Bertram G. Katzung MD, PhD
http://cmp.ucsf.edu/faculty/bertram-katzung
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Androgen production in men declines with age hypertension kidshealth order lasix 40 mg amex, resulting in loss of muscle mass, increased adiposity and other problems. However, testosterone replacement therapy for age-related decline in muscular strength, sexual performance and other parameters remains controversial. Although prostate cancer in men is often hormonally sensitive, there are few studies reporting the incidence of prostate or other cancers in men receiving androgen replacement treatments. Benefits of Oral Contraceptives In considering the potential side effects of the use of oral contraceptive agents, it is important to recognize that certain benefits accrue. In addition to a significant reduction in the risk of ovarian and endometrial cancers, the use of these agents decreases the risk of pelvic inflammatory disease, uterine leiomyomas, endometriosis and fibrocystic disease of the breast. There is evidence of the effectiveness of these preparations in decreasing the incidence of bone fractures and mitigating many of the problems relating to hormone deficits. However, there are significant risks associated with hormonal replacement following menopause. With the cessation of treatment, the risk of deep vein thrombosis and embolism declines to that in women who never received hormone replacement. There appears to be little overall benefit of either type of preparation in protecting from cardiovascular or cerebrovascular deaths. In the 12th century Maimonides wrote: Comparing the air of cities to the air of deserts is like comparing waters that are befouled and turbid to waters that are fine and pure. In the city, because of the height of its buildings, the narrowness of its streets and all that pours forth from its inhabitants, the air becomes stagnant, turbid, thick, misty and foggy. Humans are surrounded by, breathe in and consume many chemicals that are added to , or appear as contaminants in, foods, water and air. Absorption (whether via pulmonary, gastrointestinal or cutaneous routes) depends largely on the chemical in question. Thus, the insecticides chlordane and heptachlor are lipid soluble and so rapidly absorbed and stored in body fat. The storage, distribution and excretion of chemicals control their concentrations in the organism at any given time. Agents stored in adipose tissue may exert prolonged lowlevel effects, while more water-soluble materials that are easily excreted by the kidney usually have a shorter duration of action. Among the most important chemical hazards to which humans are exposed are environmental dusts and carcinogens. Inhalation of mineral and organic dusts occurs primarily in occupational settings. Inhaling mineral dusts leads to pulmonary diseases known as pneumoconioses, while organic dusts may produce hypersensitivity pneumonitis. In any consideration of this topic, one must differentiate between acute poisoning and chronic toxicity.
Biotin (B7) Most biotin is found in meats and cereals prehypertension stage 1 stage 2 lasix 100 mg visa, where it is largely bound to protein. Biotin is an obligatory cofactor for five carboxylases that participate in intermediary metabolism, including the Krebs cycle. The distinction between deficiencies of these two B vitamins was elucidated by Herbert, who, in 1962, developed megaloblastic anemia following a self-imposed experimental diet lacking only folate. Folate is present in almost all foods, including meat, dairy products, seafood, cereals and vegetables. Deficiency is thus usually a consequence of a generally poor diet, as is seen in some alcoholics, rather than a diet deficient in any single constituent. Because the settings in which folate deficiency occurs affect many nutrients, isolated folate deficiency is rare. Folate supplements given during early pregnancy have been shown to decrease the incidence of fetal neural tube defects. This effect is not clearly related to a folate deficiency and may be a pharmacologic benefit. Because neural tube formation occurs before many women know they are pregnant, fortification of cereal and grain products with folic acid has been mandated in the United States since 1998. Cyanocobalamin (B12) Deficiency of vitamin B12 is almost always seen in cases of pernicious anemia and results from the lack of secretion of intrinsic factor in the stomach (see Chapter 19), which prevents absorption of the vitamin in the ileum. Parasitization of the small intestine by the fish tapeworm Diphyllobothrium latum (from undercooked fish) may lead to vitamin B12 deficiency because the parasite absorbs the vitamin in the gut lumen. Folic Acid (B9) Folic acid is a heterocyclic derivative of glutamic acid and serves as a methyl group donor, especially in nucleotide synthesis. Folate, together with vitamin B12 (see below), is a key cofactor in methylation reactions. Folate also is critical in the generation of purine nucleotides and the conversion of uracil to thymidine. The latter reaction is important for understanding the consequences of folate deficiency in causing megaloblastic anemia. In addition, pernicious anemia is complicated by a neurologic condition called subacute combined degeneration of the spinal cord. Comprehensive discussions of vitamin B12 deficiency are found in Chapters 26 and 32. Choline Choline is an amine that is found in many foods, especially wheat products, peanuts, soybeans, fish and meat. It is incorporated principally into membrane phospholipids and is the major dietary source of methyl groups. Choline is necessary for lipid signaling, transport and metabolism, and for cholinergic neurotransmission.
Syndromes
It is characterized by cutaneous and (less commonly) visceral nodules blood pressure medication lip purchase 40 mg lasix mastercard, in which endothelium-lined channels and vascular spaces are admixed with spindle-shaped cells (see Chapter 24). Congenital and acquired immunodeficiency states are associated with B-cell hyperplasia, usually manifested as generalized lymphadenopathy. This lymphoproliferative syndrome may be followed by the appearance of high-grade B-cell lymphomas. Lymphomas in chronically immunodeficient patients may manifest as invasive polyclonal B-cell proliferations or monoclonal B-cell lymphomas. B-cell hyperplasia and generalized lymphadenopathy precede malignant lymphoproliferative disease. Many approaches have been tried, from killed whole virus, to isolated viral proteins, to gene delivery of viral proteins using various vectors. As a consequence, systemic levels of inflammatory responses, tissue factor triggering of clotting and T-cell compartment exhaustion all contribute to tissue injury. The presence of unresolved infections (see below) then magnifies these populations, leading to exaggerated immune responses. A defect in immunoregulatory Treg cells has been postulated, as the ensuing clinical course reflects exaggerated activation of preexisting memory cells and their conversion into effector cells. The most common of these is Graves disease (see Chapter 27), but other autoimmune diseases have also been implicated. Gastrointestinal epithelial dysfunction leads to ongoing leakage of gut microbes and their antigens into the lymphoid tissues and beyond. These may present atypically and present vexing problems in differential diagnosis. Tumors that remain localized are considered benign, while those that spread to distant sites are called malignant, or cancer. The neoplastic process entails not only cell proliferation but also variable modification of the differentiation of the involved cell types. Some tumors that look histologically malignant may not metastasize or be able to kill a patient. Thus, basal cell carcinomas of the skin may invade subjacent structures locally but rarely metastasize and are not lifethreatening. On the other hand, some tumors showing benign histologic characteristics may be lethal. Aggressive meningiomas do not metastasize, but their local invasiveness may cause death by compromising vital structures. In particular, Hippocrates described cancer of the breast, and in the 2nd century ad, Paul of Aegina commented on its frequency. The incidence of neoplastic disease increases with age, and longer life spans in modern times enlarge the population at risk. In previous centuries, humans did not live long enough to develop many cancers that are particularly common in middle and old age, such as those of the prostate, colon, pancreas and kidney. If all cancer deaths caused by tobacco smoke are removed from the statistics, the overall age-adjusted cancer death rate has been decreasing.
This effect does occur in childhood blood pressure medication for sleep 100 mg lasix buy amex, and the risk may be cumulative with longer duration of therapy [100], [101], [102], [103], [104]. The incidence in very young children is not known, and perimetric testing is often impossible in this group. However, concerns remain that these changes reflect a medication-related neurotoxic effect [108],[109]. Patients were deemed to be clinical responders if they had cessation of spasms at day 14 of treatment and continued to be seizure-free by the end of assessment period at day 42. Using a more stringent electro-clinical criteria for outcomes, combination therapy also was found to be more effective (66%) compared to hormonal therapy alone (55%). A long-term follow-up study at 18 months showed that combination therapy did not result in improved developmental outcomes, although those with early 1445 clinical response to treatment was associated with improved developmental and epilepsy outcomes at 18 months. The authors concluded that rapid diagnosis and effective treatment of infantile spasms improve outcomes [111]. Other Agents in Infantile Spasms Valproate [112],[113], nitrazepam [114], pyridoxine [115], felbamate [116], intravenous immunoglobulin [117], topiramate [118], zonisamide [119], ganaxolone [120], levetiracetam [121], and the ketogenic diet [122],[123] have been studied in small uncontrolled trials. However, there is insufficient evidence of efficacy and safety to recommend any of these therapies at this time [16],[73]. This protocol has been shown to achieve seizure freedom in 96% of children so treated [124]. A suggested protocol using Synacthen (cosyntropin or tetracosactide) based on the study done by Snead et al. Usually, a response is seen within the first 7 days; if within 2 weeks no response is noted or a steroid effect is evident, the lot is changed. Parents are taught to administer the injection, measure urine glucose three times daily with Chemstix, and recognize spasms so as to keep an accurate seizure calendar. Any diagnostic workup indicated by clinical circumstances is also performed, including screening for occult infections. Blood pressure must be measured daily at home during the first week and three times weekly thereafter. The patient is monitored in the outpatient clinic weekly for the first month and then biweekly, with appropriate blood work at each visit. If relapse occurs, the dose may be increased to the previously effective dose for 2 weeks and another tapering begun. Recommended Protocols for Prednisone and Prednisolone If prednisone is chosen because of its oral formulation and lower incidence of serious side effects, the pretreatment laboratory evaluation described earlier is performed.
Cortical Thickness Bernhardt and colleagues assessed the reproducibility of neocortical thinning and its clinical significance with respect to surgical outcome [44] blood pressure medication that causes hair loss order lasix 40 mg on line. In both groups, similar topology and rates of neocortical thinning were found predominantly in frontocentral, temporal and cingulate regions, demonstrating that static and dynamic effects of epilepsy similarly impact the neocortex of patients with or without hippocampal atrophy [44]. This was subsequently echoed in a meta-analysis that showed more marked atrophy in the ipsilateral hippocampus, with moderate effect sizes, in patients with longer epilepsy duration and more frequent seizures [45]. This allows the simultaneous consideration of information from consecutive slices, whereas conventional visual analysis examines the brain volume one slice at a time and thus requires a high level of expertise to synthesize information from consecutive slices. Increased sensitivity, however, may be associated with an increase in falsepositive results. Practically, balance between sensitivity and specificity may be achieved on a case-by-case basis. In the absence of false positives in normal controls, these changes could be due to occult dysplastic regions undetectable by visual analysis or represent an abnormal gyration [7]. It is also conceivable that these changes may potentially become active at a later stage and cause seizure recurrence after surgery [58]. It would be thus advisable to interpret the significance of structural abnormalities beyond the primary structural lesion in relation to electroclinical data and functional imaging modalities. Such models were first proposed by Bernasconi in a 2001 study [62], which showed 30% increased sensitivity compared to standard visual evaluation. The resulting binary image is then convolved with a smoothing kernel, revealing areas of ambiguous transition. This image is subtracted from junction images created from a normal database, generating a z-score map that shows areas of abnormal "junction. Limited resection (panel E) included the abnormality and rendered the patient seizure free. These first-order texture models were combined into a single composite map to optimize visibility. The upper panels display the T1-weighted derived computational models normalized with respect to controls (z-score maps). The normalized composite map identifies the lesional area as the only anomaly compared to controls and shows almost identical overlap with the lesion label obtained through manual segmentation.
Advances in technology offer alternative options to driving for persons with epilepsy and have the potential to lead to greater independence blood pressure pills buy lasix 100 mg. Ride sharing companies give access to transportation on demand through mobile applications. Further development and optimization of self-driving cars could potentially mitigate motor vehicle accidents entirely related to seizures. They are also reported to have lower household incomes, which are estimated to be 93% of the U. Although many factors are likely to contribute to the high rate of unemployment among persons with epilepsy, poorly controlled epilepsy is associated with a high level of unemployment [49]. Age of epilepsy onset also impacts employment status, with an earlier age of onset correlating with work difficulties later in life [50]. In patients with adult-onset epilepsy, initial seizure control or lack of control does affect work status. Newly diagnosed, unprovoked seizures in adults do not seem to negatively impact employment rates. The same study associated the development of refractory seizures in adults with reduced income [51]. Many persons with epilepsy have to deal with the reality of employment discrimination. A survey of young persons with epilepsy enrolled in Anon-the-job training program in Ireland indicated that 50% of the participants believed they were being actively discriminated against when seeking employment [52]. A similar percentage of employed persons with epilepsy in Australia felt they were discriminated against [53]. Widely available education regarding epilepsy has the potential of reducing stigma within the community and, hopefully, within workplaces [54],[55]. The law was intended to help persons with epilepsy and persons with other disabilities obtain and retain employment. Furthermore, what constitutes a reasonable accommodation was left open to interpretation. The standard may be based on the actual cost of any modifications required that allow a person to keep a specific job. Administrative and court rulings have made it clear that the protection sought has not been achieved [57]. The law was passed in an effort to clarify and be more inclusive on what constitutes disability under the law. Major life activities specifically covered in the law are highlighted in Table 96. The major life limitations due to epilepsy can result from seizures or the complications and side effects of medications used to treat the seizures. All the possible accommodations that may affect the person with epilepsy would be lengthy.
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Anatomical Remarks and Surgical Techniques Listen Several techniques of hemispherectomy hypertension 4019 order 100 mg lasix free shipping, hemispherotomy, and other hemispheric disconnections have been described. Many of these procedures have four common principles: (a) disruption of the descending and ascending fibers through the corona radiata and internal capsule, (b) removal of the mesial temporal structures, (c) complete callosotomy, and (d) disruption of the frontal horizontal fibers, including the occipitofrontalis fasciculus and uncinate fascicle [27],[28]. The main difference among the various techniques lies in how the lateral ventricle is accessed-whether access starts from the temporal horn or from the body of the lateral ventricle and the extent of brain resection necessary to gain access to the ventricular system. In the following paragraphs, we describe the differences between the several techniques. Anatomical Hemispherectomy Anatomical hemispherectomy refers to complete removal of frontal, temporal, parietal, and occipital lobes preserving the thalamus and basal ganglia. Patient positioning is optimized to allow access to the lateral surface of the affected cerebral hemisphere and to minimize neck torsion. The midline incision extends from the hairline to a point 4 to 5 cm above the inion. The incision is made with caution in the younger patient with an open anterior fontanelle to avoid inadvertent sagittal sinus injury. The skin edges are then reflected and periosteum and temporalis muscle fascia visualized. The muscle is mobilized off the underlying bone with a "T" incision, reflecting each muscle cuff inferiorly. Burr holes are done at the keyhole, the floor of the middle fossa just above the zygomatic arch, and lastly along the parasagittal areas just off the midline to avoid sagittal sinus injury (if anterior fontanelle is closed). The optimal craniotomy flap allows exposure to the midline, orbitofrontal base, floor of the middle fossa, and total length of the sylvian fissure. After the dura mater is opened in an H fashion, the sylvian fissure is identified and venous drainage patterns inspected. The distance from the superior craniotomy edge to the interhemispheric fissure is verified. The locations of major draining veins to the sagittal sinus are noted and carefully protected until later in the procedure to avoid early and often devastating blood loss. The sylvian fissure is split along its entire length using bipolar electrocautery, suction, and sharp microdissection (loupe magnification is preferred for this portion of the procedure). This should be done carefully to minimize bleeding, but cortex can be aspirated as necessary to aid in exposure. Once opened, the insular cortex including the inferior and superior circular sulci should be visualized along the length of the sylvian fissure.
Human tumor cells show great heterogeneity in their appearance blood pressure medication plendil buy 100 mg lasix free shipping, proliferative activity and so forth. Thus, most human tumors are mixtures of small and large cells, often with diverse shapes, varying nuclear appearances and differences in mitotic activity. Epigenetic changes in cell populations may lead to tumor progression or cell death. These changes may be retained or readily discarded, as selective pressures dictate. This type of deviousness allows for diverse populations of tumor cells to alternate between stemness-slowly dividing, tumor-reconstituting cells-and rapidly dividing, nonreconstituting cells. Furthermore, tumor cells may achieve such metamorphoses without incurring further mutations. Some malignant tumors may represent constantly shifting therapeutic targets, with incredible plasticity in adapting to a changing chemotherapeutic milieu via the ability to shift phenotypes rapidly to evade antineoplastic drugs, and then to shift back to reemerge from a defensive posture and reassert an aggressive nature. They divide infrequently, which allows them to evade destruction by cytotoxic chemotherapeutic agents that preferentially kill rapidly dividing cells. Also, because they proliferate less, they rely less on mutant cell activation signaling pathways and resemble normal cells more than do their highly mitotically active progeny. Thus, the main determinants of their survival make them more likely to persevere through treatments, even kinase inhibitors, that kill the rapidly dividing cells that make up the vast majority of the tumor. Their numbers, as a percentage of remaining viable tumor cells, increase after radiation. Intratumor heterogeneity refers to variation in the same parameters among different tumor cells and areas, and between a primary tumor and its metastases, within one patient. In fact, however, the term "tumor heterogeneity" has two basic and different meanings. Similarly, almost all cases of chronic myeloid leukemia show the t(9;22) translocation to generate mutant bcr-abl protein. The successful targeting of bcr-abl is emblematic of the goal of developing agents that are specific for mutations that are necessary for tumor survival. As comforting as this paradigm is for hematologic malignancies (at least selected ones), the situation for characteristic mutations in solid tumors has been more problematic. Even though some studies that have focused on selected individual genes have found mutational patterns, these studies in retrospect may have exercised such high levels of selectivity that many other, perhaps more important, mutations were not detected. More extensive genetic analysis of the protein-coding parts of the genome (whole exome sequencing) have shown wide diversity among individual solid tumors. Viral oncogenicity appears to be mediated mainly by the viral transcriptional activator Tax. Tax therefore probably initiates transformation, but additional genetic events are required for the complete malignant phenotype. Although only a few such studies have been reported, they generally confirm our worst fears along these lines. In one study of renal cell carcinomas, multiple biopsies of a single tumor mass showed that only 34% of protein-coding genetic alterations were concordant between different pieces of that one tumor mass.
When analyses also included metastases heart attack jack black widow lasix 100 mg buy online, or comparison of pre- and posttreatment tumor samples, concordance was even lower. Therefore, sophisticated tools to analyze tumors have not exactly allowed us to impose a man-made paradigm-either analytical or therapeutic-on the field of cancer biology. When patient-to-patient variations in tumor genotypes are considered, it is clear that tumors are incredibly more complicated than we had imagined. Two mechanisms have been invoked to explain the mechanism of carcinogenesis in virus-related liver cancer. It also activates telomerase expression and promotes tumor development via other mechanisms that are independent of p53. E7 binds to Rb, thus releasing its inhibitory effect on E2F transcriptional activity and allowing cell cycle progression. During the last half century, a cell line derived from cervical cancer, HeLa cells, has maintained worldwide popularity in the study of cancer. However, the human tumors that develop as a result all appear to entail viral orchestration of the same types of cancer hallmark traits (see above) that characterize sporadic cancers that occur independently of such infections. In 1958, Denis Burkitt described a form of childhood lymphoma in a geographical belt across equatorial Africa, which he suggested might have a viral etiology. They manifest a pronounced tropism for epithelial tissues, and their full productive life cycle occurs only in squamous cells. Occasionally, condylomata acuminata and laryngeal papillomas undergo malignant transformation to squamous cell carcinoma. This association holds for both ectocervical squamous carcinoma and endocervical adenocarcinoma. Some viral proteins also inhibit apoptosis and act in multiple ways to accelerate cell cycle transit. The lack of an adequate T-cell response often reported in chronic malarial infections might result in uncontrolled B-cell proliferation, thus providing a context for further genetic changes that may lead to the development of lymphoma. One of these is a translocation in which c-myc is being brought into proximity to an immunoglobulin promoter. Proliferation of B cells and inhibition of suppressor T cells induced by malaria 3. Deregulation of c-myc by translocation in a single transformed B cell, with effects on other signaling pathways 4. Fortunately, 70% of patients with this disease are cured by radiation therapy alone. These lesions are clinically and pathologically indistinguishable from true malignant lymphomas, but most of them are polyclonal.
Surviving infants may recover completely or have long-term impairment blood pressure medication insomnia lasix 40 mg buy low price, usually in the form of cerebral palsy or hydrocephalus. However, many cases of cerebral palsy have been shown by ultrasound studies to be related to brain damage 2 weeks or more prior to birth rather than from birth trauma. Peripheral Nerve Injury Brachial palsy, with varying degrees of paralysis of the arm, is caused by excessive traction on the head and neck or shoulders during delivery. Function may return within a few months if the palsy results from edema and hemorrhage. Fractures of other long bones and the nose occasionally occur during birth but heal easily. Rupture of the Liver the liver is the only internal organ other than the brain that is injured with any frequency during labor and delivery. Hepatic rupture may cause a hematoma large enough to be palpable and to cause anemia; surgical repair of the laceration may be required. As more predisposing factors and environmental, biochemical, structural and genetic contributors are identified, the number of deaths that truly have no identifiable pathogenesis has diminished. Nevertheless, many authorities still embrace a more inclusive definition of this syndrome. Low socioeconomic status (poor education, unmarried mother, poor prenatal care) Black or Native American parentage (in the United States, and independent of economic status; in other countries indigenous populations, like Maoris in New Zealand and Aborigines in Australia, are also at higher risk) Age younger than 20 years at first pregnancy Maternal cigarette smoking and/or alcohol consumption during and after pregnancy Use of illicit drugs during pregnancy Increased parity Risk factors for the infant are more controversial. A definite cause, such as seizures or aspiration after vomiting, is known in only half the cases of an apparent life-threatening event. Various inherited arrhythmia syndromes have been implicated in sudden infant death. Facial nerve palsy usually presents as unilateral flaccid paralysis of the face caused by injury to the seventh cranial nerve during labor or delivery, especially with forceps. If severe, the entire affected side of the face is paralyzed and even the eyelid cannot be closed. Most (90%) cases occur before 6 months of age, although infants up to 1 year are included in currently accepted criteria. These include hypoplasia of the arcuate nucleus, decreased serotonin receptors and decreased muscarinic cholinergic activity in favor of increased, abnormal nicotinic activity. Comparable abnormalities are seen in experimental animals exposed to nicotine in utero and are associated with depressed ventilatory responses to hypercarbia and hypoxia. Ten percent of deaths in children are due to cancer, exceeded only by accidental trauma. Examples include pancreatic rests in the walls of gastrointestinal organs, and adrenal tissue in the renal cortex. Medial hypertrophy of small pulmonary arteries, persistence of extramedullary hematopoiesis in the liver, right ventricular hypertrophy and increased periadrenal brown fat have also been seen and suggest a degree of chronic hypoxia. However, except for brainstem pathologies, none of these changes occurs with any regularity.
Tyler, 27 years: Patients who have been taking phenytoin, barbiturates, and/or acetazolamide for 5 years or more show decreased bone mineral density compared with healthy controls [37].
Sobota, 50 years: In open wounds, keratinocytes migrate between provisional matrix (see below) and preexisting or newly formed stromal collagen, which is coated with plasma glycoproteins, fibrinogen and fibronectin.
Shawn, 64 years: Disease progresses to septic shock within hours to days after appearance of the bubo.
Zarkos, 28 years: A gray (Gy) corresponds to 100 rads (1 joule/kg of tissue) and a centigray (cGy) is equivalent to 1 rad.
Darmok, 36 years: In a few cases, streptococcal pharyngitis leads to rheumatic fever or acute poststreptococcal glomerulonephritis.
Marlo, 45 years: The significance of electrocorticographic findings in focal cortical dysplasia: a review 2003;5(suppl 2): S115S123.
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