didiasis of the intestinal tract or yeast infections of cancers in young men. The risk of testicular cancer is increased in males candidiasis Disease caused by the yeast Candida whose testicles did not move down normally into the albicans. Candida albicans can cause vaginal yeast scrotum during childhood (undescended testicles). Candidiasis ticle (orchiectomy) and examination of the tissue tends to develop when the normal balance of bacte- under a microscope. Testicular cancer is almost ria is upset, as sometimes occurs with the use of always curable if it is found early. Prevention measures include the use of probiotics, and in some cases, dietary changes. Candidiasis is usually a minor and easily hormone, which is important to the normal regula- addressed problem, but it can be an important tion of the metabolism in the body. Persons who received radiation to the head or neck in childhood canker sore A common small, frequently painful should be examined by a physician for thyroid can- and sensitive crater in the lining of the mouth. Sores typically last for 10 of thyroid cancer is a lump, or nodule, that can be to 14 days and generally heal without scarring. The only certain way to tell whether a thyroid lump is cancer is by examining thyroid tis- cannabis Marijuana (Cannibis sativa), a drug sue obtained via biopsy. Use of cancer, uterine A malignant tumor of the uterus cannabis produces a mild sense of euphoria, as well (womb), which occurs most often in women as impairments in judgment and lengthened between the ages of 55 and 70. The walls of capillaries act as semi- of topical creams) and, in severe cases, surgical permeable membranes that permit the exchange of drainage. Others include cancer of the pancreas, carbohydrate One of the three nutrient com- stomach, breast, and lung, as well as certain types of pounds, along with fat and protein, used as energy thyroid and ovarian cancer. Carbohydrates take before therapy are associated with cancer that has the form of simple sugars or of more complex already metastasized (spread). Intake of com- plex carbohydrates, when they are substituted for carcinogen A substance or an agent that causes saturated fat, can lower blood cholesterol. The International Agency for Research on Carbohydrates produce 4 calories of energy per Cancer has classified many substances and gram. When eaten, all carbohydrates are broken processes as probably or definitely causing cancer down into the sugar glucose. The agency has divided these substances and processes into three categories: agents (such as carbon monoxide poisoning A potentially arsenic, asbestos, and benzene); mixtures (such as deadly condition caused by breathing carbon in coal tars, tobacco products, and smoke); and monoxide gas, which prevents oxygenation of the exposures (such as in aluminum production, shoe blood. Common causes of carbon monoxide poison- manufacturing and repair, and the rubber industry). Carbon monoxide is also emitted by automobile and other engines, so these should not carcinogenic Having a cancer-causing potential. Inexpensive alarms are available that can carcinoma Cancer that begins in the skin or in detect dangerous buildups of carbon monoxide. Examples are treatment for carbon monoxide poisoning is imme- carcinoma of the breast, colon, liver, lung, pan- diate reoxygenation of the blood in a hospital. Carboxyhemoglobin carcinoma, squamous cell Cancer that begins is formed in carbon monoxide poisoning and leads in squamous cells, which are thin, flat cells that to oxygen deficiency in the body. Squamous cells are found in carbon monoxide may be exhaust (such as from a the tissue that forms the surface of the skin and the car, truck, boat, or generator), smoke from a fire, lining of some organs of the body.