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Afer intramuscular administration of a single 10–20-mg tions of fast-dissolving lyophilisate preparations of lorazepam result dose buy doxepin 75mg online, diazepam peak serum concentrations of 35–300 ng/mL are in a slower and more erratic absorption with a high inter-individual reached within 30–60 min [22 cheap doxepin 10 mg line,23] purchase 25mg doxepin amex. In a study of 20 patients undergoing minor gynae- layed peak do not encourage use of diazepam by the intramuscular cological surgery discount doxepin 25 mg otc, 2. Te maximal plasma concentration Afer rectal administration as a solution or gel formula- occurred at 40 min afer oral administration and at 60 min afer tion, diazepam is rapidly absorbed and peaks within 3–30 min sublingual administration [50]. Absorption is faster in children and efective cannot be recommended for seizure emergencies. Distribution In an open-label trial in status epilepticus, a minimum efective Most benzodiazepines, including clobazam and its active N-desme- serum level of 30. Te average con- epam, diazepam, lorazepam, midazolam and nitrazepam, are exten- centration was 60. In seven patients who were treated with 5 mg lorazepam in- and rapidly penetrate the blood–brain barrier, resulting in a rapid travenously for status epilepticus, mean plasma concentrations afer onset of action. Apparent volumes of distribution are in excess of 30 s, 1, 2, 4 and 10 min were 272, 237, 170, 106 and 80 ng/mL, 1 L/kg, indicating extensive penetration into tissues. In a study in healthy subjects [31], serum levels afer a a result of their lipophilic nature they also redistribute relatively single bolus injection of 5 mg lorazepam remained above 30 ng/mL rapidly from the brain to other lipophilic tissues in the body, a pro- for 18 h [5]. Tere was no diference in concentration tional intravenous doses is short for diazepam (<2 h) and mida- between those patients whose status epilepticus was stopped and zolam (3–4 h) and longer for lorazepam (up to 72 h) [32,53,54,55], those in whom the status epilepticus was not controlled [5,32]. Elimination Afer parenteral administration of the acidic aqueous solution as Benzodiazepines are eliminated almost entirely by metabolism. Terefore, there is a rapid onset of action with peak sedation clonazepam by nitroreduction, acetylation and hydroxylation, afer 3 min of intravenous dosing [6], but only a short duration of N-desmethyldiazepam (derived from clorazepate) by glucuronida- action is observed. Peak concentrations following a single 5-mg in- tion and hydroxylation, and nitrazepam by nitroreduction, acetyla- travenous bolus are 113 ± 16 ng/mL [34]. Clobazam is converted to the active metab- tion, peak concentrations are reached within 20–30 min, with 91% olite N-desmethylclobazam, whereas clorazepate is a prodrug for bioavailability for midazolam hydrochloride [6], although much N-desmethyldiazepam. Diazepam is extensively metabolized by the slower absorption rates may occur in some patients. Te main pharmacologically active metabolite mately 50% in adults and 27% in children [35,36,37]. Te buccal or N-desmethyldiazepam has a longer half-life than diazepam and intranasal routes, like the rectal route, avoid the hepatic frst-pass may be responsible for some of the antiepileptic efects of diaze- efect. Unlike the rectal route, buccal and intranasal applications are pam during prolonged use, but has few implications for emergen- socially acceptable and widely preferred by doctors, caregivers and cy treatment. Intranasal administration of midazolam has been ex- at the 3-hydroxy group [5] and it has no active metabolites [58]. However, to apply a therapeutic results from oxidation of the imidazole ring [59], is pharmacologi- dose of midazolam into the nose of an adult, 2–3 mL of the solution cally active but has a shorter half-life than midazolam and therefore need to be instilled, which leads to discomfort, lacrimation and lo- contributes little to the overall clinical efect [60]. A useful alternative is a concentrated form of an lives in non-induced healthy adults are in the order of 10–50 h for intranasal spray (2. Studies in elderly patients have demonstrated that the Te buccal or sublingual route ofers the advantage of good toler- clearance of clobazam, midazolam and N-desmethyldiazepam is ability, even with larger volumes of solution [48]. Clobazam Clonazepam Clorazepate Primary indication Oral treatment: frst-line and, Oral treatment: second- to third-line Oral treatment: second- or third-line more often, second- or third-line therapy of myoclonic seizures, but therapy of focal and generalized therapy of focal and generalized also other generalized seizures seizures, mostly as add-on seizures (including non-convulsive and focal seizures, as add-on or as status epilepticus), as add-on or as monotherapy monotherapy Intravenous use: second-line therapy for premonitory or early status epilepticus Usual Tablets: 10 mg Tablets: 0. With hypotonia intravenous use, respiratory depression and hypotension Diazepam Lorazepam Midazolam Nitrazepam Adults and children, Adults and children, Adults, continuous infusion: Oral treatment: second- to intravenous use: premonitory intravenous use: refractory status epilepticus third-line therapy of West and early status epilepticus premonitory and early Adults, continuous infusion: early syndrome and myoclonic , serial seizures, acute status epilepticus (preferred status epilepticus seizures, but also other symptomatic seizures drug in stage 1 of status Children, buccal, or intranasal focal and generalized epilepticus), acute repetitive route: premonitory and early seizures, mostly as add-on seizures, acute symptomatic status epilepticus, acute repetitive seizures seizures, acute symptomatic seizures Vials: 5 mg/mL, 10 mg/mL Vials: 2 mg/mL, 4 mg/mL Vials: 1 mg/mL, 5 mg/mL Tablets: 5 mg, 10 mg Rectal gel: 2. These rates may be increased according to response Higher infusion rates have been used (and may be required), both in adults and in paediatric patients Intranasal or buccal: 5–10 mg (adults); 0. Use in acute repetitive term use in periods of seizure seizures and status epilepticus exacerbation. May be an option has fallen gradually out of favour, for initial monotherapy in selected having been largely superseded patients. Tolerance and withdrawal by midazolam, lorazepam and seizures represent main drawbacks diazepam. Tolerance, withdrawal seizures and, in children, drooling represent signifcant drawbacks aValues refer to the active metabolite N-desmethyl-diazepam, for which clorazepate is a prodrug. Diazepam Lorazepam Midazolam Nitrazepam Rapid onset of action with the Rapid onset of action by the Water solubility permits alternative Broad-spectrum activity intravenous route intravenous route routes in the emergency against many seizure types Rectal formulation available Long lasting effect (>24 h) treatment of seizures. Tolerance, diazepam administration is routes are increasingly used withdrawal seizures and, becoming less commonly for pre-hospital emergency in children, drooling used, because buccal and, management by non-medical represent signifcant to a lesser extent, intranasal personnel. Intramuscular route drawbacks midazolam provide a more may be a useful alternative to the socially acceptable alternative intravenous route in the out-of- hospital setting 404 Chapter 30 Drug interactions treatment. Te clearance of clobazam and N-desmethylclobazam is decreased However, it was also noted that ‘it is not clear who will best beneft by stiripentol, and the resulting increase in the serum concentrations and over what time-frame’ [72]. In these earlier studies, a 50% or of clobazam and, to a greater extent, N-desmethylclobazam is likely greater seizure reduction compared with placebo was reported in to contribute to the clinical efects of stiripentol in patients receiving 57. Side-efects were only described in two of is decreased by about 40% when co-administered with valproic acid the studies, and were reportedly present in 85% [69] and 36% [70] [62]. Tere was no diference among groups in the rate of adverse considered to be devoid of enzyme-inducing properties, 2-week efects leading to drug withdrawal and on the frequency of discon- treatment with 40 mg/day clobazam has been found to cause a 27% tinuation because of inadequate seizure control. A cal signifcance when benzodiazepines are used in single doses in Cochrane systematic review included these two studies (n = 163) emergency settings. However, they may afect dose requirements in to assess the role of clobazam monotherapy in the treatment of ep- patients who need prolonged infusions for the management of re- ilepsy [74]. Te larger of these studies, which was pla- tic and toxic efects occur vary considerably. Dose adjustments are cebo-controlled, randomized 238 patients aged 2–60 years and in- guided by direct evaluation of clinical response, and monitoring se- cluded a low-dose group (target dosage 0. In interpreting these Because of its rapid action, the role of clobazam has been studied fndings it should be noted that results were calculated using the in catamenial epilepsy [86]. A double-blind trial compared cloba- last-observation-carried-forward analysis, in which patients who zam (20–30 mg/day) with placebo in 18 women with catamenial had fewer seizures but discontinued prematurely (e. Te treatments were administered for the 10 days that adverse efects) are still counted as responders. Specifcally, discon- overlapped their menses; in 14 women clobazam was superior to tinuation rates because of adverse events in this trial were 3. A subsequent paper reported an indirect comparison of the rel- Compared with other benzodiazepines, clobazam does not have ative efcacies of clobazam, felbamate, lamotrigine, topiramate and a defnite role as an emergency treatment for seizures. Tere are rufnamide as adjunctive treatments for Lennox–Gastaut syndrome anecdotal reports on the use of oral clobazam in non-convulsive [80]. In one study, 16 patients (six with absence status, ment efect compared to placebo (Cohen’s d efect size 0. Felbamate, status epilepticus) were administered clobazam as a single oral dose lamotrigine and topiramate had lower efect sizes. In another study, cloba- tacks) suggested superiority of both clobazam dosages over all com- zam (60–70 mg given as a single dose) led to seizure cessation in parators. A Cochrane review has also concluded that clobazam may four adults with complex partial status epilepticus whose seizures be useful for tonic–atonic seizures occurring in this syndrome [81]. Te efcacy of stiripentol in this syndrome may be ex- Clonazepam plained, at least to some extent, by its ability to increase serum cloba- zam and N-desmethylclobazam concentrations (see Chapter 48).

Central cloudy corneal dystrophy congcnitales rcpartics sur trois generations ct attcignant deux of Francois purchase 10mg doxepin fast delivery. In vivo confocal microscopy of pre- decorin fame shift m utation in a family with congenital stromal Dcscem cts m em brane corncal dystrophy order 25 mg doxepin with mastercard. Prc-D csccm ets m em brane In: Bncydopcdia o f Molecular M echanisms of Disease (Corncal corncal dystrophy doxepin 75 mg without prescription. Berlin: o f decorin leads to abnorm al collagen fibril m orphology and skin Springer cheap 10mg doxepin overnight delivery, 1921. Nouvcllc dystrophic hcrcdofamilialc du families with corneal endothelial dystrophy. Encyclopedia o f M olecular M echanisms o f Disease (Corneal pathological study of Fran^ois-Ncetens speckled corneal dystrophy. Am identified in the C O L S A I and C O L 8 A 2 genes in familial 1-uchs cor­ J O phthalm ol 1961;51:275-8. Five characterized by epithelial like endothelial cells which influence cases in the same family. In: Rncyclopedia of Molccular Mechanisms of Disease endothelial dystrophy associated w ith glaucoma. Am J tion in young children with congenital hereditary endothelial dys­ O phthalm ol 1960;50:1111-24. C linical differentiation o f rcccssivc vcrandcrungcn und Keratoconus in cincr Familie. Gracfes Arch congenital hereditary endothelial dystrophy and dom inant Klin Hxp O phthalm ol 1974;191:37-43. Br ) Ophthalm ol In: lincyclopcdia o f M olccular M echanisms o f Disease (Corneal 1994;78:77-8. Serial analysis o f gene relatives in congenital hereditary endothelial dystrophy. In advanced cases, corneal scarring from clinical disease, at least when each marker for severity of corneal edema and decompensation further reduces visual keratoconus is considered independently. Symptoms are highly variable and depend on the suggest that all keratoconus patients can be recruited into stage of progression of the disorder. Ethnic origin influ­ keratoconus progression and only careful examination ences the incidence of keratoconus. Currently, computer-assisted toconus of 25 per 100,000 (1 in 4,000) per year for Asians, videokeratography allows detection of keratoconus at an compared with 3. For that reason, that comparative study from Britain described a fourfold greater diagnostic m ethod is almost certainly the best one for incidence of kcratoconus in Asians from the Indian subcon­ the diagnosis of keratoconus and keratoconus suspects in tinent compared to Caucasians living in the same geographic families with keratoconus* area. In a prospective study by Karimian and colleagues, 300 eyes of 150 relatives of 45 patients with keratoconus were evaluated and keratoconus was diagnosed in 21 (14%) of the apparently unaffected relatives of patients with keratoconus. Note bulging of inferior lid on downgaze conus can be more frequent than anticipated. In multifactorial disease both genetic retardation and bilateral keratoconus associated with a and environmental factors play a role in the disease patho­ significant reduction in visual acuity, recurrent febrile genesis. Monozygotic twin studies constitute an adequate seizures, and sinoatrial heart block. The higher the rate been reported in the literature of keratoconus in children of of concordance between monozygotic twins, the greater is consanguineous parents. The concordance and coworkers studied risk factors for keratoconus includ in monozygotic twins supports the evidence of heredity as a ing age, sex, race, eye rubbing, family history, mitral valve factor in the etiology of keratoconus. In cases discordant for keratoconus bing was the most significant predictor of keratoconus reading, eye rubbing and hormonal influences were sug­ using multivariate analysis (odds ratio of 6. Another study presented a case with bilateral recurrent kera- Multifactorial traits result from the interaction of multiple toconus in corneal transplants performed in a patient with genes or their products. Environmental factors play addi­ self-induced keratoconus secondary to compulsive eye tional roles in modifying these traits. Jafri and coworkers proposed have a sporadic form of the disease, there is sufficient that the microtrauma of eye rubbing by susceptible indi­ and growing evidence to suggest that keratoconus is in fact viduals injures the epithelium, leading to cytokine release, a genetic disorder. Numerous keratoconus loci indicate a myofibroblast differentiation, a change in biomechanical genetically heterogeneous condition, in which several gene forces, and thinning of corncal tissue. In that study 11 sequence found to be significantly higher in white compared to Asian variants were observed, including the previously reported keratoconic patients. In addition, three synony­ environmental risk factor triggering keratoconus in 26. In addition, two undescribed intronic The association of de novo chromosome abnormalities polymorphisms were reported. Two chromosomal rearrangements unrelated patients with keratoconus; of the four mutations have been reported in association with keratoconus. The 13q32 region isolated kcratoconus is a known locus for neocentromere formation,51resulting in chromosomal imbalances. Tetrasomy of 13q32-qter has 2p24 53 been observed, with eye abnormalities including agenesis, 3 p l4 -q i3 54 microphthalmia, iris, and choroidal colobomas. It is 13q32 45 interesting to note that recently a novel keratoconus locus has been identified at 13q32. Despite extensive study, no mutations in any genes have been identified for Linkage analysis identifies chromosomal region(s) associ­ any of these keratoconus loci. Several loci have been identified studies of keratoconus, there arc limitations that should be for keratoconus (Table 16. Since Зр 14-q 13 in a two-generation Italian family with autosomal in keratoconus subdinical forms of the disease may exist dominant keratoconus. Currently, developments in computer­ keratoconus was identified using the genome-wide scan ized vidcokcratography allow the detection of early forms approach on 5ql4. Still, some families display a specific inheritance pattern with reduced penetrance,45 which can cause problems in the interpretation of data. In a study of 133 individuals from 25 families, and using nonparametric and parametric analysis of affecteds-only, Bisceglia found several regions suggestive of linkage. This study represents the first keratoconus linkage replication study of the chromosomal region 5q21. Clinical and epidemiological features o f keratoconus: genetic and external factors in the pathogenesis of the disease. A 48-year clinical and epide­ In nearly all patients, keratoconus is an isolated sporadic m iologic study o f keratoconus. Am J O phthalm ol 1986;10l: disorder; however, in some cases it may be a sign of a syn­ 267-73. Topographic evaluation of with keratoconus, with a reported prevalence ranging relatives of patients with kcratoconus. Br | reports linking keratoconus and connective tissue diseases O phthalm ol 20D8;92:1108-11. Kcratoconus in two pairs of such as subtypes of Ehlers-Danlos syndrome, osteogenesis identical twins.

This light-gathering plant protein absorbs light eff- ciently and emits a brilliant red fuorescence generic 25mg doxepin with amex. A cell passing through a laser beam length (color) and intensity to a specifc collection tube buy doxepin 25mg with mastercard. Fluorochrome staining of cells permits absorbed light to be emitted as fuorescence cheap doxepin 10mg overnight delivery. Dim is an adjective used in fow cytometry to indicate the Forward angle light scatter permits identifcation of a cell in relative fuorescence intensity of cells being analyzed cheap doxepin 75mg online, with fow and determination of its size. If higher-angle light scat- dim representing the lowest intensity and bright designating ter is added, some specifc cell populations may also be iden- the greatest intensity of fuorescence. Light scatter measured at 90° to the laser beam and fow stream yields data on cell granularity or fne structure. Immunophenotyping is the use of monoclonal antibodies Light scatter depends on such factors as cell size and shape, and fow cytometry to reveal cell surface or cytoplasmic anti- cell orientation in fow, cellular internal structure, laser beam gens that yield information that may refect clonality and cell shape and wavelength, and the angle of light collection. This type of data is valuable clinically in aiding the diagnosis of leukemias and lymphomas through the use of a battery of B cell, T cell, and myeloid markers. Right angle light detector However, immunophenotyping results must be used only in α cell complexity conjunction with morphologic criteria when reaching a diag- nosis of leukemia or lymphoma. It is often used as a second label in fuorescence antibody Light Forward light detector techniques where fuorescein, an apple-green label, is also used. Chemiluminescence is the conversion of chemical energy into light by an oxidation reaction. A high-energy peroxide Forward scatter—diffracted light intermediate, such as luminol, is produced by the reaction Related to cell surface area of a precursor substance exposed to peroxide and alkali. Detected along axis of incident light in the forward direction The emission of light energy by a chemical reaction may Side scatter—reflected and refracted light occur during reduction of an unstable intermediate to a Related to cell granularity and complexity stable form. The apportion- Neutrophils ment of cells by this method follows the Poissonian dis- 600 tribution, which yields 37% of aliquots without any cells and 63% with one or more cells. This technique can be 400 used to estimate a certain cell’s frequency in a popula- Monocytes tion. For example, it may be employed to approximate the 200 frequency of helper T lymphocytes, cytotoxic T lympho- Lymphocytes cytes, or B lymphocytes in a lymphoid cell suspension or 0 to isolate cells for cloning in the production of monoclonal 0 200 400 600 800 1000 Forward Light Scatter antibodies. A small square of cotton, linen, or paper 600 impregnated with the suspected allergen is applied to the skin for 24 to 48 h. The development of red- ness (erythema), edema, and formation of vesicles constitutes 200 a positive test. The impregnation of tuberculin into a patch was used by Vollmer for a modifed tuberculin test. There 0 are multiple chemicals, toxins, and other allergens that may 400 450 500 550 600 650 700 Wavelength (nm) induce allergic contact dermatitis in exposed members of the population. The peak absorption is around 488 A skin test is any one of several assays in which a test sub- nm and the peak emission is around 530 nm. Skin tests have long been used to determine host hypersensitivity or immunity to a particular antigen or product of a microorganism. Examples include the 104 tuberculin test, the Schick test, the Dick test, the patch test, the scratch test, etc. A minute quantity of diluted erythrogenic toxin is inoculated 101 intradermally in the individual to be tested. The tuberculin test refers to the 24- to 48-h response to intradermal injection of tuberculin. A positive skin test implies an earlier induration within 24 to 48 h in positive individuals. Its prepa- ration parallels the extraction of old tuberculin or purifed Stormont test: A double intradermal tuberculin test. The tine test is a human tuberculin test that involves the Brucellin is a substance similar to tuberculin, but derived intradermal inoculation of dried, old tuberculin using a four- from a culture fltrate of Brucella abortus that is used to test pointed applicator that introduces the test substance 2 mm for the presence of delayed-type hypersensitivity to brucella below the surface. The Vollmer test (historical) is a tuberculin patch test The Schick test is a test for susceptibility to diphtheria. Development of redness and induration is used in a skin test for cell-mediated immunity against the within 24 to 36 h after administration constitutes a positive microorganism in a manner analogous to the tuberculin skin test if it persists for 4 d or longer. Neither redness nor capsulatum that is injected intradermally, in the same manner induration appears if the test is negative. The dye intercalates between the base pairs to stain double-stranded nucleic acids. For this test, 150 toxin that has been diluted and heated to 70°C for 15 min is injected intracutaneously. Heating destroys the toxin’s abil- 100 ity to induce local tissue injury; however, it does not affect the components of the diphtheria bacilli or of the medium 50 that might evoke an allergic response in the individual. S G2/M If the size and duration of the reaction at the injection site 0 in the control approximates the reaction in the test arm, the 0 200 400 600 800 1000 result is negative. A positive by fow cytometry permits the percentage of cells in each phase of Schick reaction suggests that diphtheria immunization is the cell cycle to be determined. Longpass Shortpass Bandpass 460 500 540 460 500 540 460 500 540 The Casoni test is a diagnostic skin test for hydatid disease in humans induced by Echinococcus granulosus infection. In sensitive individuals, a wheal and fare response develops within 30 min following intradermal inoculation of a tape- worm or hydatid cyst fuid extract. The ticular fuorescent dye is optimized by placing a flter in front of multiple needles advance 2 to 3 mm into the skin. Also called the detector which allows a narrow range of wavelengths to pass tine test. The Montenegro test is a diagnostic assay for South American leishmaniasis induced by Leishmania brasilien- Laser sis. The intracutaneous injection of a polysaccharide antigen derived from the causative agent induces a delayed hypersen- sitivity response in the patient. It was developed by Robert Koch for use in tuberculin skin tests nearly a century ago. Time Romer reaction (historical): Romer in 1909 described erythematous swelling following intracutaneous injection of Laser diphtheria toxin in small quantities. The Lr is the occurs when the particle is in the center of the beam, and the maxi- smallest amount of toxin which, after mixing with one unit of mum amount of scatter is achieved. As the particle leaves the laser, antitoxin, will produce a minimal skin lesion when injected the pulse comes back down to the baseline. However, the procedure is not without danger, as even individual by intradermally injecting the antibodies, which a scratch test with highly diluted penicillin preparations in become anchored to mast cells through their Fc receptors. This is followed hours or even days later by intravenous injection of antigen mixed with a dye such as Evans Blue. Vascular permeability factors act on the vessels to permit Sheath tube plasma and dye to leak into the extravascular space, forming Vent tube a blue area that can be measured with calipers. The lymphocytes are gated, markers are set using a two-color isotype control, then subse- Forword-angle quent immunofuorescence analyses of the remaining fles are light scatter detector completed. Histamine-release assays Cells sorted may be informative in urticaria, asthma, and atopic derma- titis patients. By contrast, the cover slip abrasion of the skin which is then covered with a glass slide.

Presently buy 25mg doxepin free shipping, India is the epicenter of metabolic disorders Scientist contributed and cardiovascular risks buy doxepin 10 mg without a prescription. A physiologist knows that regular The Nobel Prize in Physiology or Medi­ physical exercises with a good eating habit retard the pro­ cine 2014 was divided buy discount doxepin 10 mg on-line, one half awarded cess of atherosclerosis and oxidative stress that prevents to John O’Keefe cheap 25 mg doxepin free shipping, the other half jointly to occurrence of cardiovascular and cerebrovascular acci­ May-Britt Moser and Edvard I. Moser “for dents, many metabolic diseases, and retards degeneration their discoveries in Neurophysiology that constitute a positioning system in the and decay. They studied the movements of style himself for his personal health but also encourages rats and signals from nerve cells in the others to adapt to such a life. In 1971 he discovered that when a rat was at a certain location We give emphasis on preventive and promotive in a room, certain cells were activated, John O’Keefe aspects of health, which will be more promulgated by and that when the rat moved to another (Born: 18 November 1939, physiologists and will be established as preventive and location, other cells became activated. Research in basic and clinical physiology has contributed The inventions and discoveries in medical science and advances in medicine are mainly due to research contri­ to enormous growth of clinical medicine. Therefore, from its inception in reveals the mechanism and pathophysiology of diseases, 1901, the Nobel Prize in the field of medical sciences has whereas clinical research unravels the management and been designated as ‘Nobel Prize in Physiology’ or ‘Physio­ prevention of diseases. The collaborative starting from Emil Adolph Von Behring (1901), Sir Ronal research between physiology and clinical departments Ross (1902), Prof. Ivan Petrovich creates avenues for clinical research, ignites research Pavlov (1904) to Dr. Edward (2010), John O’Keefe interest in clinicians, improves research outlook, attracts (2014) are physiologists or physicians who have worked in extramural financial support from various funding agen­ medical physiology or medical fields linked to physiology. The ultimate Etiopathogenesis of the diseases and physiological basis of objective of a medical research should be to reduce management are elucidated through research discoveries suffering, facilitate healing, cure the ailment, prevent the in physiology. Physiologists 6 Section 1: General Physiology should make efforts for larger participation of physician systems in the body work inter­dependently for maintain­ in research and ensure research to be more applied and ing an effective homeostasis. In this process, no organ­system Physiology for Ethics is big or small, as contribution of each organ leads to ful­ fillment of the primary objective of supplying blood, oxy­ Physiology teaches the ethics and values of life. Derangement of any ate judgment and application of knowledge for healing of these participating systems leads to development of the human suffering is true physiology. We should understand that this basic practice was devised by Hippocrates, an ancient Greek principle of a structured system of working is essential for physician. Hippocrates was a teacher at the School in the creating a healthy environment and harmonious progress Health Temple at Cos, Greece. Inner progress is achieved by improvement Scientist contributed in body physiology. For example, practice of pranayama ‘Hippocratic Oath’ with modification is as not only improves breathing capacity and oxygenation of follows….. In human body, there I will practice my profession with conscience are subtle physical centers such as spinal­cord center, and dignity; heart center, throat center, pineal center, etc. Focusing the consideration; I will respect the secrets that are confided in concentration on these centers releases the energy from me, even after the patient has died; the center that helps in purifying and enriching the mind I will maintain by all the means in my power, Hippocrates and body. A My colleagues will be my sisters and brothers; physiologist having the holistic knowledge of working of I will not permit considerations of age, disease or disability, creed, ethnic the body and with true aspiration for progress is privileged origin, gender, nationality, political affiliation, race, sexual orientation, for acquiring higher knowledge, force and consciousness. Thus, to study human physiology is an opportunity, to become a physiologist is a privilege, to encourage others Physiology for Integral Knowledge to practice physiological means of health-promotion is a Physiology provides the knowledge to gain and maintain unique occasion, and to practice physiology for integral good health. Knowledge in physiology is fundamental in understanding all other subjects in medicine. Scientist contributed Leonardo da Vinci (1452–1519) ‘The Great Lady Anatomy’ painting of Leonardo da This picture of Leonardo has a very close resemblance with Sri Vinci. Unicellular vs Multicellular Organisms Leonardo left extraordinary drawings of physiological interest on body functions, muscle actions, and on heart valves, papillary muscles of Unicellular Organisms ventricle and hydraulic operations in the cardiovascular systems. He had many In unicellular organisms such as ameba, the processes that paintings that are widely acknowledged and appreciated. Among them, sustain life are carried out by a single cell interacting with commonly known are the paintings of Mona Lisa, The Last Supper and the environment around it. The painting of ‘great lady anatomy’ depicting the internal anatomical structures with details of some of the internal nisms have simpler organization: organs in a female (given below), is the first kind of scientific picture on 1. As they are surrounded by fresh water, the O2 and the human anatomy and physiology. The presence of contractile proteins in the cell enables Musculoskeletal system: This system enables the body it to move by pseudopodia away from noxious stimuli adopt posture against gravity, and move about in the or towards food, and facilitates the movements in environment. Reproduction is achieved by simple cell division, and digest, and absorb nutrients, water and electrolytes, and no meeting of sexes is involved. Blood contains cells further organized into functional systems meant for per­ that take part in body defence mechanisms. Cardiovascular system: The heart is the central pump that generates pressure for flow of blood in the blood ves­ Major Physiological Systems sels that serve as vehicular system for blood to flow. The body systems can be broadly divided into: Urinary system: The urinary system consisting mainly 1. The systems to support the body for locomotion and a major role in maintaining the constancy of the composi- external works. The movements are performed by the tion of the fluid immediately surrounding each cell (the muscles and bones (the musculoskeletal system), and extracellular fluid), which is referred to as the internal the nerves supplying the skeletal muscles. The systems for internal communication, integration Endocrine system: Hormones secreted by various and regulation: The communication between the cells endocrine glands serve mainly regulatory functions. They and organs and control of organ systems is achieved by the circulating blood, gaseous exchange at tissue control metabolism, growth, development and reproduc­ level through respiration, the hormones secreted from tive functions. The major objectives of this systemic organization are to provide nutrition and energy for carrying out external works, provide support to the body for locomotion, execution and protection from environment, to control body activities, and to reproduce the offspring for continuation of the species. Name the scientist who gave the concept of milieu interior, and the scientist who coined the term homeostasis. Understand that dysfunctions are mainly due to failure of homeostatic regulations. Concept of Homeostasis 42 liters, of which 28 liters is present inside the cells and 14 liters is present outside the cell. The electrolyte com- Homeostasis is defined as the maintenance of constancy position of the extracellular fluid roughly resembles that of the internal environment of the body. In the nineteenth of seawater, which is rich in sodium and chloride, and poor century, Claude Bernard, a French physiologist, was first in potassium. The intracellular fluid contains more potas- to introduce the concept of milieu intérieur, which means sium and less sodium-chloride. He had following Scientist contributed remarkable observations: Claude Bernard, a student of François 1. The volume and composition of the fluid are main- Magendie (1783–1855) was a genius and great tained constant, independent of the changes in the French physiologist of all time. He suggested that the ability to regulate internal envi- sized the concept of integrated interrelation ronment is the major reason for humans and animals between the parts of a living being. He to live a normal life in spite of changes and challenges Claude Bernard demonstrated the glycogenic function of the (1813–1878) imposed on them by the external environment. He noted the difference between intracellular and juice, vasomotor mechanism (sympathetic control) for regulation of blood flow. He was the first to provide satisfactory explanation for the mechanism of action of any drug.

It is stored in the producing cells in a pre- be a cause of increased susceptibility to bacterial infection formed state cheap doxepin 10mg amex. The chemotactic cytokine buy doxepin 25 mg fast delivery, neutrophil-activat- tions with antigen and parallels the release of histamine 75 mg doxepin sale. Flow cytome- secreting a large variety of chemical mediators from storage try and nitroblue tetrazolium reduction can be used to access neutrophil activation purchase doxepin 10mg without prescription. Leukocidin is a bacterial toxin produced especially by staph- ylococci that is cytolytic. It is toxic principally for polymor- phonuclear leukocytes and, to a lesser extent, for monocytes. It contains an F and an S component that combine with the cell membrane causing altered permeability. Basophilic is an adjective that refers to an affnity of cells or tissues for basic stains leading to a bluish tint. In various clinical states associated with hypoxia, the adenosine level increases fve- to tenfold, suggesting that it may play a role in the release of mediators. The incubation of mast cells with adenosine does not induce the release of mediators. However, by preincubation with adenosine and subsequent challenge with a mediator-releasing agent, the response is markedly enhanced. Exocytosis refers to the release of intracellular vesicle con- sites in their granules upon stimulation. Their to the plasma membrane with which they fuse to permit the anatomical location at mucosal and cutaneous surfaces and contents to be released to the external environment. They include immunoglobulin released from plasma cells and mast can be identifed easily by their characteristic granules, cell degranulation, which releases histamine and other pharma- which stain metachromatically. The size and shape of mast cological mediators of anaphylaxis to the exterior of the cell. On their surfaces, they have Fc receptors for from conditions within the organism; derived externally. Mast cells also contain proteolytic enzymes such as plasmin and also hydroxylase, β glucuronidase, phosphatase, and a high uronidase inhibi- tor, to mention only the most important. Some substances released from mast cells are not stored in a preformed state but are synthesized following mast cell activation. These represent secondary mediators as opposed to the preformed primary mediators. Mast cells of the gastrointestinal and respiratory tracts that contain chondroitin sulfate produce leukotriene C4, whereas connective tissue mast cells that contain heparin produce prostaglandin D2. It is produced through the action of adenylate cyclase on ade- nosine triphosphate. The cell has macrophages, as suggested by fewer surface receptors, cyto- a reniform nucleus with delicate lace-like chromatin. It is actively phagocytic and phagocytic, and constitute 2 to 10% of the total white blood plays a signifcant role in antigen processing. The monocyte in the blood circulation numbers are elevated in both benign and malignant condi- is 15 to 25 μm in diameter. It is comprised provides nonspecifc immunity and is dependent on the activ- of a two-chain, i. It plays a physiologic role in wound repair and pro- A blast cell is a relatively large cell that is greater than 8 μm cesses requiring accumulation of connective tissue. It also has marrow giant cells that are multinuclear and from which a kinase insert in the cytoplasm. The receptor protein must blood platelets are derived by the breaking up of membrane- undergo a conformational change for signal transduction. Platelets function in blood clotting by releasing It is found on megakaryocytes and platelets. Whereas red marrow is hemopoi- etic and is present in developing bone, ribs, vertebrae, and long bones, some of the red marrow may be replaced by fat and become yellow marrow. In mammals, the bone marrow is the site of B cell development and the source of stem cells from which T lymphocytes develop following migration to the thymus, where they mature. A stromal framework com- prised of fbroblasts, fat cells, endothelial cells and fbers support the developing hematopoietic cells. Bone marrow transplants are useful in the treatment of aplastic anemia, leukemias, and immunode- β lysin is a thrombocyte-derived antibacterial protein that is fciencies. Patients may donate their own marrow for subse- effective mainly against Gram-positive bacteria. It is released quent bone marrow autotransplantation if they are to receive when blood platelets are disrupted, as occurs during clotting. Lymphoid system refers to the lymphoid organs and the A stromal cell is a cell of nonhematopoietic origin that facil- lymphatic vessels. Stromal cells and their organization are fully as complex as the cells whose development they regulate. For example, stromal cells of the thymus have been the best characterized with respect to their role in T lymphocyte maturation. Tonsil Adenoids are mucosa-associated secondary lymphoid tis- Tymus sues located in the nasal cavity. Spleen Each lobe is subdivided by prominent trabeculae into inter- connecting lobules and each lobule comprises two histologi- cally and functionally distinct areas—cortex and medulla. Lymph The cortex consists of a mesh of epithelial–reticular cells nodes enclosing densely packed large lymphocytes. The epithelial cell component is of endoder- Bone mal origin; the lymphoid cells are of mesenchymal origin. The prothymocytes, which migrate from the bone marrow to the subcapsular regions of the cortex, are infuenced by this figure 2. When cells become renegade and resist apop- tosis, as in cancer, the outlaw cells create a dire situation for the organism. Mistiming of, or errors in, apoptosis can Hassall’s have devastating consequences on development. Apoptotic corpuscle fdelity is, therefore, critical to the well-being of an organ- ism. The process of apoptosis (programmed cell death) is regulated by signals generated when cytokines bind to their receptors. The process of education is exerted by hormonal substances produced by the thymic epithelial cells. The cortical cells pro- Apoptosis proceeds through cleavage of vital intracellular liferate extensively. Caspases are inactive until a signal initiates activa- The surviving cells acquire characteristics of thymocytes.

Retropharyngeal Abscess A short trial of antibiotic therapy is often indicated before any decision is made to proceed with surgical drainage of the abscess buy cheap doxepin 10mg online. Laryngeal Papillomatosis The laryngeal papilloma is the most common benign tumor of the larynx during childhood order doxepin 10mg with amex. Adjunctive treatment with alpha-interferon has been shown to reduce the relapse rate in both children and adults discount doxepin 25mg on line. Patients with vocal cord paralysis may be able to phonate because the thyroid muscle may serve as a tensor of the vocal cords and is not affected in most cases of vocal cord paralysis doxepin 10 mg cheap. A neurological disorder such as brain stem compression by an Arnold Chiari malformation should be considered when acquired vocal cord paralysis is evaluated among pediatric patients. If a specific lesion may be addressed medically or surgically, such therapy should be undertaken. Occasionally, respiratory embarrassment is of sufficient magnitude to merit surgical intervention with an external arytenoidopexy or a tracheostomy. A recent meta analysis suggests that an external arytenoidopexy and an external arytenoidectomy are equally effective and that the two combined are significantly more effective than carbon dioxide ablative procedures. Intrathoracic Mass Lesions Causing Respiratory Obstruction Rapid evaluation and aggressive medical therapy is needed. Endotracheal intubation is indicated only if respiratory function becomes severely compromised. Trauma Post-extubation Stridor Although most cases of postextubation stridor are caused by laryngeal edema, when this problem persists, other causes should be sought. Racemic epinephrine, delivered by aerosol nebulizer, probably works by stimulation of alpha adrenergic receptors causing vasoconstriction, which in turn, reduces tracheal edema. Racemic epinephrine works rapidly, so improvement, when it occurs, should be observed within a few minutes of completion of therapy. Although data from animal studies suggest that corticosteroid use at the time of extubation may reduce tracheal edema, inflammation and capillary dilatation, several human studies have failed to show reduction in postextubation stridor after corticosteroid use. In most cases postextubation stridor is self limited but occasionally reintubation may be necessary. It has been reported that subglottic stenosis occurs infrequently after nasotracheal intubation with a proper–sized endotracheal tube. It is thought that nasotracheal intubation may reduce the movement of tube within the trachea and diminish tracheal injury. Mild subglottic stenosis may be treated expectantly but more severe forms must be treated surgically. Foreign Body Aspiration Foreign bodies are removed from the tracheobronchial tree with a bronchoscope. Occassionally bronchoscopic extraction is unsuccessful, and a pulmonary lobectomy is required. Traumatic Injury to the Airway Most commonly these are blowout injuries that usually occur near the carina, and most involve mainstream bronchi. Small tracheobronchial disruptions may be managed conservatively, most of these lesions require surgical repair. Angioedema If this should involve the soft tissues of upper respiratory tract, laryngeal obstruction may result. Occasionally endotracheal intubation is warranted in view of severe respiratory embarrassment. The anatomical site of presentation to allow for stratification of airway risk and planning of appropriate triage for airway intervention. The basic pathophysiology is partial obstruction of airways which may be congenital or acquired and may lead to respiratory failure. The classical clinical presentation is snore, stertor and stridor and symptoms and signs of respiratory failure. The history is diagnostic in 80-85% cases and a plain lateral film of neck is the most important diagnostic investigation to clinch the diagnosis. First stabilize the patient and then perform detailed examination and investigations. Do not send the patient for X-ray or other investigations without an accompanying competent person and resuscitation equipments. Surgery for pediatric vocal cord paralsis: A meta-analysis, Otolaryngol Head Neck Surg 2002;126:349-55. Stridor: intracranial thology, causing postextubation vocal cord paralysis, Pediatrics 1991;39-43. Evaluation of risk factors for laryngeal edema after tracheal extubation in adults and its prevention by dexamethasone. A placebo-controlled, double-blind, ulticenter study [see comments], Anesthesiology 1992;77:245-51. Bacterial tracheitis: Report of eight new cases and review, Rev Infect Dis 1990;12:729-35. Bacterial tracheitis among children hospitalized for severe obstructive dyspnea, Pediatr Infect Dis J 1990;9:293-95. Efficacy of helium-oxygen mixtures in the management of severe viral and post-intubation croup, Canadian Anaesth Soc J 1979;26:206-12. Airway endoscopy in the diagnosis and treatment of bacterial tracheitis in children, Int J Pediatr Otorhinolaryngo 1993;I27:147-57. Routine use of dexamethasone for the prevention of postextubation respiratory distress, J Perinatol 1989;9:287-90. The use of balloon- expandable metallic stents in the treatment of pediatric tracheomalacia and bronchomalacia, Arch Otolaryngol Head Neck Surg 1999;125:203-07. Molecular analysis of resistance to interferon in patients with laryngeal papillomatosis, Cytokines Cell Mol Ther 1999;5:79-85. Surgical implications of bronchopulmonary dysplasia, Pediatr Surg 22:1132- 19S7;1136. A comparison of nebulized budesonide, intramuscular dexamethasone, and placebo for moderately severe croup, N Engl Med 1998;339:498-503. Blunt pediatric laryngotracheal trauma: case reports and review of the literature, Am J Emerg Med 1994;12:207-11. Steroid treatment of laryngotracheitis: a meta-analysis of the evidence from randomized trials, Pediatrics 1989;83:683-93. Pericardial fl”p,aor- topexy: an ea~and sate technique In the treatment of tracheomalacia. Retropharyngeal abscess management in children: current practices, Otolaryngol Head Neck Surg 1999;121:398-405. Effectiveness of continuous positive airway pressure in the treatnent of bronchomalacia in infants: A bronchoscopic documentation, Crit Care Med 1986;14:125-27. Tracheobronchial abnormalities in infants with bronchopulmonary dysplasia, Pediatr 111:779. Epiglottis: Incidence of extraepiglottis and pneumonia: Report of 72 cases and review of the literature, Pediatrics J 1976;58:526-31. Topical mitomycin as an adjunct to choanal atresia repair, Arch Otolaryngol Head Neck Surg 2002;12S:39S-400. Central vocal cord paralysis and paresis presenting as laryngeal stridor in children, Laryngoscope 1990;100:10-13.