Tzyy-Choou Wu, M.D., M.P.H., Ph.D.

• Director, Gynecologic Pathology Division
• Professor of Pathology

https://www.hopkinsmedicine.org/profiles/results/directory/profile/0003704/tzyy-choou-wu

The most extensively documented deficiency of selenium in humans is Keshan disease spasms from coughing cheap 200 mg flavoxate mastercard. This is an endemic cardiomyopathy first discovered in Keshan County in China where there are very low concentrations of selenium in the soil and food muscle relaxer z 200 mg flavoxate buy otc. This deficiency occurs most frequently in children under 15 years of age and in women of childbearing age and is characterized by various degrees of cardiomegaly and cardiac decompensation muscle spasms 72885 purchase genuine flavoxate line. Kashin­Beck disease is an osteoarthropathy found in areas where combined deficiency of selenium and iodine occurs with elevated exposure to mycotoxin and fulvic acids (Fairweather-Tait et al muscle relaxer 93 generic flavoxate 200 mg overnight delivery. Other potential effects of selenium deficiency include immune dysfunction muscle relaxant used for migraines discount flavoxate, and susceptibility to cancer or infectious/ inflammatory diseases (Högberg and Alexander, 2007; FairweatherTait et al. Established tolerable upper intake limits of selenium in adults are 200 to 300 µg per day (Duffield-Lillico et al. Metabolic balance studies in adults indicate about 50 to 70 µg per day is required to maintain selenium balance and presumably to satisfy selenium requirement (Högberg and Alexander, 2007). Intentional or accidental ingestion of a large dose of sodium selenate or sodium selenite can be life-threatening. Symptoms of fatal selenium intoxication 1008 include nausea and vomiting, followed by pulmonary edema and rapid cardiovascular collapse (Fairweather-Tait et al. Chronic selenium toxicity (selenosis) can occur with environmental exposure when the intake exceeds the excretory capacity. Effects are mainly dermal and neurological including hair and fingernail loss, tooth discoloration, numbness, paralysis, and occasional hemiplegia. Selenosis occurred in several villages in China where people were exposed to very high selenium in food (Fairweather-Tait et al. Intoxication from environmental selenium has also been noted in people residing in Venezuela and South Dakota. Selenium toxicity in animals was recognized in South Dakota when the livestock that had been grazed in areas with high soil selenium developed alkali disease and blind staggers. In a study of people living in this area, poor dentition, a yellowish discoloration of the skin, skin eruptions, and diseased fingernails and toenails were found (Fairweather-Tait et al. Grasses, grains, and most weeds do not accumulate selenium even when grown in high selenium areas, so that these plants add little to the selenium content of livestock feed. But there are several plant species that are classified as "selenium accumulators" and they may contain selenium at very high concentrations (100­10,000 mg/kg). These plants usually grow in nonagricultural areas and when consumed by livestock may cause selenium intoxication. Selenium has various bioinorganic interactions, which may affect the toxicity of selenium or other metals. Selenium forms complexes with copper, and toxicity of either selenium or copper is influenced by the intake of the other elements. The methylation of selenium can influence other methylation reactions, and can alter arsenic metabolism and toxicity (Zeng et al. Selenium prevents the toxic effects of cadmium and can reduce the toxic effects of methylmercury. Selenium supplementations appear to decrease human cancer rates, especially for prostate cancer (Duffield-Lillico et al. Increasing selenium content of forage crops has been shown to be beneficial in reducing cancer risk. Some experimental evidence supports a role for selenium in reduction of spontaneous tumors or tumors formed by organic carcinogens in rats and mice. The tissue levels of chromium are reduced among diabetic individuals, but the effects of chromium supplementation in type 2 diabetes are still controversial (Cefalu and Hu, 2004). The adequate intake of chromium is now proposed as 35 and 25 µg/kg per day for men and women, respectively, which is lower than previous 50 to 200 µg per day. It was thought to have adverse effects and perhaps the potential to cause cancer (Vincent, 2004), but an in-depth study of chronic chromium picolinate feeding has now shown no evidence of carcinogenesis in male or female mice or female rats only and equivocal evidence of a response (preputial gland tumors) in male rats (Stout et al. In contrast, zinc toxicity is relatively uncommon and occurs only at very high exposure levels. Zinc is ubiquitous in the environment and is present in most foodstuffs, water, and air. The major route of zinc intake is through the diet, the contents of which vary from 5. Occupational exposure to dusts and fumes of metallic zinc occurs in zinc mining and smelting. The zinc content of substances in contact with galvanized copper or plastic pipes may be high. Toxicokinetics the absorption of zinc from the gastrointestinal tract is homeostatistically regulated. Zinc uptake from the intestinal lumen involves passive diffusion and a carrier-mediated process through zinc-specific transmembrane transporters such as ZnT-1. Intestinal absorption of zinc can be reduced by dietary fiber, phytates, calcium, and phosphorus, while amino acids, picolinic acid, and prostaglandin E2 can enhance zinc absorption. The highest concentrations of zinc are found in prostate, pancreas, liver, and kidney. In plasma, zinc concentration is about 1 mg/L, and is bound to albumin (60%­80%), which represents the metabolically active pool of zinc. The concentration of zinc in the plasma is not a sensitive indicator of zinc status and does not reflect the dose­response relationship between zinc levels in the body and effects at various target sites. Zinc ions are involved as intercellular and intracellular messengers, and the homeostasis of zinc has to be tightly controlled. Other effects of trivalent chromium include the beneficial roles in growth, prostate is probably related to the rich content of zinc-containing enzyme acid phosphatase. Essentiality and Deficiency More than 300 catalytically active zinc metalloenzymes and 2000 zinc-dependent transcription factors exist (Ziegler and Filer, 1996; Cai et al. Zinc participates in a wide variety of metabolic processes, supports a healthy immune system, and is essential for normal growth and development during pregnancy, childhood, and adolescence. Zinc deficiency is related to poor dietary zinc intake, dietary phytate (inositol hexakisphosphate) intake, chronic illness, or over supplementation with iron or copper (Prasad, 2004). Symptoms of zinc deficiency include growth retardation, appetite loss, alopecia, diarrhea, impaired immune function, cognitive impairments, dermatitis, delayed healing of wounds, taste abnormalities, and impaired sexual function (Prasad, 2004; Cai et al. Acrodermatitis enteropathica is a rare autosomal recessive disorder involving zinc deficiency that can begin to appear after weaning from breast or formula feeding. The deficiency is due to mutations in a zinc-specific transporter that is highly expressed in the intestine. The disease is characterized by periorificial and acral dermatitis, alopecia, and diarrhea (Maverakis et al. Zinc supplementation, alone or with other micronutrients, is recommended for zinc-deficient children, especially in developing countries. Synaptically released zinc might contribute to excitotoxic brain injury, and the release of excess, toxic free zinc in to the brain that occurs during excitotoxic brain injury could be a factor that sets the stage for the later development of Alzheimer disease. A single, high-dose injection of zinc increases plasma -amylase activity and can produce fibrosis and necrosis of pancreatic exocrine cells, but does not affect the islets of Langerhans cells (Cai et al. Zinc and Carcinogenicity Epidemiological studies of workers in electrolytic zinc and copper refining industries have not found an increased incidence of cancer associated with occupational zinc inhalation. In contrast, zinc deficiency may be associated with increased risk of cancer in humans (Prasad and Kucuk, 2002). Zinc supplementation could decrease oxidative stress and improve immune function, which may be a possible mechanism for its cancer preventive activity (Prasad and Kucuk, 2002). In experimental animals, zinc prevents cadmium-induced testicular cancer, but facilitates cadmiuminduced prostate tumors (Waalkes, 2003). As a hard trivalent ion, aluminum binds strongly to oxygen donor ligands such as citrate and phosphate. The chemistry of aluminum compounds is complicated by a tendency to hydrolyze and form polynuclear species, many of which are sparingly soluble (Harris et al. Aluminum has many uses, mainly in the form of alloys, and finds use in packing, construction, transportation, electrical applications, and beverage cans. Human exposure to aluminum comes primarily from food and secondarily from drinking water. The amount of aluminum in the food supply is small compared with pharmaceutical use of aluminum in antacids and buffered analgesics (Soni et al. Occupational exposures to aluminum occur during mining and processing, as well as in aluminum welding. The levels of exposure can vary greatly according to the type of industry and hygiene conditions. Inhalation of aluminum-containing dust particles is of health concern (Sjögren et al. Aluminum exists predominantly in forms that are innocuous to humans and most species. However, acidic conditions, such as acid rain or dry acid deposition, can dramatically increase the amount of aluminum in ecosystems, resulting in well-described destructive effects on plants, fish, and other wildlife. However, aluminum is not bioaccumulated to any significant extent except in the tea plant (Sparling and Lowe, 1996). Toxicity Acute zinc toxicity from excessive ingestion is uncommon, but gastrointestinal distress and diarrhea have been reported following ingestion of beverages standing in galvanized cans. Following inhalation of zinc oxide, and to a lesser extent other zinc compounds, the most common effect is "metal fume fever" characterized by fever, chest pain, chills, cough, dyspnea, nausea, muscle soreness, fatigue, and leukocytosis. Acute inhalation of high levels of zinc chloride as in the military use of "smoke bombs" results in more pronounced damage to the mucous membrane including interstitial edema, fibrosis, pneumonitis, bronchial mucosal edema, and ulceration. Chronic intakes of zinc (150­450 mg per day) have been associated with low copper status, altered iron function, and reduced immune function. Recently, excessive use of denture adhesive cream has been recognized as a potential source for zinc toxicity. Following long-term exposure to lower doses of zinc (60 mg per day), symptoms generally result from a decreased dietary copper absorption, leading to early symptoms of copper deficiency, such as decreased erythrocyte number or decreased hematocrit (Yates et al. Zinc can also act as a neurotransmitter for normal brain functions (Frederickson et al. It modulates the solubility of -amyloid in the brain and protects against -amyloid toxicity, but excess zinc may trigger neuronal death that is independent or synergistic with the toxic effect of -amyloid (Valko et al. In contrast, excess zinc released by Toxicokinetics Aluminum is poorly absorbed following either oral or inhalation exposure and is essentially not absorbed dermally. Inhalation of particulate aluminum may result in direct transfer to brain tissue via the olfactory system (Tjalve and Henriksson, 1999). Absorption from the gut depends largely on pH and the presence of complexing ligands, particularly carboxylic acids, through which aluminum becomes absorbable. Biological speciation is also of major importance in distribution and excretion of aluminum in mammals (Sjögren et al. In plasma, 80% to 90% of aluminum binds to transferrin, an iron transport protein with receptors in many tissues. The transferrin pathway is also considered a mechanism for aluminum transport across the blood­brain barrier (Yokel, 2006). In patients with impaired renal function, tissue aluminum concentrations can increase and are associated with encephalopathy and osteomalacia. Aluminum compounds can alter absorption of other elements in the gastrointestinal tract. For instance, aluminum inhibits fluoride absorption and may decrease the absorption of calcium and iron compounds and salicylic acid, which, in turn, may affect the absorption of aluminum (Exley et al. The binding of phosphorus by aluminum in the intestinal tract can lead to phosphate depletion and, potentially, osteomalacia. Aluminum interacts with calcium in bone and kidney, resulting in aluminum osteodystrophy (Goyer, 1997). Aluminum may also alter gastrointestinal tract motility by inhibition of acetylcholine-induced contractions, which is probably why aluminum-containing antacids often cause constipation. Most cases of aluminum toxicity in humans are observed in patients with chronic renal failure, or in persons exposed to aluminum in the workplace, with the lung, bone, and central nervous system as major target organs. Aluminum affects similar target organs in animals and can produce developmental effects. Lung and Bone Toxicity Occupational exposure to aluminum dust can produce lung fibrosis in humans, but this effect is probably due to lung overload caused by excessive deposition of dust (Sjögren et al. Osteomalacia has been associated with excessive intake of aluminum-containing antacids in otherwise healthy individuals. Osteomalacia also can occur in uremic patients exposed to aluminum in the dialysis fluid. In these patients, osteomalacia may be a direct effect of aluminum on bone mineralization as bone levels are high (Soni et al. Neurotoxicity Aluminum is neurotoxic to experimental animals, with wide species and age variations. Impairment of cognitive and motor function and behavioral abnormalities are often observed. Whereas studies in animals have provided some insights in to the mechanisms of the neurotoxicity of aluminum in experimental models, the relationship to any human disease is still uncertain. The disorder, which typically arises after three to seven years of dialysis treatment, may be due to aluminum intoxication. Sources of the excess aluminum may be from oral aluminum hydroxide commonly given to these patients or from aluminum in dialysis fluid derived from the tap water used to prepare the dialysate fluid. The high serum aluminum concentrations may be related to increased parathyroid hormone levels that are due to low blood calcium and osteodystrophy common in patients with chronic renal disease. The syndrome may be prevented by avoiding the use of aluminum-containing oral phosphate binders and by monitoring of aluminum in the dialysate.

Although sclerosing peritonitis typically has a chronic evolution skeletal muscle relaxant quizlet purchase flavoxate 200 mg free shipping, it may arise rapidly after treatment of acute bacterial peritonitis [92] spasms colon symptoms order 200 mg flavoxate fast delivery. Reduction in acute peritonitis with improvement in aseptic techniques has not reduced the incidence of sclerosing peritonitis [93] and >80% of patients on peritoneal dialysis for >15 years do not develop sclerosing peritonitis [87] muscle relaxant lyrics flavoxate 200 mg with visa. Sclerosing mesenteritis Sclerosing mesenteritis is used to describe a variety of previously reported entities with similar or overlapping clinical and pathological features spasms causes cheap 200 mg flavoxate overnight delivery, including retractile mesenteritis muscle relaxant tinnitus purchase flavoxate with amex, mesenteric panniculitis, mesenteric lipodystrophy [105], liposclerotic mesenteritis, xantho-granulomatous mesenteritis and mesenteric lipogranuloma. It represents a rare fibrosing tumefactive process primarily involving the small bowel mesentery, with variable degrees of associated inflammation and fat necrosis, reflecting the spectrum of descriptive terms applied. The condition is more common in males and a wide age range is affected, with the median in the seventh decade [105,106]. Non-specific symptoms of abdominal pain, vomiting, pyrexia or weight loss are prominent in some whereas in others the inflammatory process is clinically silent, the condition being recognised only during routine clinical abdominal examination or at laparotomy for some unrelated reason. A minority of cases present at a late stage, when florid post-inflammatory mesenteric fibrosis produces intestinal obstruction or mesenteric venous thrombosis. Progression from the inflammatory to the sclerotic form is not inevitable, however, and some cases show apparent complete spontaneous resolution. The macroscopic appearances in the inflammatory phase of sclerosing mesenteritis are of ill-circumscribed oedematous or rubbery thickening of the mesentery or omentum, most notably at the root of the small intestinal mesentery. In some cases the condition affects a segment of the mesentery diffusely whereas in others one or more discrete inflammatory mesenteric masses are found. Cystic spaces containing liquefied fat or chyle may be seen, the latter resulting from lymphatic obstruction. Later, in the fibrotic phase, there is sclerotic thickening of the mesentery with retraction and distortion of the bowel and formation of adhesions. The histological appearances in the early stages of the disease are those of mesenteric fat necrosis with neutrophil polymorphs, clusters of lipophages, foreign body-type giant cells and cholesterol clefts. In the peritoneum this thickening may produce either discrete plaques or an almost continuous sheet over the serosal surface of the liver, spleen and the underpart of the diaphragm, accompanied by an ascitic transudate. It has been regarded by some as a complication of tuberculosis but there is no good evidence to support this view. Eosinophilic peritonitis Examples of peritonitis in which the predominant inflammatory cell type is the eosinophil leukocyte are uncommon. Some are associated with metazoal infection [100] (see above), malignant disease or eosinophilic gastroenteritis [101], but the most common setting now is in patients undergoing chronic peritoneal dialysis [102,103]. Its pathogenesis is unknown but a hypersensitivity reaction to plasticisers or other constituents of dialysis bags, lines or catheters may be responsible. Peritoneal malakoplakia Malakoplakia of the pelvic peritoneum has been described at caesarean section in a woman who had had a coliform urinary tract infection earlier in the pregnancy [104]. There have been several individual reports of lymphomas and sclerosing mesenteritis arising separately in the same patient, associated with a poor prognosis [111,112]. Occasional examples of sclerosing mesenteritis are associated with a more widespread panniculitis such as the Pfeifer­Weber­Christian syndrome (relapsing nonsuppurative nodular panniculitis) [113], whereas in other cases the condition extends in to the retro-peritoneum to overlap with idiopathic retro-peritoneal fibrosis [114,115]. The relationship between sclerosing mesenteritis and the family of IgG4-related sclerosing disorders, including idiopathic retro-peritoneal fibrosis, has been investigated [106,111,116]. Lymphocytic venulitis is a morphological feature shared with this group of conditions [111]. Although based on small numbers of cases examined, it would appear that a minority of cases of sclerosing mesenteritis shows significant infiltration by IgG4-positive plasma cells, or increased IgG4:total IgG immunostaining ratio, raising the possibility that a subset is IgG4 mediated [106,111]. In the absence of secondary intestinal complications and with the confident exclusion of any underlying malignancy, sclerosing mesenteritis usually follows a benign course [105,106,117]. Aggressive surgery is therefore not indicated in the treatment of this condition, with medical therapy in the form of oral steroids and tamoxifen more appropriate, and surgical intervention reserved for complications [106,117]. Neoplastic infiltration of the mesentery may lead to mesenteric fibrosis resembling sclerosing mesenteritis. Any form of malignancy can produce the effect but the mimicry is greatest in cases of well differentiated endocrine carcinomas of the midgut (so-called carcinoid tumours), which may elicit a particularly dense fibrotic reaction when they invade the mesentery, leading to retraction and kinking [107]. This mesenteric fibrosis, along with a distinctive elastic vascular sclerosis of the mesenteric blood vessels induced by such endocrine tumours, may result in intestinal ischaemia or even frank infarction [108,109]. When involving the pancreatic region, sclerosing mesenteritis can closely mimic pancreatic cancer [110]. Given the often marked desmoplastic stromal reaction and low cellularity Fat necrosis after pancreatitis Intra-abdominal leakage of pancreatic enzymes in pancreatitis may lead to fat necrosis, not only of the peri-pancreatic tissues but also of the omentum, mesenteries or retroperitoneum. Although this is easily recognised both macroscopically and microscopically in the acute phase, it may be more difficult later, when the original pancreatitis has settled, but the areas of fat necrosis remain to become organised in to markedly fibrotic tumour-like masses. Often there is calcification but this is not specific for fat necrosis resulting from pancreatitis. One feature that may point to a diagnosis of pancreatic fat necrosis is the presence of strongly birefringent crystalloids of saponified free fatty acids within the ghost adipocytes, often accompanied by basophilic debris [118]. Symptoms and investigative findings in 145 patients with tuberculous peritonitis diagnosed by peritoneoscopy and biopsy over a five year period. Cryptococcus neoformans peritonitis in a patient with alcoholic cirrhosis: case report and review of the literature. Konstantinidou E, Alexiou C, Demonakou M, Sakellaridis T, Fotopoulos A, Antsaklis G. A practical method for the identification of particulate and crystalline material in paraffin ­ embedded tissue specimens. Diagnosis and management of peritonitis in continuous ambulatory peritoneal dialysis. Translocation of gut bacteria in rats with cirrhosis to mesenteric lymph nodes partially explains the pathogenesis of spontaneous bacterial peritonitis. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. Fine-catheter aspiration cytology of peritoneal cavity improves decisionmaking about difficult cases of acute abdominal pain. The changing epidemiology of subphrenic abscess and its clinical and radiological consequences. Barium peritonitis: a rare complication of upper gastrointestinal contrast investigation. Varied light and scanning electron microscopic appearances of barium sulphate in smears and histological sections. Granulomatous peritonitis due to cellulose fibers from disposable surgical fabrics: laboratory investigation and clinical implications. Intraperitoneal ivalon mimicking peritoneal malignancy after plugged percutaneous liver biopsy. Gallstones split at laparoscopic cholecystectomy: a new cause of intraperitoneal granulomas. Meconium periorchitis: a clinicopathologic study of four cases with a review of the literature. Meconium periorchitis: intrauterine diagnosis and neonatal outcome: case reports and review of the literature. An infrequent complication of cesarean section with distinctive histopathologic features. Peritoneal keratin granulomas complicating endometrial carcinoma: a report of two cases and review of the literature. Necrotic pseudoxanthomatous nodules of the omentum and peritoneum: a peculiar reaction to endometriotic cyst contents. Rapid onset of massive ascites as the initial presentation of systemic lupus erythematosus. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Colchicine in the prevention and treatment of the amyloidosis of familial Mediterranean fever. Sclerosing peritonitis, an unusual reaction to a beta-adrenergic-blocking drug (practolol). A study of 16 cases and a survey of small bowel function in patients taking beta adrenergic blockers. Sclerosing obstructive peritonitis after continuous ambulatory peritoneal dialysis. Encapsulating peritoneal sclerosis in patients undergoing continuous ambulatory peritoneal dialysis in Japan. Effects of peritoneal dialysis solutions on the secretion of growth factors and extracellular matrix proteins by human peritoneal mesothelial cells. Fulminant sclerosing peritonitis immediately following acute bacterial peritonitis. Are tumefactive lesions classified as sclerosing mesenteritis a subset of IgG4-related sclerosing disorders Sclerosing mesenteritis affecting the small and the large intestine in a male patient with non-Hodgkin lymphoma: a case presentation and review of the literature. Report of a case of the concomitant occurrence of retractile mesenteritis and retroperitoneal fibrosis. Sclerosing mesenteritis presenting with small bowel obstruction and subsequent retroperitoneal fibrosis. Fat necrosis presenting as obscure abdominal mass: birefringent saponified fatty acid crystalloids as a clue to diagnosis. Sclerosing encapsulating peritonitis ­ a rare complication of ventriculoperitoneal shunts. Eosinophilic gastroenteritis presenting as small bowel obstruction: a case report and review of the literature. Sclerosing mesenteritis, mesenteric panniculitis and mesenteric lipodystrophy: a single entity Sclerosing mesenteritis: clinical features, treatment, and outcome in ninetytwo patients. The nomenclature of many of these conditions has evolved over recent years but there persist many morphological and immunophenotypic similarities between the tumours and non-neoplastic lesions. Primary tumours of the peritoneum are regarded as those with primary peritoneal manifestation in the absence of a visceral origin. They may be classified according to their likely histogenetic cell of origin: mesothelial, subserosal mesenchymal and uncertain (from putative uncommitted pluripotent stem cells). In each compartment there are reported tumours with biological behaviour ranging from benign to malignant. Since that time more conditions have emerged and, although there is no perfect classification scheme for tumours of the peritoneum, Table 47. Tumour-like lesions arising in the peritoneum encompass a variety of cysts of the omentum and mesentery, pseudotumours, as well as diverse metaplastic conditions. Some are developmental, others post-inflammatory in nature, but for some the precise nature of the lesion is not known. These tumour-like conditions may mimic both primary and secondary peritoneal neoplasms and therefore accurate diagnosis is important. This chapter presents a review of the various conditions with particular emphasis on the diagnostic features and the role of ancillary investigations that may be of value in discriminating between them. Mesothelial hyperplasia and mesothelial tumours Mesothelial hyperplasia the normal peritoneum is lined by flat, bland and monotonous mesothelial cells with underlying fibrovascular connective tissue devoid of inflammation. Any inflammatory process or serosal injury may induce mesothelial proliferations that range from mild cuboidal cell change to florid multi-layering with cytonuclear atypia and mitoses [2,3]. The presence of reactive mesothelial hyperplasia is common in association with pelvic inflammatory disease, endometriosis [4], hernial sacs or ascites, or in people with abdominal neoplasia [5]. Reactive mesothelial hyperplasia must be distinguished from müllerian endosalpingiosis or endometriosis, and this is usually straightforward on morphological grounds alone. Cytological features such as multi-nucleation, pleomorphism and mitoses, and the presence or absence of inflammation, have been found to be insufficient for the confident separation of reactive and malignant mesothelial proliferations [6]. The most reliable criterion of mesothelial malignancy is the presence of frank stromal invasion in to subserosal mesenchymal tissue and fat. This morphological feature is accentuated by immunohistochemical labelling with broadspectrum cytokeratin. It is composed of a mixture of histiocytes, reactive mesothelial cells, lymphocytes and fibrin. Immunohistochemistry has an important role in distinguishing reactive and neoplastic mesothelial proliferations in serous cytology and histological samples. Occasional cases have been reported in the omentum and mesentery, and rarely in extra-abdominal sites. Adenomatoid tumours are nearly always incidental findings, occurring as small (<10 mm), grey­white or tan-coloured nodules. The Tumours and tumour-like lesions of the peritoneum 821 intervening stroma may be fibrotic or contain smooth muscle. The mesothelial cells may exhibit cytoplasmic vacuolation and a signet ring-like appearance, whereas in more cystic lesions they may be flattened and mimic a vasoformative neoplasm. Some adenomatoid tumours have elements akin to well differentiated papillary mesothelioma [10], others may be reminiscent of multicystic mesothelioma, outlining their common histogenesis [11], but cytonuclear atypia is not seen. The mesothelial nature of the lesional cells may be confirmed by immunohistochemistry (calretinin, cytokeratin 5/6) and, if necessary, by electron microscopy (long slender microvilli, numerous tight junctions). The differential diagnosis includes metastatic adenocarcinoma, vascular tumours (particularly epithelioid haemangioendothelioma) and localised malignant mesothelioma. Although microcystic or adenomatoid areas may be seen in malignant mesothelioma, this is almost always a diffuse serosal neoplasm. Moreover, marked cytonuclear atypia, mitoses and necrosis are not features of benign adenomatoid tumour. Well differentiated papillary mesothelioma this is an uncommon tumour arising predominantly in the female peritoneum or less frequently in the tunica vaginalis testis in men [12]. More recently similar tumours have been reported in the pericardium and pleura [13]. There is no epidemiological evidence linking well differentiated papillary mesothelioma with asbestos, although a history of asbestos exposure has been reported in anecdotal cases [13,14]. Clinically most cases are asymptomatic and incidental findings, although occasionally torsion of pedunculated tumours may cause abdominal pain. In general, well differentiated papillary mesotheliomas follow either a benign indolent or low grade malignant course with progressive disease extending over a 5- to 10-year period [15].

Incorporation of therapeutic interventions in physiologically based pharmacokinetic modeling of human clinical case reports of accidental or intentional overdosing with ethylene glycol muscle relaxant radiolab order online flavoxate. A review of the effects of prenatal or early postnatal ethanol exposure on brain ligand-gated ion channels spasms during meditation order genuine flavoxate online. The use of Markov chain Monte Carlo uncertainty analysis to support a public health goal for perchloroethylene muscle relaxant vecuronium generic 200 mg flavoxate otc. Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology spasms sleep buy discount flavoxate 200 mg on line. The morphological development of glycol etherinduced testicular atrophy in the rat muscle relaxant overdose order 200 mg flavoxate visa. Tissue distribution and macro-molecular binding of extremely low doses of [14C]-benzene in B6C3F1 mice. Effects of volatile solvents on recombinant N-methyl-D-aspartate receptors expressed in Xenopus oocytes. Effects of the abused solvent toluene on recombinant N-methyl-D-aspartate and non-N-methyl-D-aspartate receptors expressed in Xenopus oocytes. Formate in serum and urine after controlled methanol exposure at the threshold limit value. Stable expression of human cytochrome P4502E1 in HepG2 cells: characterization of catalytic activities and production of reactive oxygen intermediates. The uptake and elimination of 1,1,1-trichloroethane during and following inhalation exposures in rats. The impact of exercise and intersubject variability on dose estimates for dichloromethane derived from a physiologically based pharmacokinetic model. Ovarian luteal cell toxicity of ethylene glycol monomethyl ether and methoxy acetic acid in vivo and in vitro. Irreversible impairment of active avoidance behavior in rats prenatally exposed to mild concentrations of carbon monoxide. Identification of S-(1,2,2-trichlorovinyl)N-acetylcysteine as a urinary metabolite of tetrachloroethylene: bioactivation through glutathione conjugation as a possible explanation for its nephrocarcinogenicity. Critical review of the epidemiology literature on the potential cancer risks of methylene chloride. Disrupted G1 to S phase clearance via cyclin signaling impairs liver tissue repair in thioacetamide-treated type I diabetic rats. Effect of exercise or smoking on the uptake, metabolism and excretion of methylene chloride vapor. Covalent binding of chloroform metabolites to nuclear proteins-no evidence for binding to nucleic acids. Validation of a gas chromatography/mass spectrometry method for quantification of aerosolized Jet Propellant 8. Toxicokinetics of propylene glycol monot-butyl ether following intravenous or inhalation exposure in rats and mice. 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Development and characterization of a rodent model of methanol-induced retinal and optic nerve toxicity. Ethylene glycol intoxication: pathophysiology, diagnosis, and emergency management. S-(1,2,2-Trichlorovinyl)-L-cysteine sulfoxide, a reactive metabolite of S-(1,2,2-trichlorovinyl)-L-cysteine formed in rat liver and kidney microsomes, is a potent nephrotoxicant. Volatile organic compounds and pulmonary function in the Third National Examination Survey. Effects of glutathione transferase theta polymorphism on the risk estimates of dichloromethane to humans. Perturbation of artificial and biological membranes by organic compounds of aliphatic, alicyclic and aromatic structure. Human Health Evaluation Manual Supplemental Guidance, Dermal Risk Assessment, Interim Guidance. Induction of hepatomas in mice by repeated oral administration of chloroform, with observations on sex differences. Effects of subchronic exposure of rats to 2-methoxyethanol or 2-butoxyethanol: thymic atrophy and immunotoxicity. Adduction of the chloroform metabolite phosgene to lysine residues of human histone H2B. Trichloroethylene, trichloroacetic acid, and dichloroacetic acid: do they affect fetal rat heart development A human physiologically based pharmacokinetic model for trichloroethylene and its metabolites, trichloroacetic acid and free trichloroethanol. Comparison of the chronic toxicity of triethylene glycol with that of diethylene glycol. Ethylene glycol monomethyl ether effects on health and reproduction in male rabbits. Identification of trichloroethylene and its metabolites in human seminal fluid of workers exposed to trichloroethylene. Pulmonary bronchiolar cytotoxicity and formation of dichloroacetyl lysine protein adducts in mice treated with trichloroethylene. Physiologically based pharmacokinetic modeling of human exposure to 2-butoxyethanol. Plasma disposition and metabolic fate after single increasing intravenous, peroral, or percutaneous doses in the male Sprague­Dawley rat. Gas-phase and particle-phase organic compounds emitted from motor vehicle traffic in a Los Angeles roadway tunnel. The role of calcium oxalate crystal deposition in cerebral vessels during ethylene glycol poisoning. Factors affecting tetrachloroethylene concentrations in residences above dry cleaning establishments. Partition coefficients of lowmolecular-weight volatile chemicals in various liquids and tissues. A toxicokinetic study of inhaled ethylene glycol ethyl ether acetate and validation of a physiologically based pharmacokinetic model for rat and human. The aryl hydrocarbon receptor has an important role in the regulation of hematopoiesis: implications for benzene-induced hematopoietic toxicity. A review of health effects of carbon disulfide in viscose industry and a proposal for an occupational exposure limit. Gamma-glutamyltransferase isozymes pattern in workers exposed to tetrachloroethylene. Evaluation of the potential impact of pharmacokinetic differences on tissue dosimetry in offspring during pregnancy and lactation. A study of ethylene glycol exposure and kidney function of aircraft de-icing workers. Metabolic and cellular basis of 2-butoxyethanol-induced hemolytic anemia in rats and assessment of human risk in vitro. Metabolic basis of ethylene glycol monobutyl ether (2-butoxyethanol) toxicity: role of alcohol and aldehyde dehydrogenases. Structure­activity relationships for the in vitro hematotoxicity of n-alkoxyacetic acids, toxic metabolites of glycol ethers. Calcium channel blockers protect against ethylene glycol monomethyl ether (2-methoxyethanol)-induced testicular toxicity. Hemolytic anemia, thrombosis, and infarction in male and female F344 rats following gavage exposure to 2-butoxyethanol. Pediatric pharmacokinetic data: implications for environmental risk assessment for children. Pharmacokinetic and pharmacodynamic factors that can affect sensitivity to neurotoxic sequelae in elderly individuals. Evaluation of child/adult pharmacokinetic differences from a database derived from the therapeutic drug literature. Phospholipase A2 activation and cell injury in isolated rat hepatocytes exposed to bromotrichloromethane, chloroform and 1,1-dichloroethylene as compared to effects of carbon tetrachloride. The relationship between multiple myeloma and occupational exposure to six chlorinated solvents. Potential role of -2µglobulin, protein droplet accumulation, and cell replication in the renal carcinogenicity of rats exposed to trichloroethylene, perchloroethylene and pentachloroethane. Chlorinated hydrocarbon-induced paroxisomal enzyme activity in relation to species and organ carcinogenicity. Changes in breath trihalomethane levels resulting from household water-use activities. Toluene abuse embryopathy: longitudinal neurodevelopmental effects of prenatal exposure to toluene in rats. Methylene chloride induced mouse liver and lung tumors: an overview of the role of mechanistic studies in human safety assessment. Pulmonary toxicity and carcinogenicity of trichloroethylene: species differences and modes of action. The role of glutathione conjugation in the development of kidney tumors in rats exposed to trichloroethylene. Biological monitoring of kidney function among workers occupationally-exposed to trichloroethylene. Perchloroethylene-induced rat kidney tumors: an investigation of the mechanisms involved and their relevance to humans. The cytotoxicity of oxalate, metabolite of ethylene glycol, is due to calcium oxalate monohydrate formation. Exposure to various benzene derivatives differently induces cytochromes P450 2B1 and P450 2E1 in rat liver. Congenital malformations and occupational exposure to glycol ethers: a European collaborative case­control study. Bayesian population analysis of a harmonized physiologically based pharmacokinetic model of trichloroethylene and its metabolites. Hydrocarbon nephropathy in male rats: identification of the nephrotoxic components of unleaded gasoline. Catalase mediates acetaldehyde formation from ethanol in fetal and neonatal rat brain. Methanol, formaldehyde, and sodium formate exposure in rat and mouse conceptuses: a potential role of the visceral yolk sac in embryotoxicity. Re-evaluation of the 2-year chloroform drinking water carcinogenicity bioassay in Osborne­Mendel rats supports chronic renal tubule injury as the mode of action underlying the renal tumor response. Glutathione depletion modulates methanol, formaldehyde and formate toxicity in cultured rat conceptuses. Pediatric susceptibility to 18 industrial chemicals: a comparative analysis of newborn with young animals. Spontaneous neoplasm incidences in Fischer 344 rats and B6C3F1 mice in two-year carcinogenicity studies: a National Toxicology Program update. The subchronic toxicity of tetrachloroethylene (perchloroethylene) administered in the drinking water of rats. Changes in lung permeability correlate with lung histology in a chronic exposure model. Development of a physiologically based pharmacokinetic model of 2-methoxyethanol and 2-methoxyacetic acid disposition in pregnant rats. Acute experimental poisoning by diethylene glycol: acid base balance and histological data in male rats. Chloral hydrate sedation for pediatric echocardiography: physiologic responses, adverse events, and risk factors. Increased incidence of renal cell tumors in a cohort of cardboard workers exposed to trichloroethene. Ethylene glycol: an estimate of tolerable levels of exposure based on a review of animal and human data. Acute toluene exposure alters expression of genes in the central nervous system associated with synaptic structure and function. Fetal hematopoietic alterations after maternal exposure to ethylene glycol monomethyl ether: prolymphoid cell targeting. Prolonged menstrual cycles in female workers exposed to ethylene glycol ethers in the semiconductor manufacturing industry. Drug­drug, drug­dietary supplement, and drug­ citrus fruit and other food interactions: what have we learned Occupational Exposures in Petroleum Refining: Crude Oil and Major Petroleum Fuels. Glycolate causes the acidosis in ethylene glycol poisoning and is effectively removed by hemodialysis. Effect of 18 hr fast and glutathione depletion on 1,1-dichloroethylene-induced hepatotoxicity and lethality in rats.

Oral administration of some of the benzidinebased dyes on days eight to 12 of pregnancy in the mouse or rat produces reproductive effects in the female offspring similar to those seen with the lower dose levels of busulfan spasms caused by anxiety discount flavoxate 200 mg buy online, albeit at much higher dose levels (1 g/kg/day) (Gray and Kelce spasms synonyms generic flavoxate 200 mg otc, 1996) muscle relaxant dosage generic 200 mg flavoxate with visa. Low levels of occupational exposure have been measured during the production and use of 1 muscle relaxant for pulled muscle 200 mg flavoxate buy,3-butadiene muscle relaxant at walgreens cheap flavoxate line. A diagrammatic representation of the sites of actions of female reproductive toxicants is presented in. The involvement of the autonomic nervous system in this process, as well as in oviductal transport of both the male and female gametes, raises the possibility that drugs known to alter the autonomic nervous system may alter function and therefore fertility. The progression of the fertilized eggs through the oviduct and uterus is under hormonal regulation and chemicals such as the estrogens can stimulate oviductal transport and interfere with uterine endometrial function, precluding implantation (Cummings and Perreault, 1990). These female sex steroids determine ovulation and prepare the female accessory sex organs to receive the male sperm. Sperm, ejaculated in to the vagina, must make their way through the cervix in to the uterus, where they are capacitated. The conceptus then returns from the oviducts to the uterus and implants in to the endometrium. This axis can be disrupted, resulting in infertility at any level of the endocrine system. Uterus Uterine endometrium reflects the cyclicity of the ovary as it is prepared to receive the conceptus. In primates, at the end of menstruation, all but the deep layers of the endometrium are sloughed. Under the influence of estrogens from the developing follicle, the endometrium increases rapidly in thickness. After ovulation, the endometrium becomes slightly edematous, and the actively secreting glands become tightly coiled and folded under the influence of estrogen and progesterone from the corpus luteum. When fertilization fails to occur, the endometrium is shed and a new cycle begins. In the young adult rat, the female has a four to five day estrous cycle which lacks a functional luteal phase (Knobil and Neill, 1994, Chap. During the estrous cycle, the uterus and vagina display remarkable changes in morphology over the brief cycle. Uterine weight and fluid content increase many folds during proestrus under the influence of estrogen. The vaginal cytology also changes daily throughout the estrous cycle, and this can be monitored by examining the cytology of the cells sloughed from the vaginal epithelium in to the lumen with daily vaginal lavages. Uterine weight is a very useful index of estrogenicity in the immature or adult ovariectomized female rats. Because uterine weight and histology fluctuate greatly during the estrous cycle, studies which necropsy females at different stages of the cycle will often be too variable to detect anything but the most profound effects on these end points, but nonetheless it can still be a useful end point and should be measured. A single vaginal lavage, taken at necropsy could be used as a covariate to analyze for treatment effects. In considering these processes, there are numerous potential targets for the action of chemicals upon the system. So for example, there are a number of examples of nutritional deficits (and overexposures) of critical vitamins and minerals (eg, vitamin A and zinc) that are essential for normal reproduction. Perturbing the homeostasis of these nutrients can lead to direct effects on spermatogenesis and subsequent issues with fertility. In the hamster markedly changing the light:dark cycle to reduce the hours of daylight can influence melatonin levels and through a cascade of signaling responses cause regression of the testes and concurrent decreases in testicular steroids and mating behavior. This is a normal circumstance in the wild, but care should be taken in laboratory situations to ensure appropriate housing for the conduct of reproduction studies with this species. The testis also has a finely tuned circulatory system in mammals, termed the pampiniform plexus, designed to shunt the arterial venous blood supply and aid in scrotal cooling. Some chemicals can actually target this structure and the testis circulatory system to induce ischemic shock to the testis again resulting in injury and reduced fertility, with cadmium being an example of an agent that can induce testicular damage via this "indirect" mechanism (Setchell and Waites, 1970). In rodents, there is a highly efficient process for the production of sperm in large numbers. Control testis indicating different cellular associations noted in different seminiferous tubule cross-sections. Diagrammatic representation of a portion of a seminiferous tubule showing the cellular arrangements and testicular compartments. Thus, the seminiferous tubules can be divided in to a number of physiological compartments (as indicated in. It is here that a concentration of sperm and changes in their fluid environment occur as the sperm are ushered through the epididymis and acquire motility and fertilizing ability. The germ cells enter diplotene and then diakinesis with two meiotic divisions, which eventually results in the production of the haploid spermatid population. These initially round cells then undergo an incredible metamorphosis to produce the elongated spermatozoa that mature and are then released in to the seminiferous tubule lumen. The spermatogonial stem cells undergo another round of mitotic division every approximately 13 days in the rat to produce another wave of division and differentiation. For the rat, the time taken for a spermatogonial stem cell to become a mature spermatozoan is approximately eight weeks (and 10 weeks for humans) with an additional 10 days to two weeks for the released sperm to mature in the epididymis and be capable for ejaculation and fertilization of the ovum. One of the consequences of these successive longitudinal waves of differentiation is the highly ordered sequence of events reflected in seminiferous tubular morphology. The most primitive germ cells, the spermatogonia, reside at the periphery of the tubule and as they mature, they move toward the tubule lumen for eventual release (in a process termed spermiation). Thus when we take a cross section through a seminiferous tubule, this is essentially taking a "snapshot" in time of the various spermatogenic cycles. A transverse section of a tubule covering one cycle of the epithelium will contain cellar representatives at different stages of maturity from successive waves (from Foster, 1988). It is possible for the various species to construct a morphological diagram of the nature of these cellular associations. The most common system employed for the rat was based on that published by Leblond and Clermont (1952) and describes 14 different patterns of cellular association (or stages- usually depicted by a roman numeral). We know that different biochemical events can go on during the different stages and indeed this can provide clues as to potential mode of action of chemicals that produce stage-specific lesions. Such occurrences do occur regularly (eg, certain phthalate esters, glycol ethers, antiandrogenic agents, etc). Diagram of the 14 stages of spermatogenesis of the rat testis (after Leblond and Clermont, 1952). These bodies originate at the luminal surface of the tubule and then as they are resorbed, can be seen to move through the Sertoli cell toward the base of the tubule and eventually disappear. Having this "extra" layer of germ cells is a lesion frequently missed by pathologists without a good knowledge and appreciation of the stages of the spermatogenic cycle. Once sperm are released in to the seminiferous tubule lumen and proceed to the epididymis, they can also be the target of toxicant action. Chlorosugars and epichlorohydrin have both been shown to inhibit energy metabolism in sperm that prevents them from functioning normally. We are now learning more about the molecular events that drive fertilization, and it seems likely that here may be a potential target for the action of chemicals to disturb the process. We certainly know of the requirement for the expression of critical cell surface markers by the sperm that facilitate the normal binding of the sperm to the egg surface membrane. Lastly, there is the potential for effects in the male to induce paternally mediated developmental toxicity in the embryo/fetus. While this is not a common occurrence, it has been documented with one or two specific chemicals (eg, cyclophosphamide (Trasler et al. The number of known environmental chemicals that produce adverse responses in human males is not large. All of these have been shown to induce effects in rodents and especially the rat, although there may be differences in sensitivity based on dose. However, this does not imply that all chemicals known to produce injury in the rats would indeed show toxicity in humans. The human does not employ a longitudinal wave for the production of sperm in the testis noted above for the rat, rather cellular associations are organized in a helical fashion that is intrinsically less efficient for sperm production (when estimated on a sperm produced per gram of tissue basis) and thus humans are usually deemed more sensitive, from the risk assessment standpoint, because there are a greater range of values for semen parameters for the human population than the rat and a lesser decrement in sperm number or function is more likely to push larger numbers of men in the population in to the infertile range. Posttesticular Processes Following the release of mature spermatids from the seminiferous epithelium, the extraneous cytoplasm and organelles form the residual body that is phagocytosed by the Sertoli cell and moves from the periphery of the tubule to its base. These nonmotile sperm are moved along the tubules by a peristaltic-like action of the myoepithelial cells of the tubule and eventually empty in to the rete testis. In rodents, but not humans, a large blood plexus forms over the rete (which is close to the surface and near the pole of the testis) where fluid exchange can take place. The efferent ducts then empty in to the caput (head) of the epididymis which is a single highly coiled tube derived from the Wolffian duct in utero. The epididymis can be divided in to three anatomical portions: the caput, corpus (body), and cauda (tail), which has a changing chemical environment and fluid composition from the efferent ducts through to the cauda. The sperm undergo maturation in the caput and corpus and begin to acquire motility, whereas the cauda is principally used for sperm storage, although expression of some critical surface markers does occur that are involved in the process of fertilization. In humans, the passage of sperm takes approximately six days and is longer in rats (10 days). During the movement along the epididymal, tubule fluid is removed by active transport and this stage of the process is one that can be interfered with by toxicants resulting in an inappropriate environment for normal sperm development. Most mammals possess seminal vesicles and a prostate (in experimental animals, the exception is that dogs do not have seminal vesicles) and the accessory sex organs are depicted in. The physiology and anatomy of these organs vary widely among mammalian species with the rodent having a clear lobular pattern to the prostate that is not seen in humans. These organs are predominantly glandular/secretory in nature and produce much of the seminal plasma for the ejaculation of sperm to survive within the female reproductive tract. The seminal plasma contains many nutrients for sperm motion as well as distinct proteins and ion content. For example, a diminution in energy substrates can affect sperm motion characteristics. These "accessory sex organs" are androgen dependent for their function and/or development and are frequently recorded in toxicity studies as indicators of androgen action. Parasympathetic nerve stimulation results in dilatation of the arterioles of the penis, which initiates an erection. Erectile tissue of the penis engorges with blood, veins are compressed to block outflow, and the turgor of the organ increases. In the human, afferent impulses from the genitalia and descending tracts, which mediate erections in response to erotic psychic stimuli, reach the integrating centers in the lumbar segments of the spinal cord. The efferent fibers are located in the pelvic splanchnic nerves (Andersson and Wagner, 1995). Emission is the movement of the semen in to the urethra; ejaculation is the propulsion of the semen out of the urethra at the time of orgasm. Afferent pathways involve fibers from receptors in the glans penis that reach the spinal cord through the internal pudendal nerves. Emission is a sympathetic response produced by contraction of the smooth muscle of the vas deferens and seminal vesicles. Semen is ejaculated out of the urethra by contraction of the bulbocavernosus muscle. The spinal reflex centers for this portion of the reflex are in the upper sacral and lowest lumbar segments of the spinal cord; the motor pathways traverse the first to third sacral roots of the internal pudendal nerves. Little is known concerning the effects of chemicals on erection or ejaculation (Woods, 1984). Pesticides, particularly the organophosphates, are known to affect neuroendocrine processes involved in erection and ejaculation. Many drugs act on the autonomic nervous system and affect potency (Table 20-5) (see also Buchanan and Davis, 1984; Stevenson and Umstead, 1984; Keene and Davies, 1999). Impotence, the failure to obtain or sustain an erection, is rarely of endocrine origin; more often, the cause is psychological. The occurrence of nocturnal or early-morning erections implies that the neurological and circulatory pathways involved in attaining an erection are intact and suggests the possibility of a psychological cause. Normal penile erection depends upon the relaxation of smooth muscles in the corpora cavernosa. In the rat, prenatal exposure to the antiandrogenic fungicide, vinclozolin, induces a significant reduction of erections at all dose levels during the ex copula penile reflex tests in male offspring (Colbert et al. Note that multinucleate giant cells and germ cell debris sloughed in to the tubular lumen. Foster (1989) showed that five-day dosing with 5 mg/kg/day produced a minimal to moderate testicular lesion within two weeks and with 10 mg/kg/day a moderate to severe lesion. Testicular weight remained reduced for many weeks after the treatment period with significant dose-related effects on fertility (measured by pregnancy rate and implantation success). Detailed electron microscopic evaluation has shown initial lesions to be present in the Sertoli cells of the testis, which results rapidly in germ cell apoptosis and death. The earliest studies using a 10 week dosing regimen (five day/week by gavage in corn oil) reported effects at 6 mg/kg/day (Linder et al. Effect of m-dinitrobenzene on percentage of females pregnant in a serial mating study design. Note that the range of germ cell types affected consequent to the Sertoli cell injury produced by the compound and the reversibility of the effects after 16 weeks (two spermatogenic waves-see. The earliest features of these studies after a single dose (250 or 500 mg/kg/day) were that there are Sertoli cell vacuoles and swollen germ cell mitochondria, followed by (or concurrent with) a breakdown of the membrane between the Sertoli cell and the pachytene spermatocyte in a spermatogenic stage-specific manner. This is followed quickly (within hours) by the death of (probably those) pachytene spermatocytes (Foster et al. Continued treatment at a low effective dose seems to affect just the vulnerable cell types, so that a window of missing cells appears downstream from the stage of damage as time progresses. As with other testis toxicants, higher dose levels produce a more widespread lesion involving other cell types (Foster et al. Effect of ethylene glycol monomethyl ether (or its metabolite methoxyacetic acid) 24 hours after a single oral dose (100 mg/kg/d). Note the damaged spermatocytes (arrows) in lower tubule compared to the upper normal tubule.

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