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During ventricular repolarization one would expect the vector to be exactly opposite to that during ventricular depolarization discount solian 50 mg on-line medicine hat mall, i generic solian 100 mg with amex medicine qid. However purchase 50 mg solian visa xerostomia medications side effects, the timing of repolarization is such that it proceeds from the outside to the inside: thus order 100mg solian mastercard symptoms uric acid, the last part depolarized is the first to be repolarized. This restores the vector to be downward and thus in the same general direction as the R wave, i. The “normal” T vector loop is shown in Figure 10, although variations on this pattern are relatively common. Relative to this central terminal, the exploring electrode can be positioned on any particular site of the body. These unipolar leads (V leads) give rather small signals when the potential is thus recorded on either of the three corners of the triangle and referred to the Wilson central terminal. Later, Goldberger showed that the shape of these recordings is not substantially altered by interrupting the connection between the central terminal and the site to be studied. The resulting leads augment the amplitude of the recording by 50% and are therefore called the augmented unipolar limb leads. Vectocardiography considers the frontal, the sagittal and the transverse plane together. Six additional unipolar electrocardiographic leads -- the precordial leads -- provide information in the transverse plane. They use as reference the central terminal of Wilson and place the exploring electrode at six sites across the precordium. These precordial leads are called V1, V2, V3, V4, V5 and V6 as shown in Figure 11. By virtue of bringing the exploring electrode much closer to the heart the typical signals recorded from V1, V2, V3, V4, V5 and V6 cannot be correctly interpreted as projections of vectors on leads which are remote as compared to the size of the dipole. On the other hand, precordial leads provide more direct information about specific sites within the ventricle. Finally, it is important to keep in mind that there are simplifications inherent in this explanation of the electrocardiogram and its vectorial interpretation: 1. The importance of the electrocardiogram ultimately rests on its diagnostic value as an empirical tool to detect alterations in cardiac rhythm, in conduction pathways, in serum electrolytes and myocardial oxygenation. Blood vessels can be involved by all major categories of pathology, such as Congenital, Infective, Autoimmune, Neoplastic, Traumatic, Metabolic, and Toxic mechanisms. This lecture will present only a brief introduction to the broad range of vascular diseases, with a more thorough discussion of atherosclerosis. Noninfective: These are immune-mediated but they typically involve different types of patients, tissues and vessel sizes. The pathogenesis is poorly understood in most of these, and they will be discussed individually later in the course. Classification based on vessel size (with some typical features of presentation): 1. Small vessel: serum sickness, H-S purpura, cryoglobulinemia, drug-induced angiitis a. The stiffening is caused by hyperplasia of cells, increased extracellular matrix, deposition of proteins, or mineralization. In many forms of arteriosclerosis, the stiffening is due to a wound healing response to chronic Injury to the blood vessel wall. Often the stiffening is associated with stenosis of the vessel lumen, but aneurysm can also occur. Atherosclerosis: A type of arteriosclerosis involving larger arteries with lipid deposition and inflammation. Arteriosclerosis of vascular interventions: Intimal or medial thickening in response to angioplasty, stents, anastomosis, or autologous grafts. Graft arteriosclerosis: Due to immunologic injury to arteries in non-autologous organ transplants. Arteriolosclerosis: Sclerosis of small arteries and arterioles, usually due to hypertension or diabetes. Hyaline arteriolosclerosis due to deposition of plasma proteins and extracellular matrix in the wall (in elderly and hypertensives) b. Hyperplastic arteriolosclerosis (onion-skinning) due to smooth muscle hyperplasia ( in severe hypertension. It is a chronic disease that has a complicated multifactorial etiology with a variable presentation. Hyperlipidemia, inflammation, and thrombosis are key mechanisms in vascular injury and repair, which underlie atherosclerosis. There have been many efforts to establish other causative agents, including elevations of homocysteine, but the most important factors in atherosclerosis continue to be the “classic” ones: serum lipid levels, hypertension, diabetes, smoking, family history, age, and male sex. Vulnerable to injury from common agents like smoking, abnormal serum lipids, homocysteine levels, etc. Progression of Atherosclerotic lesions: Lesions Of Blood Vessels - Andrew Connolly, M. Thrombosis is a regular feature of ulcerated plaques, and organization of mural thrombi may contribute to bursts of plaque thickening. Sudden ischemic events are due to thrombosis at sites of atherosclerotic plaque degeneration (Plaque rupture or erosion). Removal of risk factors can slow progression, and convert vulnerable plaques to stable plaques. Fixed Stenosis: critical narrowing with malfunction or atrophy of supplied tissues. If tissue demand for oxygen goes up and supply of oxygen cannot, this can lead to ischemia or infarction (e. Plaque rupture: atherosclerotic plaque ruptures causing immediate thrombosis due to blood mixing with thrombogenic atheromatous debris. Dissection: blood enters intimal defect under pressure and splits tissue planes, often in the media. Statins improve lipoprotein profile and possibly decrease inflammation in atheromas. Surgical management is recommended for larger diameter ones, which are at risk for catastrophic rupture. Stanford (Types A & B): Stanford A originates within or proximal to the aortic arch and usually requires surgery; Stanford B originates after the arch and can usually be managed medically. Intimal tear usually connects with a dissection plane along outer 2/3 of medial layer. Complications include hemorrhage, rupture, compression of nearby viscera, and branch occlusion, leading to the associated signs and symptoms. Rupture: Note: A “false aneurysm” is really a contained perivascular hematoma that communicates with the lumen and mimics an aneurysm. Aortic Dissections Stanford Types A and B: Thromboembolic Disease - Andrew Connolly, M. Some of the consequences of these diseases are due to local changes around the blood vessel, such as edema and hemorrhage, while other consequences are due to changes in tissue perfusion. The most common cause of severe morbidity and mortality in our society is inadequate tissue perfusion due to arterial lesions, causing heart attacks, strokes, pulmonary emboli, renal failure and blindness.
Diseases
- Cardiomyopathy diabetes deafness
- Carotenemia
- Oral-facial-digital syndrome, type IV
- Androgen insensitivity syndrome (AIS)
- Familial deafness
- Karsch Neugebauer syndrome
The ear infections were probably caused by bacteria and viruses brought in by the parasites order solian 50mg fast delivery symptoms 4 days after conception. They all cheap solian 100 mg with mastercard medications quinapril, including herself buy cheap solian 50 mg on line medicine kim leoni, had stomach problems cheap 50mg solian visa treatment hiatal hernia, a lot of allergies, asthma, ear infections, and milk intolerance. His sister, Nola, had itching legs and headaches besides; she was toxic with bismuth and antimony (from shampoo fragrance and laundry fragrance). We found she had the three large flukes plus Chilomastix, dog whip worm, and amoebas in her intestine (but not in body organs). Her stomach and intestines were much too sensitive to accept parasite herbs, or in fact, anything— anything except slippery elm powder. Her blood test showed high phosphate levels since she was dissolving her bones to get cal- cium. By the 12th day of the parasite program she no longer needed colitis medicine; her bowel movements were down to twice a day, soft and formed, but still with a little blood streaking. She was able to eat fruits and vegetables but agreed to stay off wheat and corn until her liver was cleansed. In another week she was free from all abdominal complaints except a heaviness over the uterus, possibly due to two missed periods. She was sure she wanted her period, not a pregnancy and this seemed to be her God-given right. Three weeks later she had a flare up of colitis due to Salmonella in food; it also gave her a urinary tract infection. This time she took Quassia herb to kill invaders in addition to the maintenance parasite program which she had begun to neglect. She treated her urinary tract infection with betaine-hydrochloride (to acidify the stomach), began using plastic utensils to reduce her nickel intake (see Prostate Pain, page 124)) and drank a lot of water. This experience taught her valuable lessons that she was eager to learn, benefiting her family and herself immensely. Her parasites were only intestinal flukes and their stages, and Endolimax, an amoeba. It was a simple task for her to clear her problems by killing them and by sterilizing her dairy foods. He had intestinal flukes and all their reproductive stages in his body, also pancreatic flukes, Capillaria roundworm, and Diphyllobothrium erinacea scolex. He was started on half-doses of kidney herbs and only part of the parasite program in view of his colostomy and possible diarrhea. Two weeks later we continued testing, finding pinworms, Haemonchus, Leishmania tropica, Paragonimus, Sarcocystis, Stephanuris and Trichuris (whip worm. His blood test showed a high thyroid hormone level (T4), contributory to over activity of his bowel He was started on goat milk, vitamin C (3 gm. The thymus is under the top of the breastbone and is a very important organ of immune function. He was given a list of benzene-polluted products to avoid and was started on the parasite killing herbs after killing the flukes instantly with the frequency generator. Two weeks later his side was very much better, his benzene was gone and he was eager to rid himself of lower back pain, which he also had. This ended his problems and began a new chapter of better care for his health by his parents. Tim Melton, age 16, had several colitis attacks yearly, requiring hos- pitalization, from third grade to the present. He had been an iced tea drinker and had numer- ous oxalate and cysteine crystals deposited. The first step is to simply kill enteric (bowel) free-loaders and get into good bowel habits. In fact, very many parasites temporarily invade the bladder because the body is trying to excrete many of them. Pets should not be kept indoors since they have many of these para- sites, too, and they are easily transmitted to us. Schistosomes are the real perpetrators but after the bladder wall is weakened, other parasites and their bacteria and viruses ac- cumulate here too. Dental metal, environmental toxins, including radon, asbestos, formaldehyde, must be cleaned up. They get worse and worse until pain killers are necessary just to get out of bed and move about the house. Did they migrate to the uterus from the intestine or did they develop there from eggs? Once an avenue to the uterus is established, numerous other parasites move in the same direction: Clonorchis, the human liver fluke and even Eurytrema, the pancreatic fluke, can invade the uterus wall. This disarms your organs so they are left helpless against fluke stages left there by the blood and lymph. There are solvents in grocery store bread, grocery baked goods and cholesterol-reduced foods. Use no powdered mixture intended for weight loss or weight gain, nor vitality supports, nor dietary supple- ments. Some solvents (I often see methyl ethyl ketone and methyl butyl ketone) choose the uterus to ac- cumulate in. Gardnerella, especially, is found in cases of endometriosis, ovarian cysts and menstrual problems. The flukes evidently travel from the uterus to other parts of your body cavity, distributing bits of the uterine lining as they go. Once this distribution has occurred, can the bleeding (regular menstrual bleeding) at these extra sites ever be stopped? Zap to kill the four common flukes, Gardnerella, all other common parasites, and urinary tract bacteria (common ones include Proteus, Salmonella, Campylobacter, Chlamydia, Trichomonas). To heal the uterus so it no longer attracts parasites, clear up its internal pollution besides solvents. This means mainly the dental metal that has piled up and environmental toxins such as asbestos, arsenic, fiberglass, and formaldehyde. The advice given by obstetricians to get pregnant to solve your pain problem is most unwise. Be careful not to get pregnant while you are killing parasites and getting mercury removed from your teeth. Joanne Biro, age 22, had severe cramping pain with her periods, di- agnosed as endometriosis. She had a xylene (solvent) buildup in both her brain (cerebrum and cerebellum) and uterus. Denise Leyva, 22, was on birth control pills to control the growth of endometrial tissue. She had hexanedione and methyl butyl ketone buildup in her uterus sup- porting the intestinal fluke and its eggs in the uterus. She was advised to stop eating cold cereals and commercial bev- erages and kill the parasites immediately. In spite of repeatedly killing the flukes and bacteria with a frequency generator and making herculean efforts she was no better off eight months later.
Combinatorial chemistry affords techniques for the systematic creation of large but structurally diverse libraries purchase 100mg solian mastercard medications vs medicine. From a technical perspec- tive proven solian 50 mg symptoms vitamin d deficiency, there are several avenues of approach to library creation: 1 order 50mg solian overnight delivery treatment goals and objectives. Pharmacological activity privileged structures Benzodiazepines Dihydropyridines Hydantoins c proven solian 100mg treatment for strep throat. Novel template structures Dihydrobenzopyrans Historically, the first major libraries were oligomers of naturally occurring monomers. If atypical amino acids and amino acids in the unnatural D configuration are included, it is possible to achieve 125,000 different compounds with relative ease. Peptide libraries are easy to synthesize and, since amino acid side chains possess a wide variety of different func- tional groups, it is possible to achieve a good measure of structural diversity. However, in general, peptides are not drugs and a peptide lead would have to be modified into a drug-like molecule. In addition to oligopeptides, other naturally occurring oligomeric libraries are possible, including oligonucleotide libraries. A step beyond the naturally occurring oligomeric libraries is to create libraries from non-naturally occurring monomeric building blocks. The medicinal chemistry literature contains a fair number of examples of such libraries, including oligocarbamates and oligoureas. Although these libraries overcome the limitations of naturally occurring oligomeric libraries, most drugs are not polymers. To address this problem, new libraries emerged in which the central moiety was a small organic molecule. The diversity library was then constructed by attaching many different substituents to this central moiety. For example, dioxapiperazines are cyclic dipeptides and thus are relatively trivial to prepare. Other monomers were selected because they had a good track record for being drug-like molecules. In preparing these various libraries, extensive use is made of solid phase synthetic methods. When performing a large number of synthe- ses, it is preferable to perform the synthetic steps on a solid bead rather than complet- ing the entire synthesis in the solution phase. The solid-phase technique makes byproduct removal and final compound purification easier. The organic chemistry literature con- tains a wealth of different types of solid-phase supports and novel linkers for attaching the synthetic substrate to the bead. If a 200,000 compound library is available, the biological evaluation assay must be rapid and reliable. If the assay were capable of test- ing five compounds per day, it would take 110 years to evaluate the entire library. The ability to inhibit an enzyme is a good example of a potentially useful assay for high throughput screening. A variety of high throughput assays have been developed and perfected over the past 10–20 years. Microplate activity assays (assay is in solution in a well; the result of the assay, such as enzyme inhibition, is linked to some observable, such as color change, to enable identification of bioactivity) 2. Affinity selection assays (compound library is applied to a protein target receptor; all compounds that do not bind are removed; compounds that do bind are then identified) Of these, microplate assays are probably the most widely used. Screening combinator- ial libraries in 96- or even 384-well microplates is time and cost efficient. Using modern robotic techniques, it is possible to perform more than 100,000 bioassays per week in a microplate system (permitting the above-described 200,000 compound library to be screened in two weeks, rather than over a century). In addition to selecting an appropriate assay, it is also necessary to have a pooling strategy. It is more efficient to test many compounds per well on the microplate, rather than one. If one could test 100 compounds per well, then the standard 96-well plate would enable almost 10,000 compounds to be evaluated in one experiment. The synthetic strategy employed during the combinatorial syntheses can be used to assist in determining these pooling strategies. In random incorporation syntheses,a single bead could contain millions of different molecular species. In mix and split syn- theses (also called pool and divide syntheses or one bead–one compound syntheses) only one compound is attached to any given solid-phase synthetic bead. The evolution of methods for combinatorial syntheses and high throughput screening will be necessary to address the explosion of druggable targets soon to be identified by the genomics and proteomics revolutions. Current drug design strategies are struggling with fewer than 500 druggable receptor proteins. Endeavoring to identify lead compounds for an additional 3500 targets will overwhelm present-day drug design technologies. Genomics and pro- teomics represent a possible pathway to enhanced future drug discovery. On June 26, 2000–the dawning of the present century–a historic milestone in genomic science was attained when researchers involved with the Human Genome Project jointly announced that they had sequenced 97–99% of the human genome–the all-encompassing collection of human genes. The human genome consists of 23 pairs of chromosomes with three billion base pair codes for approximately 24,000–30,000 functional genes (original estimates of 100,000–120,000 genes seem to have been incorrectly high). Despite the size of this flood, its flow has not filled the drug discovery pipeline with winning candidates. Determining gene structure and function through genomics definitely does illuminate the path for deciphering human biochemistry and for linking specific genes to specific diseases. Although genomics did deliver phenomenal masses of raw information, the genomics technologies have so far failed to deliver the more than 10,000 anticipated druggable targets predicted by the early hyperbole of the genomics era. Taking genomics one step further for the pur- pose of drug discovery will require linking specific proteins to those specific genes. Bridging this gap will ultimately be a daunting task that lies within the domain of proteomics. More concretely, proteomics is the molecular biology discipline that seeks to elucidate the structure and function profiles of all proteins encoded within a specific genome; this collection of proteins is termed the proteome. The proteomes of multicellular organisms present an immense challenge in that more than 75% of the predicted proteins have no apparent cellular function. Furthermore, although the human proteome has more than 100,000 proteins, only a fraction of these proteins are expressed in any individual cell type. If specific dis- eases are to be linked to specific proteins, it is imperative that ways be developed to deduce which individual protein is expressed in which individual cell. For example, drug design requires much more than merely knowing the primary amino acid sequence of a protein; it requires a precise knowledge of the protein’s three-dimensional structure, down to the level of the ångström. To date, science has no technology that enables one to use the information coded in a protein’s primary amino acid sequence to deduce the overall tertiary struc- ture of the protein. This is the multiple minima problem (also called the protein folding problem) referred to in chapter 1. The need to solve this problem has given rise to the subdiscipline of structural proteomics, a technology that is based upon the principle that structure underlies function and that endeavors to provide three-dimensional struc- tural information for all proteins.
