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By G. Killian. Concordia College, Saint Paul Minnesota.

Definition It is this potential for malignant change that Peutz-Jeghers syndrome (PJS) is named after two increases cancer risk in people with PJS buy suhagra 100mg free shipping. It is an expected purchase suhagra 100 mg overnight delivery, the gastrointestinal tract is the most common association of three very specific conditions in any one site for cancer in people with PJS suhagra 100 mg. The first condition is the appearance of freckles stomach buy discount suhagra 100mg, gallbladder, pancreas, colon, and rectum are all on parts of the body where freckles are not normally susceptible. The third condition is a risk, likely to be involved are the breasts, ovaries, uterus, greater than the risk seen in the general population, of cervix, or testicles. The gene is named Biopsy—The surgical removal and microscopic STK11, and it is located at the 19p13 site on chromo- examination of living tissue for diagnostic pur- some 19. Colonoscopy—Procedure for viewing the large However, some cases do not appear to be connected intestine (colon) by inserting an illuminated tube to STK11. As a result, PJS qualifies as a genetically het- into the rectum and guiding it up the large intes- erogeneous condition; this means that it has more than tine. Research continues in order to Endoscopy—A slender, tubular optical instrument locate the genes involved in the three out of ten cases not used as a viewing system for examining an inner related to STK11. This means that the condition occurs even Enteroscopy—A procedure used to examine the when an individual inherits only one abnormal copy of small intestine. In some people with PJS, the Esophagus—The part of the digestive tract which condition is limited to freckles on the lining of the cheeks connects the mouth and stomach; the foodpipe. One normal copy is areas of the skin, which produces areas that are usually enough to protect against the kinds of cancer much darker than the surrounding unaffected skin. This is because STK11 is a tumor Laparoscopy—A diagnostic procedure in which a suppressor gene. A properly working tumor suppressor small incision is made in the abdomen and a slen- gene makes a product that controls cell growth. Since der, hollow, lighted instrument is passed through cancer is the result of uncontrolled cell growth, tumor it. Even one working copy of through the laparoscope, and if necessary, obtain STK11 protects against cancer. Macule—A flat, discolored spot or patch on the The reason people with PJS have an increased risk of skin. If damage to the normal STK11 gene Mammogram—A procedure in which both breasts occurs later, the ability to control cell growth is lost, lead- are compressed/flattened and exposed to low ing to the kinds of cancers associated with PJS. Polyp—A mass of tissue bulging out from the nor- However, it generally takes less time to damage one gene mal surface of a mucous membrane. Therefore, people with PJS are likely to develop cancer at earlier ages than are people born with Polypectomy—Surgical removal of polyps. Tumor suppressor gene—Genes involved in con- trolling normal cell growth and preventing cancer. About half of all PJS cases occur because a child inherits a changed gene from a parent with PJS. The other half are due to a mutation in the cell from which the child Demographics develops. A person born with one abnormal gene can pass that gene on to the next generation. GALE ENCYCLOPEDIA OF GENETIC DISORDERS 911 Signs and symptoms of developing cancer. The first sign of PJS, freckling inside the mouth or in unusual places, generally appears in infants. Polyps usu- The presence of the rare cervical cancer, ovarian ally begin causing symptoms by age 10. Polyps make tumor, or testicular tumor associated with PJS leads to themselves known in a variety of ways. Sometimes the A family history of PJS is suspicious but not blood loss leads to anemia (a condition where there is a required for diagnosis, since PJS can occur as a new reduction in circulating red blood cells, the amount of mutation.

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These switching from a MAOI to another antidepressant buy suhagra 100mg online, such changes result in both down-regulation of synaptic as a SSRI cheap suhagra 100 mg mastercard, a drug-free period of 2 weeks is required to transmission mediated through noradrenergic - and - allow for the regeneration of tissue MAO and elimina- adrenoceptors and up-regulation or enhancement of tion of the MAOI suhagra 100 mg sale. When switching from an antidepres- synaptic transmission at serotonin synapses (5HT1A- sant purchase suhagra 100mg line, such as an SSRI, to a MAOI, sufficient time should receptors). This action on serotonin neurotransmission be allowed for the SSRI to be cleared from the body (at is the result of desensitized somatodendritic autorecep- least 5 half-lives) before starting the MAOI. Coadministration of a Recently, attention has focused on the actions of Li MAOI and an SSRI or venlafaxine can overstimulate on receptor-mediated second-messenger signaling sys- the serotonin receptors in the brainstem and spinal cord tems of the brain. Serotonin Li and guanine nucleotide (GTP) binding proteins (G syndrome consists of a constellation of psychiatric, neu- proteins) have been the target of many studies, since G rological, and cardiovascular symptoms that may in- proteins play a pivotal role in the function of many sec- clude confusion, elevated or dysphoric mood, tremor, ond-messenger signaling systems. Lithium is capable of myoclonus, incoordination, hyperthermia, and cardio- altering G-protein function. The molecular mechanism involves the compe- tition for Mg sites on the G protein, which are essen- TREATMENT OF MANIC-DEPRESSIVE tial for GTP binding. This action of Li has been selectively demonstrated for Lithium G proteins associated with -adrenoceptors and M1 For more than 40 years, Li has been used to treat ma- muscarinic receptors of the CNS (Fig. While it is relatively inert in individuals without a While it is not possible at present to assign a thera- mood disorder, lithium carbonate is effective in 60 to peutic role to this action of Li, it is a step toward ex- 80% of all acute manic episodes within 5 to 21 days of plaining the stabilizing actions of this drug. Because of its delayed onset of ac- eral neurotransmitter receptors share common G tion in the manic patient, Li is often used in conjunc- protein–regulated second-messenger signaling systems, tion with low doses of high-potency anxiolytics (e. It is presently unclear to what extent often maintained on low stabilizing doses of Li indefi- inhibition of inositol phosphate metabolism contributes nitely as a prophylaxis to future mood disturbances. Antidepressant medications are required in addition to Li for the treatment of breakthrough depression. Pharmacokinetics and Therapeutic Drug Mechanism of Action Monitoring Lithium is a monovalent cation that can replace Na in Lithium is readily absorbed from the gastrointestinal some biological processes. In this regard, the failure the blood-brain barrier is limited, so that cerebrospinal of Li to maintain a normal membrane potential be- fluid levels are 50% of plasma levels at steady state. However, this action of Li would not hours, and more than 90% of the dose of Li is excreted explain its relatively selective effects on the CNS, spar- into the urine. Thus, ity would be so general that the entire pool of brain competition between Li and Na for uptake sites can neurons would be affected by Li. It seems more rea- alter the elimination of Li and its concentration in to- sonable that Li produces its psychotropic actions by tal body water. Na loading enhances Li clearance, perturbation of molecular events common to a few CNS while Na depletion promotes Li retention. This im- synapses that might have been disturbed during the portant relationship explains the appearance of Li tox- course of the manic-depressive illness. Lithium can simultaneously alter the flow of synaptic information through several receptor- mediated systems by diminishing coupling between the receptor recognition site and its specific G proteins. This model explains the stabilizing actions of Li at both ends of the mood spectrum through a single action at the G-protein level. Attenuating actions of Li have been demonstrated through G-protein interactions at the -adrenoceptor and the acetylcholine M1 muscarinic receptor systems of the CNS. A second action of Li as an inhibitor of inositol diphosphate (IP ) 2 phosphatase may further attenuate the flow of synaptic information through the M1 muscarinic receptor by the eventual depletion of membrane phosphatidyl inositol-bis-phosphate (PIP2). IP3, inositol triphosphate; DAG, diacylglycerol; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; 5 -AMP,5-adenosine monophosphate; NE, norepinephrine; ACh, acetylcholine. Since Li has a low therapeutic index (approxi- physical activities (those that induce sweating) that de- mately 3) and a narrow therapeutic window (0. Mild toxicity is usually expressed ful serum Li concentrations are usually determined 12 as nausea, vomiting, abdominal pain, diarrhea, polyuria, hours after the last dose. If the serum concentration of accurate reflection of the Li concentration, since it is Li progressively rises above 2 mEq/L, frank neurolog- beyond the most variable portion (rapid elimination ical toxicity appears, beginning with mental confusion phase) of the Li elimination profile. Adverse Effects Adverse effects sometimes seen during chronic The frequency and severity of adverse reactions associ- maintenance of bipolar patients with Li include hy- ated with Li therapy are directly related to serum lev- pothyroidism (approximately 5%) and nephrogenic dia- 33 Drugs Used in Mood Disorders 395 betes insipidus. Routine laboratory monitoring proved by the FDA for treatment of acute mania and includes TSH (thyroid-stimulating hormone) and serum is now considered a first-line agent. Other anticonvul- creatinine measurements to detect hypothyroidism and sants under investigation include lamotrigine and top- any change in renal capacity to clear the drug.

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The oral compartments that ac- The rate of clearance of chlorhexidine from the mouth cumulate a drug must reversibly bind large portions of after one mouth rinse with 10 mL of a 0 generic 100 mg suhagra with amex. The clear- nounced substantivity cheap 100mg suhagra with amex, along with the relative suscepti- ance of an agent from the oral cavity is directly propor- bility of oral streptococci buy suhagra 100 mg on line, may account for the great ef- tional to the rate of salivary flow cheap 100 mg suhagra free shipping. Hence, during periods fectiveness of chlorhexidine in inhibiting supragingival of high salivary flow, a greater release of drug from oral plaque formation. Ingestion (swallow) or Expectoration clearance Metabolism Tissue Reservoirs Free Drug (epithelium, microorganisms, (tooth, oral mucosa, (in saliva) salivary enzymes) tongue, etc. Desquamative soft tissue lesions have also been reported with use of drug concentrations Although chlorhexidine affects virtually all bacteria, exceeding 0. A fre- gram-positive bacteria are more susceptible than are quently observed side effect is impaired taste sensation. Such findings corroborate ear- Bacteriostasis is the result of chlorhexidine binding to lier studies showing delayed wound healing in stan- the negatively charged bacterial cell wall (e. Oral streptococci take up sugars via As an oral rinsing agent, to date chlorhexidine has the phosphoenolpyruvate-mediated phosphotrans- not been reported to produce any toxic systemic effects. The PEP-PTS is a carrier-me- Since chlorhexidine is poorly absorbed in the oral cav- diated group translocating process in which a number of ity and gastrointestinal tract, little if any enters the soluble and membrane-bound enzymes catalyze the bloodstream. A summary of chlorhexidine oral rinses is transfer of the phosphoryl moiety of PEP to the sugar given in Table 42. High chlor- Nonionic Bisphenols hexidine concentrations cause intracellular protein pre- Triclosan is a broad-spectrum antimicrobial compound. Despite its pronounced effect It was originally used in soaps, antiperspirants, and cos- on plaque formation, no detectable changes in resist- metic toiletries as a germicide. Today, triclosan is incor- ance of plaque bacteria were found in a 6-month longi- porated into toothpaste because of its wide spectrum of tudinal study of mouth rinses. Clinical Uses Pharmacokinetics The previous routine treatment for cases of severe gin- Triclosan is retained in dental plaque for at least 8 gival disease consisted of calculus and plaque removal hours, which in addition to its broad antibacterial prop- and oral hygiene instructions. Subsequent resolution of erty could make it suitable for use as an antiplaque the gingival inflammation was largely dependent on agent in oral care preparations. With the combination of PVM/MA copolymer and triclosan, the Adverse Effects and Toxicity substantivity of the triclosan was increased to 12 hours in the oral cavity. The most conspicuous side effect of chlorhexidine is the development of a yellow to brownish extrinsic stain on Mechanism of Action the teeth and soft tissues of some patients. The discol- oration on tooth surfaces is extremely tenacious, and a Triclosan is active against a broad range of oral gram- professional tooth cleaning using abrasives is necessary positive and gram-negative bacteria. The staining is dose dependent, of its antibacterial activity is the bacterial cell mem- and variation in severity is pronounced between indi- brane. Effects at lower 42 Drugs for the Control of Supragingival Plaque 503 504 V THERAPEUTIC ASPECTS OF INFLAMMATORY AND SELECTED OTHER CLINICAL DISORDERS concentration are more subtle. In contrast to the efficacy of fluorides in preventing car- Clinical Effects ious lesions, these formulations have relatively poor an- tibacterial properties (Table 42. Finally, of considerable interest terfere with bacterial membrane function, bacterial is the observation that triclosan inhibits gingivitis by a adhesion, and glucose uptake, thereby inhibiting the mechanism independent of its antiplaque activity. The ADA Council on this surprising effect stems from research conducted us- Dental Therapeutics endorses fluorides for their caries- ing a gingival fibroblast cell culture model. Prebrushing Rinses Essential Oils The topical application of a liquid rinse before brushing A mixture of essential oils consisting of thymol 0. Prebrushing rinses usually Essential oils may reduce plaque levels by inhibiting contain a plethora of ingredients, and it is not known bacterial enzymes and by reducing pathogenicity of which constituent is the active chemical. It has been sug- plaque via reduction of the amount of endotoxin; the al- gested that sodium lauryl sulfate acts as a detergent to cohol is probably responsible for denaturing bacterial dislodge or loosen the plaque on teeth (Table 42. The substantivity of Listerine appears to be When prebrushing rinses were tested against placebo quite low, and therefore, it must be used at least twice a rinses, prebrushing rinses appeared to have no effect on day to be effective. Adverse reac- Today gingivitis and periodontitis are prevented princi- tions include a bitter taste and burning sensation in the pally through mechanical plaque control; however, den- oral cavity. Regular use of high-alcohol rinses can ag- tition free of supragingival and subgingival plaque is ex- gravate existing oral lesions and desiccate mucous tremely difficult to accomplish and maintain.

The causes of OWR are complex; create detailed images of internal body structures various alterations in multiple genes purchase 100mg suhagra free shipping, or various alter- and organs buy discount suhagra 100 mg line, including the brain suhagra 100mg without a prescription. Stroke—A sudden neurological condition related to a block of blood flow in part of the brain order suhagra 100mg, which OWR is inherited in an autosomal dominant manner. As of 2000, nearly all affected peo- Telangiectasis—Very small arteriovenous malfor- ple have a family history of OWR, which is typically a mations, or connections between the arteries and parent with the condition. Demographics As of 2000, OWR affects about one in 10,000 peo- nose are very sensitive and fragile, and AVMs in this area ple. It spans the globe, but a higher prevalence exists in can easily and spontaneously bleed. Consistent nose- the Danish island of Fyn, the Dutch Antilles, and parts of bleeds may begin by about twelve years of age, and are France. Occasionally, severe nosebleeds can Signs and symptoms cause mild to severe anemia, sometimes requiring a The symptoms in OWR result from several AVMs, blood transfusion or iron replacement therapy. Ultimately, AVMs may lead to mild or severe on the nose, lips, tongue, mouth, and fingers. They telangiectases are fragile, sudden bleeding may occur occur because the layers of mucous membranes in the from only slight trauma, and bleeding may not sponta- GALE ENCYCLOPEDIA OF GENETIC DISORDERS 851 neously stop. Thirty percent of people with OWR report more findings are present, possible/suspected when two telangiectases first appearing before age 20, and 67% findings are present, and unlikely when fewer than two before age 40. For example, severe with age, but usually does not appear until age isolated nosebleeds are very common in the general pop- forty. Because Pulmonary AVMs (AVMs of the lung) may cause nosebleeds are often the first sign in OWR, they may ini- bleeding within the lungs. As of 1998, this occurs in tially be ignored, until they become so frequent that they about 20% of people with OWR. Isolated internal bleed- because the abnormal connections between arteries and ing, or aneurysms, are quite common in the brain and GI veins bypass the natural filtering system within the lung, tract. However, not all aneurysms are caused by AVMs allowing bacteria to enter the system. Low levels of oxy- and this needs to be determined, as AVMs are more spe- gen and infection may result, causing migraine-like cific to OWR. Occasionally, AVMs may occur in the tases may also naturally occur in pregnancy or chronic spine, liver, and brain. A hereditary form of telangiectases exists, can cause blood to be forced away from the normal cir- and in this they are usually found on the face, upper culation, increasing the risk of heart failure because the limbs, and upper trunk of the body. The University of Utah offers linkage analysis to determine alterations in either Treatment and management ENG or ALK1, and results are not guaranteed. Linkage analysis is a method of genetic testing that requires sev- Treatment for OWR is based on the specific symp- eral family members, both affected and unaffected, to toms an individual experiences. The testing treatment, a review of medical history regarding nose- attempts to study family markers on the various chro- bleeds and other bleeding episodes should be noted. Results are abnormal if an alteration Stool samples may be analyzed to determine whether near ENG or ALK1 is found. If a familial alteration is there is any blood present that is not obvious to the naked identified, unaffected individuals could be offered testing eye; this may indicate anemia. If an (CBC) can also determine whether anemia is a factor, individual had the alteration, he or she would be at risk due to blood loss. Currently, no prenatal testing is blood sample, and determining whether the amount of available for OWR. It can help to determine whether the lungs and heart are func- Because testing is neither widely available nor use- tioning properly, because their roles are to help oxy- ful for diagnostic purposes, most people with OWR are genate blood. Careful imaging of the heart by identified by careful physical examination and study of echocardiogram or chest x rays can assess whether the their medical and family histories. Chest x rays may identify an OWR diagnosis include nosebleeds (especially at pulmonary AVMs. Magnetic resonance imaging (MRI) night), multiple telangiectases (especially on the lips, of the head can visualize the brain to rule out any bleed- mouth, fingers, and nose), and AVMs of various organs ing.

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