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bulletConsultant in Intensive Care Medicine,Royal Marsden Hospital,Honorary Senior Lecturer,Imperial College London

Basic evidences for drug action through receptors (i) Many drugs exhibit structural specificity of action cholesterol levels japan generic atorlip-5 5mg on-line, i cholesterol weight order atorlip-5 5mg without a prescription. A 3 carbon internitrogen separation in the side chain of phenothiazines results in antidopaminergic-antipsychotic compounds cholesterol levels and stress cheap atorlip-5 5mg online, whereas 2 carbon separation produces anticholinergic-antihistaminic compounds cholesterol lowering foods cinnamon quality atorlip-5 5mg. Thus, the cell must have some mechanism to recognize a particular chemical configuration and three dimensional structure. Moreover, certain drugs are partial agonists which occupy and submaximally activate the receptor. It has also been demonstrated that many full agonists can produce maximal response even while occupying <1% of the available receptors. A large receptor reserve exists in their case, or a number of spare receptors are present. The two-state receptor model An attractive alternative model for explaining the action of agonists, antagonists, partial agonists and inverse agonists has been proposed. The receptor is believed to exist in two interchangeable states: Ra (active) and Ri (inactive) which are in equilibrium. In the case of majority of receptors, the Ri state is favoured at equilibrium-no/very weak signal is generated in the absence of the agonist-the receptor exhibits no constitutive activation (Fig. The agonist (A) binds preferentially to the Ra conformation and shifts the equilibrium Ra predominates and a response is generated (Fig. The competitive antagonist (B) binds to Ra and Ri with equal affinity the equilibrium is not altered no response is generated (Fig. If an agonist has only slightly greater affinity for Ra than for Ri, the equilibrium is only modestly shifted towards Ra (Fig. In their case the inverse agonist stabilizes the receptor in the inactive conformation resulting in an opposite response. This model provides an explanation for the phenomenon of positive cooperativity often seen with neurotransmitters, and is supported by studies of conformational mutants of the receptor with altered equilibrium. However, receptors are now known to be capable of adopting not just two, but multiple active and inactive conformations favoured by different ligands. Molecular cloning has also helped in obtaining the receptor protein in larger quantity to study its structure and properties, and in subclassifying receptors. The cell surface receptors with their coupling and effector proteins are considered to be floating in a sea of membrane lipids; the folding, orientation and topography of the system being determined by interactions between the lipophilic and hydrophilic domains of the peptide chains with solvent molecules (water on one side and lipids on the other). In such a delicately balanced system, it is not difficult to visualize that a small molecular ligand binding to one site in the receptor molecule could be capable of tripping the balance (by altering distribution of charges, etc. Each of the four major families of receptors (described later) have a well defined common structural motif, while the individual receptors differ in the details of amino acid sequencing, length of intra/ extracellular loops, etc. Majority of receptor molecules are made up of several non-identical subunits (heteropolymeric), and agonist binding has been shown to bring about changes in their quaternary structure or relative alignment of the subunits. Many drugs act upon physiological receptors which mediate responses to transmitters, hormones, autacoids and other endogenous signal molecules; examples are cholinergic, adrenergic, histaminergic, steroid, leukotriene, insulin and other such receptors. In addition, now some truly drug receptors have been described for which there are no known physiological ligands. Accordingly, they were said to be mediated by two types of cholinergic receptors, viz. Multiple subtypes of receptors for practically all transmitters, autacoids, hormones, etc. In many cases, receptor classification has provided sound explanation for differences observed in the actions of closely related drugs. Pharmacological criteria Classification is based on relative potencies of selective agonists and antagonists. This is the classical and oldest approach with direct clinical bearing; was used in delineating M and N cholinergic, and adrenergic, H1 and H2 histaminergic receptors, etc. Tissue distribution the relative organ/tissue distribution is the basis for designating the subtype. This division was confirmed by selective agonists and antagonists as well as by molecular cloning.

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Specifications for the physical characteristics and chemical composition required for food grade salt are laid down in the Codex Alimentarius (285) cholesterol nih generic atorlip-5 5 mg visa. Iodine is usually added to cholesterol lowering foods in india buy atorlip-5 5mg amex salt after the salt has been refined and dried cholesterol medication bad taste 5 mg atorlip-5 visa, by one of two main techniques how to remove cholesterol in eggs buy atorlip-5 5 mg without a prescription. This technique is more demanding, in that it requires a salt made of small homogenous crystals and the thorough mixing of the salt after addition of the iodine compound to ensure an even distribution of iodine. Technical information on the salt iodization process is available elsewhere (287). The stability of iodine in salt depends on the water content, acidity and purity of the salt to which it is added. In order to reduce iodine losses during storage, the iodized salt must be as pure and as dry as possible, and it must be appropriately packaged. Iodine tends to migrate from the top to the bottom of a container when the water content is too high. Losses also tend to occur when packaging with impervious linings is used; as the packaging becomes damp, the iodide migrates from the salt to the fabric, and then evaporates. This is less likely to happen with potassium iodate because the iodates are less soluble and more resistant to oxidation. Types of packaging that help to prevent iodine losses include high density polyethylene bags that are either laminated with low density polyethylene or lined with a continuous film that is resistant to puncture. Because salt iodization is cheap and easy to implement, great strides in salt iodization programmes have been made in a relatively short period of time (Table 5. During the 10-year period, 1989 to 1999, the proportion of households consuming iodized salt increased from 10% to 68% and by 1999, of 130 countries affected by iodine deficiency, 98 had in place legislation requiring the iodization of salt (284). The existence of pockets of populations living in remote areas that cannot easily access iodized salt is another factor which can hinder the effective implementation of salt iodization programmes and their sustainability in some countries. It has been used in a few European countries where bread is a staple food, such as Russia (290,291), and in Tasmania. Its major limitation, compared with salt, is that sources of drinking water are so numerous and ubiquitous that iodization would be difficult to control. Moreover, iodine has limited stability in water (no longer than 24 hours) such that continuous daily dosing of the water supply would be necessary. Although the use of water as a vehicle for iodine fortification is technically more difficult than the use of salt, there are certain conditions where water iodization could be a suitable method for the correction of iodine deficiency. The simplest way of fortifying water with iodine is to add a concentrated iodine solution (as potassium iodide or iodate) in a dropwise fashion until a specified concentration in the water contained in a given vessel is reached. Alternatively, in the case of hand pumps and open wells, iodine in porous polymer containers can be introduced into the water supply. The porous containers allow the slow release of potassium iodide solution into the water supply. However, such containers have a limited shelf-life and must be changed every year. Such practices have been successful in several parts of the world; in Africa, in the Central African Republic, Mali (293) and Sudan (294), in Asia, in the central Asian republics, Malaysia (295) and Thailand and in Europe, in Italy (Sicily). In most settings, the limiting factor, especially in terms of cost-effectiveness, is that the whole population and the livestock need to use the iodized water supply point to benefit from iodization (296). The direct addition of an iodine solution to freshwater supplies has also been attempted. The result was an improvement in urinary iodine of children, and a relatively stable increase in soil iodine.

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Quantiles are introduced here new cholesterol guidelines chart buy atorlip-5 5mg with visa, because they are based on the cumulative distribution function cholesterol weight loss order 5mg atorlip-5 free shipping. The quantile q p of a random variable (or equivalently of its distribution) is defined as the smallest number q such that the cumulative distribution function is greater than or equal to cholesterol test results explained australia atorlip-5 5 mg online some p cholesterol in eggs study generic atorlip-5 5 mg online, where 0 < p < 1. This can be calculated for a continuous random variable with density function f (x) by solving qp for qp, or by using the inverse of the cumulative distribution function, qp = F (p). In essence, these divide the distribution into four equal (in terms of probability or area under the curve) segments. The analyst should exercise caution when calculating quartiles (or other quantiles) using computer packages. Statistical software packages define them differently [Frigge, Hoaglin, and Iglewicz, 1989], so these statistics might vary depending on the formulas that are used. For instance, this is the case when we are constructing q-q plots (see Chapter 5), and the sample sizes differ. We can use interpolation to find estimates of quantiles that are not represented by Equation 3. The general syntax is yint = interp1(xobs, yobs, xint); In our case, the argument of F in Equation 3. It is important to remember that the parameters estimated for some of the distributions. We refer the reader to Appendix E for a complete list of the functions appropriate to this chapter. We also provide some functions for statistics with the Computational Statistics Toolbox. These topics are covered at an undergraduate level in most introductory statistics books for engineers or non-statisticians. For the advanced undergraduate and beginning graduate student, we recommend the text on mathematical statistics by Hogg and Craig [1978]. Another excellent introductory book on mathematical statistics that contains many applications and examples is written by Mood, Graybill and Boes [1974]. Other texts at this same level include Bain and Engelhardt [1992], Bickel and Doksum [2001], and Lindgren [1993]. For the reader interested in the theory of point estimation on a more advanced graduate level, the book by Lehmann and Casella [1998] and Lehmann [1994] are classics. Most of the texts already mentioned include descriptions of other methods (Bayes methods, minimax methods, Pitman estimators, etc. For an introduction to robust estimation methods, see the books by Wilcox [1997], Launer and Wilkinson [1979], Huber [1981], or Rousseeuw and Leroy [1987] or see the survey paper by Hogg [1974]. Generate 500 random samples from the standard normal distribution for sample sizes of n = 2, 15, and 45. For each n: % Generate 500 random samples of size n: x = randn(n, 500); % Get the mean of each sample: xbar = mean(x); % Do a histogram with superimposed normal density. What happens to the coefficient of skewness and kurtosis as the sample size gets large? Generate a random sample that is uniformly distributed over the interval (0, 1). There is also a function in the Statistics Toolbox called cdfplot that will do this. Generate a random sample of size 100 from a normal distribution with mean 10 and variance of 2 (use randn(1,100)*sqrt(2)+10). What is the value of the empirical cumulative distribution function evaluated at a point that is greater than the largest observation in your random sample? Another measure of skewness, called the quartile coefficient of skewness, for a sample is given by ^ ^ ^ q 0. Investigate the bias in the maximum likelihood estimate of the variance that is given in Equation 3. Repeat this process (generate a random sample from the standard normal distribution, estimate the variance, save the value) many times.

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The walls of the pharynx contain important lymphoid tissues such as adenoids and tonsils cholesterol ratio for life insurance generic 5 mg atorlip-5 otc. An adult typically requires about 1 g of phenylalanine (Phe cholesterol of 240 5mg atorlip-5 amex, L-phenylalanine) 510 phenylketonuria considered preliminary cholesterol test how often generic atorlip-5 5 mg with mastercard. In many cases the longterm effects and safe doses of phenylalanine ldl cholesterol foods avoid discount atorlip-5 5mg on-line, tyrosine, or other amino acids are not known. A synthetic form of phenylalanine, D-phenylalanine is the mirror image of the naturally occurring form of phenylalanine, L-phenylalanine. It is not used by the body for proteins or neurotransmitters, nor is it a nutrient. D-phenylalanine seems promising as a treatment of chronic pain, particularly back pain, and dental pain. Naturally occurring phenylalanine (Lphenylalanine) does not behave in this fashion. Phosphatidylserine supports the fluidity of these membranes, which increases their ability to transmit electrical impulses passed from one cell to another. It is believed that as a person ages, nerve cells lose fluidity and cannot conduct electrical impulses as effectively as they once did; this is one reason why many older people have impaired memory function and find it harder to think and reason. Excessive phenylalanine and phenylketones can cause severe mental retardation within one to two years after birth unless the diet is corrected to lower phenylalanine intake. Since phenylalanine cannot be manufactured in the body and is required for growth, the diet must supply enough to support growth while avoiding excess. The restrictive diet can often be relaxed as children mature, and they usually can go on to lead healthy lives as adults. The body can manufacture its own phospholipids, and phospholipids occur in all foods. Many nerve fibers, especially those outside the brain and spinal cord, are insulated with a white segmented covering called myelin. Phospholipids have the ability to emulsify fat and other water-insoluble materials. Phospholipids also have the ability to form double lipid layers, which are the foundation of all cell membranes. Because these fatty acids are bent molecules they do not pack together easily, and they contribute to membrane flexibility. They are withdrawn together from bone to maintain normal blood levels; vitamin D is required for both calcium and phosphate uptake. Calcium phosphate forms hydroxyapatite, the mineral deposit of bones and teeth, which represents 80 percent of the total phosphorus in the body. If blood phosphate levels rise, kidneys excrete phosphate; when dietary phosphate is low, they excrete less. These substances store genetic information and control protein synthesis, cell division and growth and maintenance of the body. Though meat is a good source of phosphorus, it is a poor source of calcium; cheese is rich in calcium but low in phosphorus. Juices, fruit, and vegetables such as lettuce, celery, and carrots provide negligible phosphorus. When the ratio of calcium to phosphorus is approximately equal, phosphorus uptake is adequate. Excessive levels of phosphorus can cause low blood calcium, with tetany and convulsions. In the second phase, or the dark reaction, carbon dioxide reacts with hydrogen atoms to form carbohydrate. Most materials produced by plants are indigestible; generally only 5 percent of a plant is suitable for human nutrition. About 2 percent of the energy in sunlight actually reaches the ground and 1 percent of this is transformed into plant products by photosynthesis. Photosynthesis relies on the trapping of energy by the green plant pigment chlorophyll.

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