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Theories of pathogenesis include traumatic immigration and invasion of squamous epithelium through a retraction pocket erectile dysfunction pills viagra himcolin 30 gm order online, implantation of squamous epithelia in the middle ear through a perforation or surgery erectile dysfunction statistics uk 30 gm himcolin order overnight delivery, and metaplasia following chronic infection and irritation. On examination, there is often a perforation of the tympanic membrane filled with cheesy white squamous debris. The presence of an aural polyp obscuring the tympanic membrane is highly suggestive of an underlying cholesteatoma. A chronically draining ear that fails to respond to appropriate antibiotic therapy should raise suspicion of a cholesteatoma. Conductive hearing loss with a normal ear canal and intact tympanic membrane suggests either ossicular pathology or the presence of "third window" in the inner ear (see below). Fixation of the stapes from otosclerosis is a common cause of low-frequency conductive hearing loss. It occurs equally in men and women and is inherited as an autosomal dominant trait with incomplete penetrance; in some cases, it may be a manifestation of osteogenesis imperfecta. In women, the otosclerotic process is accelerated during pregnancy, and the hearing loss is often first noticeable at this time. Extension of otosclerosis beyond the stapes footplate to involve the cochlea (cochlear otosclerosis) can lead to mixed or sensorineural hearing loss. Fluoride therapy to prevent hearing loss from cochlear otosclerosis is of uncertain value. Disorders that lead to the formation of a pathologic "third window" in the inner ear can be associated with conductive hearing loss. There are normally two major openings, or windows, that connect the inner ear with the middle ear and serve as conduits for transmission of sound; these are, respectively, the oval and round windows. A third window is formed where the normally hard otic bone surrounding the inner ear is eroded; dissipation of the acoustic energy at the third window is responsible for the "inner ear conductive hearing loss. A common symptom is vertigo evoked by loud sounds (Tullio phenomenon), by Valsalva maneuvers that change middle ear pressure, or by applying positive pressure on the tragus (the cartilage anterior to the external opening of the ear canal). Patients with this syndrome also complain of being able to hear the movement of their eyes and neck. A large jugular bulb or jugular bulb diverticulum can create a "third window" by eroding into the vestibular aqueduct or posterior semicircular canal; the symptoms are similar to those of the superior semicircular canal dehiscence syndrome. Sensorineural Hearing Loss Sensorineural hearing loss results from either damage to the mechanotransduction apparatus of the cochlea or disruption of the electrical conduction pathway from the inner ear to the brain. Thus, injury to hair cells, supporting cells, auditory neurons, or the central auditory pathway can cause sensorineural hearing loss. Damage to the hair cells of the organ of Corti may be caused by intense noise, viral infections, ototoxic drugs. Congenital malformations of the inner ear may be the cause of hearing loss in some adults. Genetic predisposition alone or in concert with environmental exposures may also be responsible (see below). Presbycusis (age-associated hearing loss) is the most common cause of sensorineural hearing loss in adults. In the early stages, it is characterized by symmetric, gentle to sharply sloping high-frequency hearing loss. More importantly, the hearing impairment is associated with significant loss in clarity. There is a loss of discrimination for phonemes, recruitment (abnormal growth of loudness), and particular difficulty in understanding speech in noisy environments such as at restaurants and social events. Hearing aids are helpful in enhancing the signal-to-noise ratio by amplifying sounds that are close to the listener. Although hearing aids are able to amplify sounds, they cannot restore the clarity of hearing. Thus, amplification with hearing aids may provide only limited rehabilitation once the word recognition score deteriorates below 50%. Cochlear implants are the treatment of choice when hearing aids prove inadequate, even when hearing loss is incomplete (see below). The audiogram shows a moderate to severe downsloping sensorineural hearing loss typical of presbyacusis. The loss of high-frequency hearing is associated with a decreased speech discrimination score; consequently, patients complain of lack of clarity of hearing, especially in a noisy background. Histologically, there is distention of the endolymphatic system (endolymphatic hydrops) leading to degeneration of vestibular and cochlear hair cells. Although any pattern of hearing loss can be observed, typically, low-frequency, unilateral sensorineural hearing impairment is present. A 2-g/d low-salt diet is the mainstay of treatment for control of rotatory vertigo. Diuretics, a short course of glucocorticoids, and intratympanic gentamicin may also be useful adjuncts in recalcitrant cases. Surgical therapy of vertigo is reserved for unresponsive cases and includes endolymphatic sac decompression, labyrinthectomy, and vestibular nerve section. Both labyrinthectomy and vestibular nerve section abolish rotatory vertigo in >90% of cases. Sensorineural hearing loss may also result from any neoplastic, vascular, demyelinating, infectious, or degenerative disease or trauma affecting the central auditory pathways. Primary diseases of the central nervous system can also present with hearing impairment. Characteristically, a reduction in clarity of hearing and speech comprehension is much greater than the loss of the ability to hear pure tone.

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Its side effects are relatively tolerable in most patients and include hepatic dysfunction erectile dysfunction while drunk cheap 30 gm himcolin visa, diarrhea erectile dysfunction doctors san francisco 30 gm himcolin order free shipping, and fluid retention. Rarely, patients receiving imatinib have decreased cardiac function, which may persist after discontinuation of the drug. Nilotinib is a tyrosine protein kinase inhibitor with a similar spectrum of activity to imatinib, but with increased potency and perhaps better tolerance by certain patients. Dasatinib, another inhibitor of the p210bcr-abl oncoproteins, is active in certain mutant variants of p210bcr-abl that are refractory to imatinib and arise during therapy with imatinib or are present de novo. Dasatinib also has inhibitory action against kinases belonging to the src tyrosine protein kinase family; this activity may contribute to its effects in hematopoietic tumors and suggest a role in solid tumors where src kinases are active. The T315I mutant of p210bcr-abl is resistant to imatinib, nilotinib, bosutinib, and dasatinib; ponatinib has activity in patients with this p210bcr-abl variant, but ponatinib has noteworthy associated thromboembolic toxicity. Administered orally, it causes differentiation of the neoplastic promyelocytes to mature granulocytes and attenuates the rate of hemorrhagic complications. Adverse effects include headache with or without pseudotumor cerebri and gastrointestinal and cutaneous toxicities. After a growth factor binds to is cognate receptor (1), in many cases there is activation of tyrsosine kinase activity particularly after dimerization of the receptors (2). This leads to autophosphorylation of the receptor and docking of "adaptor" proteins. In parallel, tyrosine phosphorylated receptors can activate the phosphatidylinositol-3-kinase to produce the phosphorylated lipid phosphatidyl-inositol-3- phosphate (7). Also encountered are fatigue, diarrhea, and the hand-foot syndrome, with erythema and desquamation of the distal extremities, in some cases requiring dose modification, particularly with sorafenib. They produce stomatitis, fatigue, and some hyperlipidemia (10%), myelosuppression (10%), and rare lung toxicity. Adverse effects include neuropathy, orthostatic hypotension with or without hyponatremia, and reversible thrombocytopenia. Carfilzomib is a proteasome inhibitor chemically unrelated to bortezomib without prominent neuropathy, but with evidence of a cytokine release syndrome, which can be a cardiopulmonary stress. Other agents active in multiple myeloma and certain other hematologic neoplasms include the immunomodulatory agents related to thalidomide, including lenalidomide and pomalidomide. All these agents collectively inhibit aberrant angiogenesis in the bone marrow microenvironment, as well as influence stromal cell immune functions to alter the cytokine milieu supporting the growth of myeloma cells. Initially approved for use in mantle cell lymphoma, it is potentially applicable to a number of B cell neoplasms that depend on signals through the B cell antigen receptor. Janus kinases likewise function downstream of a variety of cytokine receptors to amplify cytokine signals, and Janus kinase inhibitors including ruxolitinib have approved activity in myelofibrosis to ameliorate splenomegaly and systemic symptoms. Acetylated histones allow access of transcription factors to target genes and therefore 103e-20 increase expression of genes that are selectively repressed in tumors. The result can be differentiation with the emergence of a more normal cellular phenotype, or cell cycle arrest with expression of endogenous regulators of cell cycle progression. Vorinostat is approved for clinical use in cutaneous T cell lymphoma, with dramatic skin clearing and very few side effects. Romidepsin is a distinct molecular class of histone deacetylase inhibitor also active in cutaneous T cell lymphoma. An active retinoid in cutaneous T cell lymphoma is the synthetic retinoid X receptor ligand bexarotene. These drugs were originally considered antimetabolites but have clinical value in myelodysplastic syndromes and certain leukemias when administered at low doses. As a class, biologic therapies may be distinguished from molecularly targeted agents in that many biologic therapies require an active response. This may be contrasted with the more narrowly defined antiproliferative or apoptotic response that is the ultimate goal of molecularly targeted agents discussed above. However, there is much commonality in the strategies to evaluate and use molecularly targeted and biologic therapies. Immune Cell­Mediated Therapies Tumors have a variety of means of avoiding the immune system: (1) they are often only subtly different from their normal counterparts; (2) they are capable of downregulating their major histocompatibility complex antigens, effectively masking them from recognition by T cells; (3) they are inefficient at presenting antigens to the immune system; (4) they can cloak themselves in a protective shell of fibrin to minimize contact with surveillance mechanisms; and (5) they can produce a range of soluble molecules, including potential immune targets, that can distract the immune system from recognizing the tumor cell or can kill or inactivate the immune effector cells. Cell-Mediated Immunity the strongest evidence that the immune system can exert clinically meaningful antitumor effects comes from allogeneic bone marrow transplantation. Adoptively transferred T cells from the donor expand in the tumor-bearing host, recognize the tumor as being foreign, and can mediate impressive antitumor effects (graft-versus-tumor effects). Three types of experimental interventions are being developed to take advantage of the ability of T cells to kill tumor cells. This occurs in three major settings: in allogeneic bone marrow transplantation; as purified lymphocyte transfusions following bone marrow recovery after allogeneic bone marrow transplantation; and as pure lymphocyte transfusions following immunosuppressive (nonmyeloablative) therapy (also called minitransplants). In each of these settings, the effector cells are donor T cells that recognize the tumor as being foreign, probably through minor histocompatibility differences. The main risk of such therapy is the development of graft-versus-host disease because of the minimal difference between the cancer and the normal host cells. First, tumor antigen­specific T cells can be developed and expanded to large numbers over many weeks ex vivo before administration. Short periods removed from the patient permit the cells to overcome the tumor-induced T cell defects, and such cells traffic and home to sites of disease better than cells that have been in culture for many weeks. The finding that mutant oncogenes that are expressed only intracellularly can be recognized as targets of T cell killing greatly expanded the possibilities for tumor vaccine development. However, major difficulties remain in getting the tumor-specific peptides presented in a fashion to prime the T cells. Tumors themselves are very poor at presenting their own antigens to T cells at the first antigen exposure (priming). Priming is best accomplished by professional antigen-presenting cells (dendritic cells). Thus, a number of experimental strategies are aimed at priming host T cells against tumor-associated peptides.

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Diagnosis Narcolepsy is most commonly diagnosed by the history of chronic sleepiness plus cataplexy or other symptoms causes of erectile dysfunction include quizlet cheap 30 gm himcolin free shipping. Many disorders can cause feelings of weakness impotence of organic organ discount himcolin online master card, but with true cataplexy, patients will describe definite functional weakness. Cataplexy occurs in about half of all narcolepsy patients and is diagnostically very helpful because it occurs in almost no other disorder. In contrast, occasional hypnagogic hallucinations and sleep paralysis occur in about 20% of the general population, and these symptoms are not as diagnostically specific. In addition, patients should be encouraged to obtain a fully adequate amount of sleep each night for the week prior to the test to eliminate any effects of insufficient sleep. Many factors can contribute to insomnia, and obtaining a careful history is essential so one can select therapies targeting the underlying factors. The assessment should focus on identifying predisposing, precipitating, and perpetuating factors. Psychophysiologic Factors Many patients with insomnia have negative expectations and conditioned arousal that interfere with sleep. These individuals may worry about their insomnia during the day and have increasing anxiety as bedtime approaches if they anticipate a poor night of sleep. While attempting to sleep, they may frequently check the clock, which only heightens anxiety and frustration. They may find it easier to sleep in a new environment rather than their bedroom, as it lacks the negative associations. Inadequate Sleep Hygiene Patients with insomnia sometimes develop counterproductive behaviors that contribute to their insomnia. These can include daytime napping that reduces sleep drive at night; an irregular sleep-wake schedule that disrupts their circadian rhythms; use of wake-promoting substances. Psychiatric Conditions About 80% of patients with psychiatric disorders have sleep complaints, and about half of all chronic insomnia occurs in association with a psychiatric disorder. Depression is classically associated with early morning awakening, but it can also interfere with the onset and maintenance of sleep. Mania and hypomania can disrupt sleep and often are associated with substantial reductions in the total amount of sleep. Panic attacks can occur during sleep and need to be distinguished from other parasomnias. Medications and Drugs of Abuse A wide variety of psychoactive drugs can interfere with sleep. Insomnia can also result from use of prescription medications too close to bedtime. Conversely, withdrawal of sedating medications such as alcohol, narcotics, or benzodiazepines can cause insomnia. Alcohol taken just before bed can shorten sleep latency, but it often produces rebound insomnia 2­3 h later as it wears off. Pain from rheumatologic disorders or a painful neuropathy commonly disrupts sleep. Most patients with narcolepsy feel more alert after sleep, and they should be encouraged to get adequate sleep each night and to take a 15- to 20-min nap in the afternoon. This nap may be sufficient for some patients with mild narcolepsy, but most also require treatment with wakepromoting medications. Modafinil is used quite often because it has fewer side effects than amphetamines and a relatively long halflife; for most patients, 200­400 mg each morning is very effective. Methylphenidate (10­20 mg bid) or dextroamphetamine (10 mg bid) are often effective, but sympathomimetic side effects, anxiety, and the potential for abuse can be concerns. These medications are available in slow-release formulations, extending their duration of action and allowing easier dosing. Sodium oxybate (gamma hydroxybutyrate) is given twice each night and is often very valuable in improving alertness, but it can produce excessive sedation, nausea, and confusion. The tricyclic antidepressants, such as protriptyline (10­40 mg/d) or clomipramine (25­50 mg/d) are potent suppressors of cataplexy, but their anticholinergic effects, including sedation and dry mouth, make them less attractive. People with insomnia are dissatisfied with their sleep and feel that it impairs their ability to function well in work, school, and social situations. Affected individuals often experience fatigue, decreased mood, irritability, malaise, and cognitive impairment. Chronic insomnia, lasting more than 3 months, occurs in about 10% of adults and is more common in women, older adults, people of lower socioeconomic status, and individuals with medical, psychiatric, and substance abuse disorders. Acute or short-term insomnia affects over 30% of adults and is often precipitated by stressful life events such as a major illness or loss, change of occupation, medications, and substance abuse. If the acute insomnia triggers maladaptive behaviors such as increased nocturnal light exposure, frequently checking the clock, or attempting to sleep more by napping, it can lead to chronic insomnia. Most insomnia begins in adulthood, but many patients may be predisposed and report easily disturbed sleep predating the insomnia, suggesting that their sleep is lighter than usual. Clinical studies and animal models indicate that insomnia is associated with activation 1 No antidepressant has been approved by the U. In fact, insomnia and nighttime wandering are some of the most common causes for institutionalization of patients with dementia, because they place a larger burden on caregivers. Conversely, in cognitively intact elderly men, fragmented sleep and poor sleep quality are associated with subsequent cognitive decline. Fatal familial insomnia is a very rare neurodegenerative condition caused by mutations in the prion protein gene, and although insomnia is a common early symptom, most patients present with other obvious neurologic signs such dementia, myoclonus, dysarthria, or autonomic dysfunction. For example: · Solvingproblems · repareforsleepwith20­30minof · Thinkingaboutlifeissues P relaxation. With improved sleep, patients often report less daytime fatigue, improved cognition, and more energy.

Syndromes

• Burns
• Throat
• Corticosteroids such as dexamethasone to reduce brain swelling
• Bronchoscopy with biopsy
• Oxygen
• Severely dry eyes
• Antihistamines that may cause sleepiness: dipenhydramine (Benadryl); chlorpheniramine (Chlor-Trimetron); brompheniramine (Dimetapp), or clemastine (Tavist).
• Femoral nerve in the thigh
• Have you had a fever?
• Balance exercises -- tai chi, yoga

The cancer stem cell hypothesis has led to the idea that current cancer therapies may be effective at killing the bulk of tumor cells but do not kill tumor stem cells erectile dysfunction in young men buy genuine himcolin line, leading to a regrowth of tumors that is manifested as tumor recurrence or disease progression erectile dysfunction pump manufacturers generic 30 gm himcolin amex. Research is in progress to identify unique molecular features of cancer stem cells that can lead to their direct targeting by novel therapeutic agents. Although normal proliferating cells also have similar needs, there are differences in how cancer cells metabolize glucose and a number of other compounds, including glutamine, as compared to normal cells. The inefficient utilization of glucose also leads to a need for alternative metabolic pathways for other compounds as well, one of which is glutamine. Similar to glucose, this provides both a source for structural molecules as well as energy production. Thus, a major problem in cancer therapy is that malignancies have a wide spectrum of mechanisms for both initial and adaptive resistance to treatments. Thus, most metastatic cancers (except those curable with chemotherapy such as germ cell tumors) eventually become resistant to the therapy being used. Both the complexity 102e-13 and dynamic nature of the microenvironment enhance the difficulty of treating tumors. There are also a number of mechanisms by or which the microenvironment can contribute ­O2 +O2 +/­O2 to resistance to anticancer therapies. One of the critical elements of tumor cell Glucose Glucose Glucose proliferation is delivery of oxygen, nutrients, and circulating factors important for growth and survival. The diffusion limit for oxyPyruvate O2 O2 Pyruvate gen in tissues is ~100­200 m, and thus, a Pyruvate 5% 85% critical aspect in the growth of tumors is the development of new blood vessels, or angioLactate Lactate genesis. In most normal tissues, is a phase in tumor development when the the vast majority of cells are differentiated and dedicated to a particular function within the dynamic balance of pro- and antiangiogenic organ in which they reside. The metabolic needs are mainly for energy and not for building factors is tipped in favor of vessel formation blocks for new cells. Stimuli for tumor angiogentrast, proliferative tumor tissues, especially in the setting of hypoxia, a typical condition within esis include hypoxemia, inflammation, and tumors, use aerobic glycolysis to generate energy for cell survival and generation of building genetic lesions in oncogenes or tumor supblocks for new cells. Although the exact mechanisms of oncogen- dilated with an uneven diameter, excessive branching, and shunting. Tumor ing to alterations in methylation status (primarily hypermethylation) vessel walls have numerous openings, widened interendothelial juncof genes (epigenetic changes) that can have profound effects on a tions, and discontinuous or absent basement membrane; this contribnumber of cellular processes including differentiation. Much needs to be learned about the specific differences in metabo- interstitial pressure within the tumor (which also interferes with the lism between cancer cells and normal cells; however, modulators delivery of therapeutics to the tumor;. Tumor blood vessels lack perivascular cells such as pericytes antidiabetic agent metformin, both alone and in combination with and smooth-muscle cells that normally regulate flow in response to chemotherapeutic agents. This leads to decreased protein synthesis and tion that can occur in hypoxic conditions because of their plasticity; proliferation. Additional approaches targeting tumor metabolism will sion molecules such as integrins. Tumor cells themselves may directly form parts of vascular channels within tumors. The pattern of vessel formation is haphazard: vessels are tortuous, dilated, and leaky and branch in random ways. This leads to uneven blood flow within the tumor, with areas of acidosis and hypoxemia (which stimulate release of angiogenic factors) and high intratumoral pressures that inhibit delivery of therapeutic agents. When tumor cells arise in or metastasize to an avascular area, they grow to a size limited by hypoxemia and nutrient deprivation. Angiogenic endothelium expresses a number of receptors not found on resting endothelium. A number of ubiquitously expressed host molecules play critical roles in normal and pathologic angiogenesis. The role of these vessels in tumor cell metastasis to regional lymph nodes remains to be determined. Different types of tumors can use distinct combinations of molecular mechanisms to activate the angiogenic switch. Therefore, it is doubtful that a single antiangiogenic strategy will suffice for all human cancers; rather, a number of agents or combinations of agents will be needed, depending on distinct programs of angiogenesis used by different human cancers. Despite this, experimental data indicate that for some tumor types, blockade of a single growth factor. Blood vessels in normal tissues exhibit a regular hierarchical branching pattern that delivers blood to tissues in a spatially and temporally efficient manner to meet the metabolic needs of the tissue (top). Vascular permeability is regulated, interstitial fluid pressure is low, and oxygen tension and pH are physiologic. Tumors have abnormal vessels with tortuous branching and dilated, irregular interconnecting branches, causing uneven blood flow with areas of hypoxemia and acidosis. This harsh environment selects genetic events that result in resistant tumor variants, such as the loss of p53. Together, these molecular abnormalities result in a vasculature that is permeable to serum macromolecules, leading to high tumor interstitial pressure, which can prevent the delivery of drugs to the tumor cells. During the first week of treatment, abnormal vessels are eliminated or pruned (dotted lines), leaving a more normal branching pattern. These changes lead to a decrease in vascular permeability, reduced interstitial pressure, and a transient increase in blood flow within the tumor. Rare but serious potential risks include arterial thromboembolic events, including stroke and myocardial infarction, and hemorrhage.

Usage: ut dict.

A twin-pair sampling design rather than a conventional unrelated case­control design has advantages owing to the pronounced between-family variability in microbiota/microbiome composition and the potential for multiple states of a community associated with disease erectile dysfunction treatment without drugs himcolin 30 gm buy with amex. Transplantation of a microbiota from suitable human donor controls representing different disease states and communities erectile dysfunction drugs sublingual purchase himcolin online now. In addition, transplantation provides a preclinical platform for identifying next-generation probiotics, prebiotics, or combinations of the two (synbiotics). The gut microbiotas (and microbiomes) of obese individuals are significantly less diverse than those of lean individuals; the implication is that there may be unfilled niches (unexpressed functions) that contribute to obesity and its associated metabolic abnormalities. Transplantation of an uncultured fecal microbiota from twins stably discordant for obesity or of bacterial culture collections generated from their microbiota transmits their discordant adiposity phenotypes as well as obesity-associated metabolic abnormalities to recipient germfree mice. It is noteworthy that invasion and prevention of obesity and metabolic phenotypes are dependent on the type of human diets fed to animals: prevention is associated with a diet low in saturated fats and high in fruit and vegetable content, but not with a diet high in saturated fats and low in fruit and vegetable content. This approach provides evidence for a causal role for the microbiota in obesity and its attendant metabolic abnormalities. It also provides a method for defining unoccupied niches in disease-associated microbial communities, the role of dietary components in determining how these niches can be filled by human gut­derived bacterial taxa, and the effects of such occupancy on microbial and host metabolism. It also provides a way to identify health-promoting diets and next-generation probiotics representing naturally occurring members of our indigenous microbial communities that are well adapted to persist in a given body habitat. A second step is to determine whether the culturable component of a representative microbiota sample can transmit the phenotype(s) observed with the intact uncultured sample. The models used may inform the design and interpretation of clinical studies of the very individuals and populations whose microbiota are selected for creating these models. A microbiota from lean donors significantly improved peripheral insulin sensitivity over that in controls. This change was associated with an increase in the relative abundance of the butyrate-producing bacteria related to Roseburia intestinalis (in the feces) and Eubacterium hallii (in the small intestine). In 10 weeks of followup, infection was cured (with cure defined as three negative fecal tests for C. Donor selection varied, although most donors were family members or relatives and most studies excluded donors who had recently received antibiotics. Resolution of infection, which was frequently assessed on the basis of symptom resolution (with C. The most common adverse events reported were diarrhea (94% of cases) and abdominal cramps (31%) on the day of infusion. The meta-analysis was limited to clinical outcomes and did not specifically address the role of the microbiota in disease resolution. This attention, coupled with an increasing public appreciation of the beneficial nature of our interactions with microbes, demands that the precautionary principle be honored and that risks versus benefits of such interventions be carefully evaluated. Consequently, the proper number of subjects to enroll and the proper populations to target remain to be established. A common yet critical problem to avoid is under-sampling of the types of objects under study. Another key issue is whether the effect size to be studied, especially in meta-analysis, is greater than or less than technical effects. A central challenge in human microbiome research is establishing the extent to which diagnostic tests and therapeutic approaches are generalizable. This challenge is illustrated by studies of the capacities of gut microbiomes to metabolize orally administered drugs. The results could be very informative for the pharmaceutical industry as it seeks new and more accurate ways to predict bioavailability and toxicity. However, these studies should prompt consideration of the fact that many clinical trials are outsourced to countries where trial participants have diets and microbial community structures that differ from those of the intended initial recipients of the (marketed) drug. Capture and preservation of the wide range of microbial diversity present in different human populations-and thus of the capacity of our microbial communities to catalyze elaborate and in many respects uncharacterized biotransformations-represent potentially fertile ground for the discovery of new drugs (and new industrial processes of societal value). The chemical entities that our microbial communities have evolved to synthesize in order to support their mutually beneficial relationships and the human genes that these chemotypes influence may become new classes of drugs and new targets for drug discovery, respectively. Birth cohort studies (including studies of twins) initiated every 10 years in these countries may be able to capture the impact of globalization, including changing diets, on human microbial ecology. Although microbiome-associated diagnostics and therapeutics provide new and exciting dimensions for personalized medicine, attention must be paid to the potentially broad societal impact of this work. For example, studies of the human gut microbiome are likely to have a disruptive effect on current views of human nutrition, enhancing appreciation of how food and the metabolic output of interactions of dietary components with the microbiota are intimately connected to myriad features of human biology. Underlying the efforts to elucidate the relations among food, the microbiome, and human nutrition is a need to proactively develop materials for educational outreach with a narrative and vocabulary that is understandable to broad and varied consumer populations representing different cultural traditions and widely ranging degrees of scientific literacy. The results have the potential to catalyze efforts to integrate agricultural policies and practice, food production, and nutritional recommendations for consumer populations representing different ages, geographic locales, and states of health. While this information can help us understand the origins of certain yet unexplained health disparities, care must be taken to avoid stigmatization of individuals or groups of individuals having different cultural norms, belief systems, or behaviors. As microbiome-directed diagnostics and therapeutics emerge, we must be sensitive to the societal impact of this work. Biologists study the experimental response of a variable of interest in a cell or organism while holding all other variables constant. In this way, it is possible to dissect the individual components of a biologic system and assume that a thorough understanding of a specific component. Biologic systems are, however, much more complex than this approach assumes and manifest behaviors that frequently (if not invariably) cannot be predicted from knowledge of their component parts characterized in isolation. Growing recognition of this shortcoming of conventional biologic research has led to the development of a new discipline, systems biology, which is defined as the holistic study of living organisms or their cellular or molecular network components to predict their response to perturbations. Concepts of systems biology can be applied readily to human disease and therapy and define the field of systems pathobiology, in which genetic or environmental perturbations produce disease and drug perturbations restore normal system behavior. Systems biology evolved from the field of systems engineering in which a linked collection of component parts constitute a network whose output the engineer wishes to predict.

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