Baha M. Sibai MD

• Professor
• Department of Obstetrics & Gynecology
• University of Cincinnati College of Medicine
• Cincinnati, Ohio, USA

The phenotypically more severe lamellar ichthyosis has proved to be genetically distinct diabetes type 1 quality of life buy amaryl without prescription, characterized by a defect in the transglutaminase-1 gene (Russell et al diabetes medications that cause weight gain buy generic amaryl, 1995) diabetes quiz questions buy 4mg amaryl with visa. Causes A majority of cases are inherited in an autosomal recessive fashion diabetic dinner recipes buy amaryl 2 mg without a prescription, but an autosomal dominant form of lamellar ichthyosis also has been described diabetes type 2 underweight order discount amaryl line. Russell et al (1995) identified a common locus of genetic mutations identified in several families with recessive lamellar ichthyosis neurological diabetes in dogs discount 4mg amaryl. The linked defects, located on chromosome 14, result in production of abnormal transglutaminase-1. This enzyme normally promotes cross-linking of intracellular proteins in the stratum corneum during terminal differentiation (Huber et al, 1995). New research has revealed genetic heterogeneity with two other loci on chromosomes 2 and 19. Clinical Findings these conditions are characterized by congenital erythroderma and a varying degree of generalized scaling. Secondary cutaneous infections with bacteria, yeasts, and dermatophytes are common complications. Prognosis and Treatment the same management principles recommended for neonates presenting with the collodion baby phenotype can be applied to infants with erythroderma, although their neonatal course is marked by fewer complications. The mainstay of therapy for children with lamellar ichthyosis is the use of topical emollients and keratolytic agents. Successful treatment with topical calcipotriol has been described previously (Delfino et al, 1994; Russell and Young, 1994). Any topically applied agent will be transcutaneously absorbed to a much higher degree than through normal skin; dosing must be monitored carefully (Abdel-Magid and el-Awad, 1994; Lucker, 1994). Ichthyosiform Syndromes Several syndromes manifesting in the neonatal period have ichthyosis as a major feature. Signs of the disorder are present at birth in one fifth of affected infants; 85% develop skin changes by 3 months of age. The characteristic cutaneous finding is coarse, brownish scaling, most prominent on the neck and extensor extremities. Extracutaneous manifestations include hypogonadism and cryptorchidism, present in up to 25% of affected males. Severely affected males may have short stature and mental retardation, a variant that has been referred to as Rud syndrome. Characteristic corneal opacities are seen in affected males and heterozygote females, but usually not until late childhood or adolescence. Light microscopic and ultrastructural findings in skin biopsy specimens are unremarkable. The genetic abnormality has been localized to the distal short arm of the X chromosome (Xp22. The diagnosis is supported by finding reduced or absent enzymatic activity of fatty aldehyde dehydrogenase from cultured skin fibroblasts, amniocytes, or chorionic cells (van den Brink, 2004). Orthopedic abnormalities (including asymmetrical shortening of the long bones) prompt radiologic evaluation that reveals chondrodysplasia punctata, characterized by punctate calcifications of the epiphyses and cartilage. Autosomal dominant, autosomal recessive, and X-linked dominant forms have been reported, and variable expressivity may reflect different patterns of X-inactivation (Ausavarat et al, 2008). Netherton Syndrome/Ichthyosis Linearis Circumflexa Netherton syndrome is a rare, autosomal recessive condition. It often manifests at birth as ichthyosiform erythroderma with flexural accentuation. The characteristic migratory, polycyclic lesions with a peripheral doubleedged scale, referred to as ichthyosis linearis circumflexa, do not appear until after 2 years of age. The syndrome is characterized by congenital ichthyosis, hair shaft defects (principally trichorrhexis invaginata), and atopic features (pruritus, hay fever, facial angioedema, and elevated immunoglobulin E), but until the advent of genetic testing, diagnosis in affected children often was not possible for the first several years of life (Judge et al, 1994b). This distinctive pattern of ichthyosis linearis circumflexa can also manifest as an isolated cutaneous condition. This steroid dehydrogenase functions upstream of the sterol isomerase, which is defective in X-linked dominant Conradi syndrome in the cholesterol biosynthesis pathway. Keratitis-Ichthyosis-Deafness Syndrome Keratitis-ichthyosis-deafness syndrome is a rare disorder of autosomal dominant inheritance (Wilson et al, 1991) that consists of congenital ichthyosiform erythroderma with characteristic pebbly palmoplantar thickening; abnormalities of the nails, hair, and teeth; vascularizing keratitis; and sensorineural deafness (Messmer et al, 2005). Vacuolated leukocytes from lipid droplets, seen on peripheral smear, help to establish the diagnosis (Judge et al, 1994a). This disease is characterized by an intracellular accumulation of triacylglycerol droplets. A major component of these granules, profilaggrin, is reduced or undetectable in the skin of affected persons (Nirunsuksiri et al, 1995). Recent molecular genetic investigations of the filaggrin gene have revealed the R501X mutation in European patients (Smith et al, 2006) versus the S2554X and 3321delA mutations in Japanese patients (Nomura et al, 2007). Erythrokeratodermia Variabilis Erythrokeratodermia variabilis also is a rare type of ichthyosis that can manifest in infancy. It usually is inherited in an autosomal dominant fashion, although a probable case of autosomal recessive inheritance has been reported (Armstrong et al, 1997). Affected persons have transient migratory areas of discrete macular erythema and fixed hyperkeratotic plaques. A mutation in the connexin 31 gene, which codes for the gap junction protein 3, was reported as the cause of erythrokeratodermia variabilis, but a subsequent case did not have a mutated connexin 31 gene (Wilgoss et al, 1999). Studies have confirmed genetic heterogeneity in erythrokeratodermia variabilis affected by the intercellular communication mediated by both connexin 31 and connexin 30. More severely affected patients have a constellation of features that has been referred to as Tay syndrome. Diagnosis is supported by detection of characteristic alternating light and dark bands within the hair shaft on examination under polarizing microscopy. Further analyses of hair and nails reveal a decrease in the sulfur-rich proteins (Itin and Pittelkow, 1990). Prognosis and Treatment for the Ichthyoses It is important to distinguish among the various forms of ichthyosis so that the physician can offer a prognosis and appropriate genetic counseling to the family. The prognosis is related to the severity of the condition and the type of ichthyosis. The clinical signs and pedigree data sometimes provide sufficient information to make a diagnosis. Unfortunately, a period of observation beyond the first 4 weeks of life is frequently needed, and laboratory confirmation of the correct diagnosis requires specialized studies (Holbrook et al, 1993). Standard therapy begins with topical care designed to hydrate the stratum corneum. Frequent, brief baths in tepid water should be followed immediately by liberal application of a bland ointment or cream emollient, such as petrolatum, Aquaphor, or Eucerin. Emollients containing keratolytics such as urea (10% to 25%), salicylic acid, propylene glycol, and -hydroxy acids also are effective but are recommended only after infancy because of the risk of toxicity associated with increased percutaneous absorption. Topical calcipotriol has been safe and effective as an agent for short-term therapy in adults with a variety of ichthyoses (Kragballe, 1995). Primary Cutaneous Ichthyoses Primary cutaneous ichthyoses are a group of familial disorders that have no prominent extracutaneous manifestations. Ichthyosis Vulgaris Ichthyosis vulgaris is the most common form of ichthyosis, with an estimated incidence of 1 in 250 births. Affected persons often have coexisting keratosis pilaris and atopic dermatitis (Rabinowitz and Esterly, 1994). All races are affected; estimates of gene frequency vary depending on the population under consideration. As with many genetic disorders, the incidence of affected persons is increased in certain racial isolates in which there is a high percentage of consanguineous marriages (Witkop et al, 1989). The characteristic pigmentary changes are due to a spectrum of biochemical defects that interfere with melanin synthesis or transport. Three types of oculocutaneous albinism have been mapped to specific chromosomal regions that code for regulatory proteins in the transport and synthesis of tyrosine, a precursor in the melanin synthesis pathway (Oetting and King, 1994). Tyrosinase is a copper-containing enzyme that catalyzes the two rate-limiting steps in the melanin biosynthetic pathway, and patients with homozygous mutations have a lifelong inability to produce melanin in the eyes, hair, and skin. Recent findings suggest that the P protein has a major role in modulating the intracellular transport of tyrosinase (Toyofuku et al, 2002). The encoded protein functions to maintain stability of tyrosinase (Sarangarajan and Boissy, 2001). Persons with tyrosinase-positive albinism accumulate pigment with increasing age, decreasing the risk of sun-induced complications. The National Organization for Albinism and Hypopigmentation can provide additional information and support for affected families (see Box 98-2). Histologic studies show an absence of melanocytes in the depigmented areas of skin and normal melanocytes in the uninvolved skin (Jimbow et al, 1975). The molecular basis of the disease has been identified as a defect of the C-kit protooncogene. This gene encodes the cell surface receptor transmembrane tyrosine kinase for an embryonic growth factor. When c-kit function is reduced, the migration of melanocytes is curtailed during embryogenesis (Tomita, 1994). Other areas of the ventral skin may also be devoid of pigment, including the central forehead, chin, and trunk, with relative sparing of the dorsal surface. Oculocutaneous albinism should be distinguished from simple ocular albinism, which has sex-linked, autosomal dominant, and autosomal recessive forms. Diagnosis Piebaldism is readily differentiated from albinism, in which the absence of pigment is uniform. Vitiligo may have a similar appearance, but it is not congenital and usually does not remain fixed. Occasional families may have associated defects such as sensorineural deafness and mental retardation (Telfer et al, 1971). Clinical Findings Affected infants, regardless of their familial skin type, have a decrease in skin pigment. Associated abnormalities may include hemorrhagic diathesis (Hermansky-Pudlak syndrome), small stature, and defective mentation. Deafness can occur in association with oculocutaneous albinism and with a number of other pigmentary disorders (Konigsmark, 1972). Prognosis and Treatment the leukoderma and white forelock remain constant throughout life. Prognosis and Treatment the most significant associated problems are visual impairment and the increased risk of sun-induced carcinogenesis. The safest approach for infants is zinc oxide Causes Several distinct subtypes of aplasia cutis have been described based on the distribution, mode of inheritance, and associated abnormalities (Frieden, 1986). Aplasia cutis may overlie embryologic malformations such as meningomyelocele and spinal dysraphia, omphalocele, and gastroschisis (Frieden, 1986; Sybert, 1985). In addition, scalp defects are associated with specific teratogens (methimazole, intrauterine varicella, herpes simplex) and malformation syndromes (trisomy 13, Johanson-Blizzard syndrome, amniotic band disruption complex, and the ectodermal dysplasias). Extensive aplasia cutis has been associated with elevated -fetoprotein in maternal serum and amniotic fluid (Gerber et al, 1993). Basically, it is a phenotypic physical finding signifying disruption of the skin in utero and is attributable to any of a number of causes. Findings of a twin fetus papyraceus or a placental infarct have suggested vascular thrombosis as a cause in infants with lesions on the trunk and limbs (Levin et al, 1980). The defects extended to the subcutaneous tissue and healed in 3 weeks with the formation of thin, white atrophic scars. Clinical Findings the defect is usually along the midline of the scalp in the parietal or occipital area. Multiple defects, particularly those on the trunk and extremities, may be strikingly symmetric in distribution (Levin et al, 1980). These defects can be complicated by meningitis, hemorrhage (which can be fatal), or venous thrombosis. Prognosis and Treatment Cutaneous and bony lesions can heal spontaneously over a period of weeks to months. Patients with larger and deeper lesions must be observed for the possibility of a complicating meningitis. Lesions that fail to heal or produce cosmetically unacceptable scars can be excised with primary closure (Kosnik and Sayers, 1975). The vesiculobullous phase manifests at birth and generally lasts for several months. The infant is otherwise well, although markedly elevated leukocyte counts and peripheral eosinophilia with as much as 79% eosinophils may be associated (Berlin et al, 2002). The vesicular phase evolves into a verrucous phase, in which warty lesions appear in roughly the same distribution as the blisters, but are most pronounced on the hands and feet. The pigmentary lesions usually fade in later years and may disappear by adulthood. Surviving females are mosaics, whereas most hemizygous males do not survive embryogenesis. B, Whorled pigmentation developing on the trunk of a 1-month-old infant who still has inflammatory lesions on the limbs. Fourth-stage lesions, seen in some affected women, consist of hypopigmented, atrophic, anhidrotic streaks, usually localized to the legs (Moss and Ince, 1987). A few infants have been reported who manifested additional defects, such as skeletal anomalies, dislocation of the hips, and intrauterine growth restriction (Sakati et al, 1983).

Dog hookworm infestation classically causes ileocolonic disease; stool studies are usually negative but patients will typically respond to empiric mebendazole (100 mg twice daily for 3 days) diabetes mellitus type 2 quiz 3 mg amaryl sale. Novel radiographic (a) and hyperenhancement of the gastric mucosa from eosinophilic gastritis blood sugar 78 discount amaryl 3mg online. Note the dense "sheet-like" configuration of the eosinophils within the submucosa blood sugar journal template buy amaryl 3mg on line. Thickened gastric or small-intestinal folds with or without nodules may be present; the differential diagnosis of enlarged small-bowel folds includes Whipple disease blood sugar jumping around buy amaryl 3 mg with visa, amyloid diabetes 2 symptoms mayo clinic cheap amaryl 4 mg online, lymphoma diabetic polyneuropathy purchase amaryl with american express, paraproteinemia, and intestinal lymphangiectasia. If endoscopic biopsies are negative but there remains a high level of clinical suspicion, then full-thickness laparoscopic biopsies can be considered. Biopsies should be sent for histopathology to evaluate for the degree of eosinophilic infiltration. The mainstay of therapy for patients with significant symptoms, such as obstruction or malabsorption, continues to be steroids. The largest natural history study to date followed 43 cases for a median of 13 years and found that approximately 40% had a single flare, while 40% relapsed and 20% had a more chronic course [23]. For refractory cases where the patient cannot be tapered off oral prednisone, transition to budesonide has been reported as a possible alternative [27]. Therapy: r Mild disease may be monitored or symptomatically managed with dietary exclusions, as some cases resolve spontaneously. Zur Kenntnis der allegischen Affektioner desima Verdauungskanal von Standpunkt desima Chirurgen aus. Eosinophilic gastroenteritis: a clinicopatholical study of patients with disease of the mucosa, muscle layer, and subserosal tissues. Eosinophilic gastroenteritis: clinical manifestations and morphologic characteristics, a retrospective study of 42 patients. Significance of eosinophil and mast cell counts in rectal mucosa in ulcerative colitis: a prospective controlled study. Intraepithelial eosinophils in endoscopic biopsies of adults with reflux esophagitis. Eotaxin: a potent eosinophil chemoattractant cytokine detected in a guinea pig model of allergic airways inflammation. Allergic proctitis and gastroenteritis in children: clinical and mucosal biopsy features in 53 cases. Radiographic features of eosinophilic gastroenteritis (allergic gastroenteropathy) of childhood. Oral administration of cromolyn in a patient with protein-losing enteropathy, food allergy, and eosinophilic gastroenteritis. Subserosal eosinophilic gastroenteritis treated efficaciously with sodium cromoglycate. Use of montelukast as steroid sparing agent for recurrent eosinophilic gastroenteritis. At upper endoscopy, there is erosive esophagitis in the distal esophagus and undigested foods in the stomach. Gastric retention after 2 hours is 48%, which is normal, but after 4 hours it is 32%, which is delayed. A diagnosis of small intestinal bacterial overgrowth is made, with impairment of small-bowel motility. Inflammatory Myopathies Inflammatory myopathies consist of a heterogeneous group of acquired disorders, including polymyositis, dermatomyositis, and inclusion-body myositis. Polymyositis and dermatomyositis are characterized by proximal muscle weakness, with difficulty lifting the arms, climbing steps, and arising from chairs. The diagnosis of inflammatory myopathy is based on elevated muscle enzymes, electromyography, and muscle biopsy. Dysphagia is progressive in patients with inclusion body myositis and may lead to aspiration pneumonia [11]. Prompt diagnosis of inflammatory myopathy is important, because it is a treatable condition [12, 13]. The Connective-Tissue Diseases the main features of connective-tissue diseases affecting the esophagus and stomach are listed in Table 25. In the later stages, there are extensive collagen infiltration in the lamina propria toward the muscularis mucosa in the esophagus and stomach. Patients with dysphagia are more Practical Gastroenterology and Hepatology Board Review Toolkit, Second Edition. It can present as a primary disorder or associated with other connective-tissue disorders. It is believed that the absence of saliva, acting as a lubricant, may lead to impaired solid bolus transit through the esophagus. Salivary gland dysfunction may contribute to symptoms of dysphagia or impaired acid clearance. Endocrine and Metabolic Diseases the main features of endocrine and metabolic diseases affecting the esophagus and stomach are listed in Table 25. Diabetes Mellitus Diabetes affects multiple levels in the neuromuscular motor and sensory control of the esophagus and stomach. The pathology of diabetic gastroparesis consists of demyelination of the vagus nerve, loss of parasympathetic and sympathetic fibers, and degeneration of the interstitial cells of Cajal in the enteric nervous system. The clinical presentation of diabetic gastroparesis is heterogeneous (see Table 25. The presence of delayed gastric emptying does not always imply a diagnosis of gastroparesis. This may explain why the severity of delayed gastric emptying, a measurement of motor dysfunction only, correlates poorly with symptom severity. Hypothyroidism Oropharyngeal dysphagia has been reported in patients with myxedema associated with edematous facies and periorbital edema. Dysphagia responds well to thyroid replacement therapy, and the manometric abnormalities are reversible. The Esophageal and Gastric Involvement in Systemic and Cutaneous Diseases 159 a variety of neurologic manifestations, including thyrotoxic myopathy and periodic paralysis. The precise cause of oropharyngeal dysphagia may be difficult to determine, because myasthenia gravis, hypercalcemia, and hypokalemia can coexist in thyrotoxicosis. Patients with dysphagia have marked weight loss and muscle wasting associated with severe hyperthyroidism. Abnormal vagal autonomic function and gastric myoelectrical activity have been described [21]. Inflammatory Diseases the main features of inflammatory diseases affecting the esophagus and stomach are listed in Table 25. The esophageal inflammation can be superficial, with chronic inflammatory infiltration in the lamina propria without basal cell hyperplasia or transmural causing extensive fibrosis and fistula formation to the bronchopulmonary tree, mediastinum, and pleura. Dysphagia can be severe, with weight loss in patients with long narrowed esophageal stricture. Barium esophagram is helpful to determine the length of esophageal stricture and the presence of fistula. However, the clinical implication of autoimmune gastritis in these patients is unclear. Hyperthyroidism Symptoms of overt hyperthyroidism are very variable, and include anxiety, emotional labiality, weakness, tremor, palpitations, heat intolerance, palpation, and weight loss. Systemic vasculitis, hyperfunction of neutrophils, and autoimmune inflammatory response are the predominant features. Esophageal and Gastric Involvement in Systemic and Cutaneous Diseases 161 adenopathy to diagnose sarcoidosis [24]. In rare cases of secondary achalasia, botulinum toxin injection and Heller myotomy may improve dysphagia, but symptoms usually persist. Neuromuscular Diseases Neuromuscular diseases represent a category of acquired and primary disorders affecting the motor neurons, peripheral nerves, neuromuscular junctions, and muscles (Table 25. Any abnormality involving the parasympathetic, sympathetic, and enteric nervous systems can potentially affect the esophagus and stomach. Infection can also be transmitted from the mother to her fetus, through blood transfusion or organ donation, and by accidental exposure in laboratory workers. During the indeterminate phase, infected individuals are asymptomatic with low-grade parasitemia and detectable T. Denervation of inhibitory and excitatory myenteric neurons has been described, followed by the replacement of neural structures by fibrosis. Dysphagia is mostly intermittent and mild in early disease, when the esophagus is not dilated. In the late stages, megaesophagus develops, and dysphagia becomes Sarcoidosis Sarcoidosis is a systemic disorder of unknown etiology characterized by accumulation of T-lymphocytes, macrophages, and noncaseating epithelial granuloma. Direct granulomatous infiltration of the esophagus can result in a markedly thickened esophagus with extensive demyelinization and axonal loss of the myenteric plexus. Endoscopic biopsy may reveal the typical non-caseating, granulomatous inflammation, but special stains are needed to exclude tuberculosis and histoplasmosis. If bronchoscopy is non-diagnostic, endoscopic ultrasound-guided biopsy can obtain adequate tissue from Table 25. T-lymphocytic infiltration, myositis, enteric ganglionitis, and reduction of interstitial cells of Cajal have been described [25, 26]. Chronic infection can be detected by serum antibodies, but falsepositive reaction may occur in connective-tissue diseases, leishmaniasis, malaria, and syphilis. In end-stage megaesophagus, surgical resection may be required, but perioperative mortality is significant [29]. Laparoscopic transhiatal subtotal esophagectomy through a left cervicotomy is a feasible approach, but surgical expertise is required [30]. Amyloidosis Amyloidosis is a heterogeneous group of disorders caused by the deposition of insoluble fibril proteins that are resistant to proteolysis. There are six subtypes of amyloid: primary, secondary, hemodialysis-related, hereditary, senile, and localized. The amyloid protein has been found in the esophagus and stomach within the mucosa, submucosa, and smooth muscle. Delayed gastric emptying has been described, but many patients do not have symptoms of gastroparesis [33]. Congo red staining of the endoscopic biopsies is often diagnostic, showing the characteristic apple-green birefringence under polarized light. Treatment of amyloidosis should be directed toward the primary cause, though effective treatment is not available. Paraneoplastic Syndromes Paraneoplastic syndromes encompass the remote effects of malignancy on various organ systems. Cancer cells express antigens mimicking neuronal tissues, thus producing an autoimmune response. The myenteric plexus is infiltrated with lymphocytes and plasma cells associated with neuronal degeneration. Many patients may be misdiagnosed with primary achalasia or idiopathic gastroparesis. Serum antineuronal antibodies may be present in some but not all patients with paraneoplastic involvement of the esophagus [34]. Cutaneous Syndromes Many acquired and inherited cutaneous diseases may affect the oropharynx and the esophagus, since they share a similar stratified squamous epithelium (Table 25. Bullous pemphigoid affects older patients and is the most common autoimmune blistering disorder, but mucosal involvement is rare. Mucous-membrane pemphigoid (cicatricial pemphigoid) has a 2: 1 predilection for women. Paraneoplastic pemphigoid has also been reported with lymphoma and with gastric and renal cancers. Esophageal manifestations of pemphigoid have been reported in case reports; they are similar to pemphigus. Desquamative gingivitis and conjunctivitis are common in mucous membrane pemphigoid. Esophageal biopsies can identify the subepithelial immune complexes of pemphigoid by immunohistology, in contrast to the intraepithelial deposits in patients with pemphigus. Acquired and Inherited Epidermolysis Bullosa Epidermolysis bullosa acquisita is an acquired mucocutaneous syndrome characterized by skin fragility and spontaneous and traumainduced mucocutaneous blisters. Tense blisters tend to occur on traumaprone areas, such as the palms, soles, elbows, and knees. Inherited epidermolysis bullosa is a group of rare inherited syndromes affecting children, with variable extracutaenous manifestations. Some children may have severe dysphagia with long and tight esophageal strictures, requiring multiple dilations and gastrostomy placement to provide enteral nutrition [37, 38]. The clinical and immunohistological findings of epidermolysis bullosa mimic mucous membrane pemphigoid, because they both cause subepithelial blisters. Lichen Planus Lichen planus is a chronic, presumed autoimmune, inflammatory disorder of the skin, nails, and mucous membrane. It causes mucocutaneous ulceration without blistering by a T-lymphocytic Pemphigus Pemphigus is a group of autoimmune intraepithelial blistering diseases involving the skin and mucous membrane. It may also affect the squamous mucosa of the oropharynx, larynx, esophagus, cervix, and anal canal. It is the result of the interaction between genetically predisposed individuals and an exogenous factor.

Studies have shown that nedocromil sodium improved symptom control and pulmonary function when it was added to an as-needed inhaled beta 2-adrenergic bronchodilator regimen diabetes mellitus merck buy generic amaryl pills, and a beneficial effect could be detected within 2 weeks diabetes news amaryl 3mg without prescription. The aforementioned drugs are used mainly as prophylaxis diabetes mellitus vaccination purchase amaryl australia, and they cannot be used in the acute phase of any bronchoconstriction events diabetes symptoms toenails buy discount amaryl 2 mg. It is estimated that more than 50% of asthma is related to allergy and the majority of patients with severe asthma have allergic-atopic asthma diabetes test blood or urine discount amaryl 1mg visa. Immunoglobulin E(IgE) antibodies diabetes type 2 risk purchase amaryl with american express, allergen type 2 helper T cells derived cytokines and eosinophils play a major role in the development of chronic airway 237 Respiratory Pharmacology 12 disease, even in mild forms of the disease. This airway inflammation is the pathogenesis of bronchial asthma, which causes an increase in airway responsiveness to many trigger factors such as aeroallergens alone or in combination with other triggers such as air pollution and viruses. Elevated levels of specific IgE toward common environmental allergens are the main component in the pathogenesis of allergic asthma. IgE antibodies cause chronic airway inflammation through effector cells activated by 2 IgE receptors: high affinity and low affinity. These patients have increased recurring hospitalizations and mortality within 1 year of initial hospitalization. Anti-IgE monoclonal antibody (omalizumab) binds IgE at the same site where the antibody binds, resulting in the inhibition of IgE effector function. This means that in allergic subjects, omalizumab prevents the activation of cellular response and the occurrence of asthma symptoms. Treatment with omalizumab reduces airway wall thickness in patients with severe persistent asthma treated with conventional treatment. The use of omalizumab also has resulted in decreased corticosteroid use and improved quality of life in asthmatic patients. Omalizumab treatment is reserved for the severe uncontrolled asthmatic patients despite best available therapy. Multiple studies have shown that adding omalizumab reduces asthma exacerbation, total emergency visits, hospitalizations, and steroid utilization, thus improving quality of life. No data exist about patients with renal or hepatic dysfunction prior to starting omalizumab, thus caution should be used in administering this drug in these patients. The field of obstructive lung disease treatment is currently undergoing major development in pharmacogenetic studies, which could target the use of specific medications in populations most likely to benefit. Which of the following is a side effect of muscarinic acetylcholine receptors antagonists Urinary retention Combination Therapy Combination therapy is used when airway symptoms are not controlled by maintenance monotherapy. Moreover, combining 2 or more classes allows the use of lower doses to achieve the same result. Combining (beta)2-adrenergic receptors agonist and muscarinic acetylcholine receptor antagonists 2. Combining muscarinic acetylcholine receptor antagonists and inhaled corticosteroid 238 A. Airway tone is mainly controlled by parasympathetic nerves carried by the vagus nerve. Levalbuterol may reduce hospitalization, have fewer adverse side effects, and provide similar bronchodilators effects at reduced dose compared to albuterol. All are side effects: 5 In patients with prostatic hyperplasia, these agents should be used with caution, since the risk of further increase and acute urinary retention can follow. Chronic diuretic administration to a patient with a fixed sodium intake initially causes a loss in totalbody Na+, but, with time, renal compensatory mechanisms balance the Na+ excretion to Na+ intake. Diuretics may be detrimental and patients receiving higher doses have worse outcomes. The failure to initiate an adequate response to a diuretic would need addition or substitution from a different class of diuretic in order to obtain a response. Loop and thiazide diuretics increase the expression of the transporters they inhibit. This leads to decreased efficacy, and when the administration of diuretics is terminated, there is a rapid increase in NaCl reabsorption. The use of dopamine for potential renoprotective effects is not warranted, especially in light of several large-scale trials that have shown lack of benefit. The term diuretic describes a drug that increases urinary solute and water excretion thus affecting the extracellular volume status of the individual. Its primary action is by affecting the absorption of sodium resulting in natriuresis. Most of the diuretics bring about their action by affecting the Na+ transport at one or more nephron segments, irrespective of their chemical class. The time course of natriuresis is finite as renal compensatory mechanisms bring Na+ excretion in line with Na+ intake-a phenomenon known as "diuretic braking. Most of the diuretics, except the potassiumsparing diuretics, mediate their effect via the solute reabsorptive pumps. Hence, these drugs have to be secreted into the lumen of the tubules in order to produce their effects. The osmotic diuretics exert their action by increasing the osmotic pressure and are effective only on the most permeable portions of the renal tubules: proximal tubule and the thin descending limb of the loop of Henle. The presence of the osmotic diuretic interferes with the passive reabsorption of water. The reabsorption of sodium, however, continues normally in the thick ascending loop of Henle. The osmotic diuretics increase the excretion of sodium, potassium, calcium, magnesium, chloride, and bicarbonate. Bhavani the commonest agents considered in this class of diuretics include mannitol, urea, sorbitol, and glycerol. The prototypical osmotic diuretic is mannitol, which is an alcohol produced by the reduction of mannose. They can be used orally for bowel preparation before colorectal surgery, colonoscopy, and barium enemas. About 10% is reabsorbed in the loop of Henle but a similar amount is metabolized by the liver [1]. This increase in renal blood flow results in washout of the medullary tonicity that further decreases reabsorption of water from the tubules. It also acts as a free-radical scavenger and reduces the harmful effects of free radicals during ischemiareperfusion injury. This latter property may have a protective effect following an ischemic insult to the kidneys by reducing the tubular endothelial swelling and maintaining tubular patency. Rapid initial volume expansion resulting in increased risk of heart failure, pulmonary congestion 2. In large doses, it can also cause renal failure because of intra-renal vasoconstriction and intravascular volume depletion 3. They have a weak natriuretic effect due to compensatory mechanisms that come into play following chronic administration [1]. Promotion of urinary excretion of toxic materials: Pharmacokinetics the carbonic anhydrase inhibitors are well absorbed after oral administration. Metabolic Alkalosis: When the alkalosis is due to excessive use of diuretics, acetazolamide can be useful in correcting the alkalosis as well as producing a small additional diuresis for correction of volume overload. There is a six-fold increased incidence of genital fungal infection in women and a slightly higher risk of urinary tract infections. There is a higher incidence of calcium and phosphate stones as they are insoluble in an alkaline pH. Hypersensitivity reactions (fever, rashes, bone marrow suppression, and interstitial nephritis) 13. They exhibit a modest and nonspecific inhibition of these adenosine receptors and produce a mild diuretic effect. The decreased reabsorption of sodium chloride alters the tonicity of the normally hypertonic medullary interstitium and leads to a reduced urine-concentrating ability of the kidneys thus facilitating diuresis. The two drugs that were initially available were the sulfonamide derivative furosemide and phenoxyacetic acid derivative ethacrynic acid. The prototypical agents of this class are the sulfonamide derivatives furosemide, bumetanide and torasemide. This protein binding is essential for the delivery of furosemide to the kidney, the site for its action [4]. Loop diuretics have to be secreted into the luminal side of the proximal tubules in order to have an effect. Thirty percent of the drug is metabolized and excreted via the gastrointestinal tract. It is primarily eliminated by the kidney by glomerular filtration and tubular secretion. Halflife varies from 1 to 3 h and depends on renal function and the dose has to be adjusted in patients with renal failure. Allergic reactions: skin rash, eosinophilia, and less often, interstitial nephritis. In normal circumstances, this increased loss of calcium is counter-balanced by increased intestinal absorption and parathyroid hormone-induced renal reabsorption of Ca2+ and hypocalcemia does not develop. The latter reduces pulmonary congestion and left ventricular filling pressures in the presence of heart failure. Furosemide, bumetanide, and torasemide may exhibit allergic cross-reactivity in patients who are sensitive to other sulfonamides, but this appears to be very rare. Use with caution in patients with hepatic cirrhosis, borderline renal failure, or heart failure. Increased intracranial pressure: they can be used even in the presence of disrupted blood-brain barrier. Approximately 90% of the drug is bound to plasma proteins and its volume of distribution is relatively low. Furosemide increases renal artery blood flow if the intravascular fluid volume is maintained. Hypercalciuria, which can lead to mild hypocalcemia and secondary hyperparathyroidism 6. Hypercalcemia in volume-depleted patients with metastatic breast or squamous cell lung carcinoma the mechanism of action and its effects are similar to those of furosemide. Ototoxicity may be slightly less frequent than with furosemide, but renal toxicity is more of a problem. They have their predominant site of action at the distal convoluted tubule and have some effect on the collecting ducts. Also like the loop diuretics, they are secreted by the organic acid secretory system in the proximal tubule and compete with the secretion of uric acid by that system. This effect can be helpful in some patients to prevent calcium stones in patients with hypercalciuria. They are weak diuretics and are usually used in combination with thiazides or loop diuretics. Serious allergic reactions-such as hemolytic anemia, thrombocytopenia, and acute necrotizing pancreatitis-are extremely rare. Vasopressin receptor antagonists promote the excretion of solute-free water, and thus are known as "aquaretics. Large doses can cause hypovolemia, hypotension, renal dysfunction, and neurohumoral activation [5]. The hypokalemia that often accompanies it cannot be completely reversed until the magnesium deficit is also treated. Therefore, dosing the drug based on body weight may not reflect the true plasma concentration of the medication. Thus, what is considered as a "low dose dopamine" may in fact produce beta 1 or alpha stimulation resulting in unwanted tachycardia and hypertension [8]. The increase in cardiac output that may follow its use, however, may be beneficial in improving the renal perfusion and increasing the urine output. Being a selective D-1 effect, it lacks the beta- or alphaadrenergic effects and hence has the potential to be safer and more effective as compared to dopamine as an effective renoprotective agent without inducing some of the adverse effects of dopamine, including tachycardia or vasoconstriction [13]. A meta analysis has demonstrated its usefulness in reducing the risk of acute kidney disease [14]. Ethacrynic acid A 50-year-old patient presents to the emergency department with mental status changes. Which of the following would be your first choice in the management of his severe hypercalcemia Dopamine is an endogenous catecholamine with a broad range of activity on dopaminergic, beta-adrenergic, and alpha-adrenergic receptors [6].

Purchase 3mg amaryl with amex. diabetic abscess.

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• Do not douche
• Showing you how to make important changes in your lifestyle
• You develop other symptoms
• Seal cracks and crevices where cockroaches may enter the house
• Some paints
• Blood chemistry tests (basic or comprehensive metabolic panel)
• Vitamin D deficiency
• Lead poisoning
• There is dark or bloody discharge from the nipples
• Very painful, sharp electric-like spasms that usually last a few seconds or minutes, but can become constant

In an adult metabolic disorder multiple sclerosis purchase amaryl 1mg visa, the total amount of dead space represents only a small amount of the total tidal volume blood glucose chart printable buy cheap amaryl online. However diabetes insipidus triphasic response purchase amaryl with a visa, in pediatrics blood glucose charts cheap amaryl 3mg mastercard, and especially neonates early signs diabetes feet buy amaryl 1mg on line, the dead space can represent a significant portion of the tidal volume diabetes in dogs clinical signs purchase amaryl on line amex. To minimize the dead space a septum can be added to the y-piece and then the volume of the y-piece is no longer part of the dead space. The pediatric circuit also consists of narrower and more rigid corrugated tubing to minimize the compliance of the system. In rats it has been shown to be a nephrotoxin, but in humans it has an unclear significance. After a prolonged exposure of high levels of compound A in otherwise healthy volunteers, there is a transient albuminuria. To minimize exposure to compound A, it is recommended to use a minimum fresh gas flow of 2 L/min. Production of Carbon Monoxide the use of desiccated soda lime in the carbon dioxide absorber can lead to the production of significant quantities of carbon monoxide. The risk of carbon monoxide production varies for the different agents: desflurane > isoflurane >> sevoflurane Since this only occurs with desiccated soda lime, there is a higher incidence of carbon monoxide production with the use of old soda lime during the first case of the day. As the soda lime is used to remove carbon dioxide, water is produced by the reaction. This rehydrates the desiccated soda lime and subsequent surgical cases have a lower incidence of carbon monoxide exposure. The highest risk is on Monday morning after the anesthesia machines were not used over the weekend. For the same reason, anesthesia machines at offsite locations where the anesthesia machines are only used infrequently also have a high risk of exposure to carbon monoxide. Any time the fresh gas flows are left on at high flows and the machine is not connected to a patient, there is a risk of drying out the soda lime. If the fresh gas flows are left on overnight when the anesthesia machine was not in use, the soda lime should be replaced. If carbon monoxide is produced, then the use of low fresh gas flows will lead to an accumulation of carbon dioxide in the system. The risk of carbon monoxide production with new soda lime is low because it arrives pre-hydrated from the manufacturer. Closed Circle System In a closed circle system the fresh gas flows of oxygen are matched with the uptake of oxygen by the patient. A closed circle system maximizes the advantages of the circle system, which include conservation of gases, humidity, and heat. However, a closed circle system exacerbates the problems listed previously for low fresh gas flows. Delivery of volatile anesthetics is particularly difficult with a closed circle system due to the changing uptake of the volatile anesthetics as the patient progresses from induction to maintenance of anesthesia. For these reasons, closed circle systems are not frequently used in clinical practice. For adult cir- 593 Breathing Systems 34 efficient use of the gases with conservation of heat and moisture. So far no current breathing systems have been able to achieve all the desired characteristics. The Mapleson systems are primarily used where a portable breathing system is required or in locations where a circle system is not available. A circle system is typically the optimum system, assuming portability is not needed. However, with all the advantages of the circle system comes a significant increase in complexity. This leads to the need for more frequent maintenance and constant monitoring of the inspired gases to ensure a safe delivery of the desired gases to the patient. If the unidirectional valves malfunction in the circle system the following can occur: A. Increasing the length of the circuit tubing in a circuit system will increase the amount of dead space A. Questions (Choose the Most Appropriate Answer) Malfunction of Unidirectional Valves the valves consist of a horizontal ceramic disc that rests on the valve seat. When the flow reverses, the disk is pushed down and it seals the valve and prevents reversal of flow. The most common malfunction of the valve is due to warping of the disc or improper seating of the disc. When this happens to either valve, the result is rebreathing of exhaled gases and potentially hypercapnia. The expiratory valve is exposed to the moisture in the exhaled gases and is the most common valve to malfunction. Components of an Ambu bag include a self-expanding bag, reservoir tubing, oxygen source, and a non-rebreather valve. The Ambu bag can be either connected to an endotracheal tube or used with a face mask to provide positive pressure ventilation. Since it is a self-expanding bag it can be used without an oxygen source, unlike the Mapleson circuits that require compressed gas to expand the reservoir bag. With the use of high flow oxygen (>8 L/min) close to 100% oxygen can be delivered to the patient. Unlike the circle system, there is no rebreathing of gases and therefore it has similar disadvantages to the Mapleson circuits. An optimal breathing system would include a simple, reliable, portable system that can also make 594 J. The following is true about the production of carbon monoxide by the soda lime carbon dioxide absorber: A. It occurs when the soda lime is exhausted and cannot absorb additional carbon dioxide. All of the following breathing circuits require compressed gas (typically oxygen) to function properly except: A. Insufflation expands if the pressure relief valve is closed and gas fills the bag. This allows the absorber to immediately start working once it is placed in the circle system. Once the reaction is underway, for every molecule of carbon dioxide that combines with a molecule of water, the end result is the production of 2 molecules of water. The most likely reason that water is not present is if the fresh gas flows were left on overnight when a patient is not connected to the circle system. The fresh gas flows have no water present, and if exposed to the absorber for several hours, this can lead to the depletion of water. When the carbon dioxide absorber is replaced, it begins working immediately so the concentration of carbon dioxide will be either unchanged or it will begin to decrease if the previous absorber was exhausted. The absorber does not absorb oxygen so the oxygen concentration will be unchanged. Since the absorber is saturated with water from the manufacturer, the water content in the circuit will likely be unchanged or increase slightly. When the absorber is replaced, it will absorb the volatile anesthetics if present and the depth of anesthesia for the patient will decrease temporarily. The absorber quickly becomes saturated with volatile anesthetics and then the depth of anesthetics will remain constant. The purpose of the unidirectional valves is to ensure that the gases move through the circuit in only 1 direction. When there is a malfunction in 1 of the valves, it allows the gases to move in both directions. Hypoxia would be unlikely because the exhaled gases still have oxygen present and even with rebreathing the patient will still receive sufficient oxygen. Malfunctioning valves will have no impact on the concentration of the volatile agents. Due to the unidirectional valves in the circle system, the gases are only able to move in 1 direction. Therefore, no matter how long the circuit is, the dead space begins at the y-piece that joins the expiratory limb and the inspiratory limb with the endotracheal tube. The essential components of a Mapleson circuit include a fresh gas inlet, reservoir bag, pop-off valve, and a face mask. The pop-off valve is where the exhaled gases are vented and this allows a scavenger system to be connected to the circuit. This is done if the Mapleson circuit is used with volatile anesthetics to prevent the contamination of the patient care area. Since the Mapleson system consists of only a few lightweight components it is highly portable. A carbon dioxide absorber is not included in the components of a Mapleson system but is instead found in the circle system. The advantages of the Mapleson system include a relatively simple and portable design. Compared to other ventilation systems, including the circle system, a Mapleson system has very low resistance during exhalation. If pure oxygen is supplied to the system in adequate flows (>5 L/min), then the patient will receive close to 100% oxygen. Since the Mapleson system does not recirculate the exhaled gases as occurs in the circle system, this leads to a loss of heat and moisture. The following are all necessary components of a circle system including: carbon dioxide absorber, unidirectional valves, fresh gas inlet, reservoir bag, and adjustable pressure relief valves. In the circle system the reservoir bag is soft plastic and only 595 Breathing Systems 34 8. Compound A is produced by the removal of hydrogen fluoride from sevoflurane by the carbon dioxide absorber. Rats exposed to compound A show signs of renal injury and healthy humans develop a transient albuminuria. Due to the potential for renal injury in humans, it is recommended to run fresh gas flows of at least 2 L/min to minimize the buildup of compound A in the circle system. The production of carbon monoxide is greatest with desflurane than isoflurane and sevoflurane has the lowest risk. The first case of the day has the highest risk of having desiccated soda lime, especially if the fresh gas flows were left on when the anesthesia machine was not in use. This leads to the first case of the day having the highest risk of carbon dioxide production. The circle system and the Mapleson circuit both require a compressed gas source to fill the reservoir bag since the bag is not self-expanding. The Ambu bag is the only system with a self-inflating reservoir bag; this allows it to be used with or without a compressed gas source. The pH (Sanz) electrode works on the principle that an electrical potential develops across a glass membrane, which is proportional to the pH difference across it. The pH electrode consists of 2 "half " cells: a glass electrode and a reference electrode. The glass electrode is an Ag/AgCl electrode system enclosed in a glass membrane and maintaining a constant pH within itself, while the reference electrode is a Hg/ HgCl electrode, which comes in contact with the blood sample through a semi-permeable membrane. Current flows from the reference electrode through the semi-permeable membrane through the sample in the measuring chamber and to the glass electrode. Depending on the pH of the sample, the potential will develop across the glass membrane, which will be displayed in pH units. It is crucial to understand the physical principles and functioning of these devices, in order to interpret the results and know their limitations. It consists of a platinum cathode and a silver/silver chloride anode immersed in a potassium chloride solution and separated from the blood by an oxygen-permeable Teflon membrane, which allows the oxygen tension in the blood to equilibrate with the electrolyte solution. Solubility of all gases increases with a fall in temperature of the solvent and thus lowers its partial pressure. This becomes especially important in significantly hypothermic patients, such as during cold cardiopulmonary bypass or deep hypothermic circulatory arrest. The advantage of this was increased cerebral blood flow allowing better oxygen delivery. However, there was concern that it could lead to micro-embolization and loss of autoregulation. Hypothermia reduces the efficacy of the bicarbonate and the phosphate buffers and the amino acids (alpha imidazole ring of histidine) become the primary buffer. The advantages are maintenance of cerebral autoregulation and normal cellular transmembrane electro-neutrality. Historically, 2 spheres, connected together to look like a dumb-bell, filled with nitrogen (a diamagnetic gas) were suspended in a magnetic field. In the resting stage the dumb-bell would try to move away from the magnetic field. However, when oxygen-containing gas was passed around it, the oxygen being attracted to the magnetic field would move the dumb-bell toward the magnetic field, 601 Physics of Instrumentation 35 depending on the concentration of oxygen. This movement could be electronically extrapolated as the concentration of oxygen.