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Chemical structure of the thyroid hormones the synthesis of these hormones requires the amino acid thyrosine and the trace mineral iodine virus undead buy generic vantin 200 mg. The production of these iodinated amino acids begins with the synthesis of thyroglobulin that is posttranslationally modified in a series of biochemically unique reactions antibiotics kellymom order vantin 100mg fast delivery. All these biosynthetic processes within the thyroid gland are controlled by feedback mechanism within the hypothalamic-pituitary-thyroid axis antibiotics for uti in renal failure purchase vantin 200 mg with visa. In thyroid gland iodine pump on basolateral plasma membrane can concentrate ions of iodine 30 times more than in blood bacteria botulism purchase vantin with amex. During the maximum activity of gland the concentration rises up to 250 times more than in blood. High increase of iodine concentration in blood, uptake of iodine higher than 2 mg/day, leads to much higher concentration of ions in thyroid gland and decrease the biosynthetic processes within the gland. This autoregulatory phenomenon is known as Wolf-Chaikoff effect which inhibits formation of thyroid hormones inside of the thyroid follicle. In its major form, Tg is a 660 kDa dimeric glycoprotein, composed of two identical subunits. A molecule of Tg contains 140 tyrosines, although only around 20% of these are actually used to synthesize T4 and T3. It is synthesized and initially processed in the endoplasmatic reticulum with the formation of dimers and with addition of N-linked glycoside residues. Further is processed in the Golgi apparatus, especially by modification of carbohydrate residues. Tg is transported via vesicles from the trans-Golgi network to the apical surface of thyrocytes and released into the lumen of thyroid follicles where it is stored in colloid as the major component (>95%). Heterogeneity of Tg within the colloid is not restricted to its iodine and carbohydrate content. Thus, although the predominant form of Tg is the 660 kDa, free 330 kDa monomers can be found in minimal amounts. Reduction or degradation of both can lead to the formation of smaller polypeptides usually in trace amounts in the colloid. The other synthetic reaction is a coupling reaction where iodotyrosine molecules are coupled together. Uptake of Tg by thyrocytes occurs by micropinocytosis, which can be either nonspecific (fluid phase) or receptor mediated. Both forms of micropinocytosis, also called endocytosis or vascular internalization, involve the formation of small vesicles at the apical membrane, which invaginate to form intracellular vesicles that fuse with lysosomes. In contrast, receptor-mediated endocytosis involves specific binding of certain substances to cell surface receptors, with high or low-affinity. Several receptors have been proposed on the apical surface, where they could mediate endocytosis, or on intracellular membranes, where they might influence intracellular trafficking. Tg binds to megalin in solid-phase assay, with characteristics of high-affinity receptor-ligand interactions. A thyroid asialoglycoprotein receptor may internalize and recycle immature forms of Tg back to the colloid. There is also evidence of low-affinity receptors on thyrocytes, but their role in Tg uptake is not finally established. T3 is produced 10 times less but most T3 is derived from T4 by deiodination in peripheral tissues, liver, kidneys and muscle, catalysed by deiodinases. In tissues, most of the effect of T4 results from this conversation to T3, so that T4 is a prohormone. The majority of the activation of the prohormone T4 to the T3 occurs through non-thyroidal deiodination. Further degradation of rT3 and T3 results in the formation of several distinct diiodothyroxines (T2). The metabolic role of the T2 isomers is poorly understood and is unclear in humans. Although some T3 is produced in the thyroid, approximately 80% is generated outside the gland, primarily by conversion of T4 in the liver and kidneys. Role of thyroglobulin endocytic patways in the control of thyroid hormone release. Minireview: Thyrotropin-releasing hormone and the thyroid hormone feedback mechanism. Thyroid-stimulating hormone and thyroid-stimulating hormone receptor structure-function relationship. Department of oncology and nuclear medicine Referral Center for Thyroid Diseases of the Ministry of Health, "Sestre milosrdnice" University Hospital, Zagreb, Croatia 2. It is estimated that over 30% of school-aged children (over 250 million) have insufficient iodine intake and in the general population, 2 billion people have insufficient iodine intake. The greatest proportion of children with inadequate iodine intake live in Europe (over 50%), where it is found that 19 countries have insufficient iodine intake. Croatia has crossed a path from severe iodine deficiency detected in the 1950 when along with the cretinism, goiter was detected in 50-90% of schoolchildren, to the period of mild to moderate iodine deficiency during the 1990 when proportion of goiter was reduced to 10 30% of schoolchildren, and finally, nowadays, iodine sufficiency has been reached. In iodine sufficient countries the most common disorder is the appearance of thyroid nodules. The frequency of the subclinical thyrotoxicosis ranges from 0,5 to 6,3%, and the highest prevalence is among women and men over 65 years of age of which half of them take thyroid hormones. Subclinical thyrotoxicosis is more often seen in the areas with iodine deficiency. It is more common in older women and ten times more frequent in women than in men. In areas with iodine sufficiency the most common causes of hypothyroidism are: chronic autoimmune thyroiditis or destructive therapy of hyperthyroidism. After the radioiodine treatment of hyperthyroidism, the development of hypothyroidism takes place almost in every patient, especially during the first year. The highest prevalence is among premenopausal women and the ratio women/men ratio is 4:1. With age there is a fall of the diffuse goiter prevalence in contrast to the rise of nodules and antibodies. It seems that the ultrasound is too sensitive test and that it detects too many nodules that have no clinical value. The prevalence of palpable thyroid nodules in iodine sufficient areas is about 5% in women and 1% in men. Much higher prevalence of thyroid nodules is detected by ultrasound, or in autopsy findings (over 50%). The prevalence of thyroid nodules detected by ultrasound or at autopsy linearly increases with age from 0% at the age of 15 years, 30% at the age of 50 years, and even up to 50% at the age of 60 to 65 years. Furthermore, the prevalence of thyroid nodules is higher in persons previously exposed to ionizing radiation and in those living in iodine deficient areas. Therefore, guidelines for management of patients with thyroid nodules are very important due to successful confrontation with appearing epidemic of multinodular goiter and in the same manner, the epidemic of thyroid cancer. Thyroid diseases: epidemiology, pathophysiology and classification During the past decades, multifold increase in the incidence of thyroid cancer was recorded worldwide, and also in Croatia. During the time period from 1968 to 2004, age standardized incidence rate of thyroid cancer has increased in Croatia 8,6 times in women and 3,6 times in men. However, mortality from thyroid cancer in Croatia has remained low in both females and males with mild declining trend in females during the last 20 years. In 2004, age standardized mortality rate from thyroid cancer in Croatia was 0,4 per 100 000 of population in both females and males. Recently, occult papillary thyroid carcinomas (papillary thyroid microcarcinomas) are frequently discovered due to improved diagnostics. World Health Organization defines papillary thyroid microcarcinoma as papillary thyroid carcinoma less or equaling 1 cm in diameter. It is generally believed that the increase in the incidence of thyroid cancer worldwide is mainly due to improved diagnostics (wide use of ultrasound and fine needle aspiration biopsy). It is presumed that if the entire pool of occult thyroid carcinomas were identified ante mortem, the result would be almost 50-fold increase in the apparent incidence of thyroid cancer.


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Researchers as those in cigarette smoke antibiotics for canine ear infection vantin 100 mg on-line, and ultraviolet radiation have found that ovarian cancers with defective from the sun antibiotic resistance review cheap 100mg vantin with mastercard. It showed eight nodules antibiotics for acne with no side effects order vantin 200 mg on line, seven of which turned a 5-centimeter mass in my lef ankle antibiotic resistance in zambia buy 100 mg vantin otc. We know this My reaction to the diagnosis would has stabilized my disease because the probably surprise most people. I wasn?t nodules in my lef lung and the nodule shocked; I just wanted a plan to deal in my hip have stayed the same size and " My hope is that this combination approach to treatment will allow me to live a normal life. To be sure, I?ll people expect cancer but it happens, and be continuing with olaratumab for at now it had happened to me. Because we are The frst part of my plan was to fnd a going for a cure, I?ve also just completed specialist. The orthopedic oncologist I six radiotherapy treatments to eliminate saw at Memorial Sloan Kettering Cancer the nodule in my hip and I?m scheduled Center recommended that I have a for open surgery to remove the nodules below the knee amputation of my lef in my lef lung at the end of July 2017. Before I went ahead with such a life My hope is that the cancer will not changing surgery, however, I obtained a come back and that I will have a normal second opinion and had a second biopsy, life expectancy for an otherwise healthy this time an open surgery biopsy. I want to keep enjoying life Once the diagnosis was confrmed, I and doing all the normal things that a was at peace with the decision to amputate. I also hope that if the cancer does come I was back in the gym shortly afer the back, the research currently being done At the start of November 2015, I was surgery, even before I had my prosthetic will have resulted in a clinical tool that fnally able to relax afer a stressful six leg ftted in March 2016. When I exercise, I don?t feel like a I was a research chemist, so I know was born, we moved, I started a new job, cancer patient; I feel in charge of my body how long it takes before basic research and I took and passed my diagnostic and that is very important to my mental can change lives. Longer follow-up of these patients has recently shown that the combination also improves overall survival (147). The phases of the cycle G1 between the checkpoints have diferent names (G1, S, G2, and M). They were approved for treating certain patients with breast cancer in February 2015 and March 2017, respectively. In this setting, the leading cause trastuzumab is usually given for one year afer surgery of cancer-related and chemotherapy. The discovery that 50 percent of diagnosed form of lung cancer in the United States (2). I was fortunate to be living near the It was also testing whether maintenance Mayo Clinic in Minnesota where they therapy with bevacizumab (Avastin) were investigating whether young after the chemotherapy would help. I was barely not to be tested because I thought I had functioning; it was hard to get up, get done everything I could to protect myself dressed, eat, anything. It was I really didn?t have many symptoms in San Francisco, so I?ve had to travel before my diagnosis apart from back and forth a lot over the past 2? The day I started the trial, I took feel something in my abdomen that I the red eye home and then few the next went to the doctor. But cancer has taught me With chemotherapy, I could barely get I had ovarian cancer that had spread that my family and friends are the most out of bed. I had important things in my life and I take the world with my family; I?ve been on advanced disease. Cancer has been part of my life for field at the time and I knew that the life events. In 1990, even in a clinical trial would improve my the path I chose, participating in clinical before there were any known breast chances of beating the statistics. The trials, is helping make a diference to the cancer susceptibility genes, the doctors trial I participated in was testing future of ovarian cancer care. Brigatinib was also able to shrink tumors that intensive basic and clinical research investigation. The other approved immunotherapeutics with other types of two, brigatinib and alectinib (Alecensa), are approved only anticancer treatments, including radiotherapy, cytotoxic for treating patients whose cancer has either progressed chemotherapeutics, and molecularly targeted therapeutics afer treatment with crizotinib or has failed to respond to (see Improving Outcomes by Combining Existing crizotinib in the frst place. Not all immunotherapeutics work shown that some tumors evade destruction by T cells in the same way (see sidebar onHow Immunotherapeutics because they have high levels of proteins that attach to and Work, p. Tese brakes, which are on the surface of The use of immunotherapeutics in the treatment of cancer T cells, are called immune-checkpoint proteins. In recent years, it has emerged as one of the most exciting new approaches this knowledge has led researchers to develop to cancer treatment that has entered the clinic. These part because some of the patients with metastatic disease immunotherapeutics are called checkpoint inhibitors. Some comprise a virus that preferentially infects and kills cancer cells, releasing molecules Some boost the killing power of the that trigger cancer-fghting T cells; immune system by enhancing these are called oncolytic virotherapeutics, T-cell function, for example, for example, talimogene interleukin-2 (Aldesleukin). One class of cancer immunotherapeutics works by approved for treating fve types of cancer. In the 12 months covered by this report, August of solid tumor characterized by the presence of specifc 1, 2016, to July 31, 2017, there was a dramatic increase in molecular characteristics, or biomarkers. The patients proportion of cancers arising at numerous sites in the body, included in the analysis had been diagnosed with any including the colon, endometrium, stomach, and rectum one of 15 types of cancer, most commonly colorectal (167). The scientifc rationale underpinning this landscape in the tumor as normal and are unlikely to approval was the result of dedicated researchers integrating be spurred into action by pembrolizumab. It was materials such as tissues, cells, granted accelerated approval for treating certain patients and/or bodily fuids. The polyps and colorectal cancer, and I had trial was being conducted at the Sidney an endoscopy every other year to check Kimmel Comprehensive Cancer Center for signs of other digestive tract cancers. In my mind, it was a matter of when, At frst it seemed that I might not be not if, I would develop cancer. So, when eligible for the trial because my liver routine blood tests showed my liver enzyme levels were fuctuating wildly. Afer interviewing three who performed the endoscopy said: surgeons, I chose to have the procedure at If somebody hadn?t told me you had Memorial Sloan Kettering Cancer Center ampullary cancer I wouldn?t have in New York. I have Lynch syndrome it seemed like At this point, chemotherapy was my a good insurance policy for me. Eileen O?Reilly, had to switch me to a continue to have annual colonoscopies My journey with cancer really began diferent chemo regimen. Afer about and endoscopies because of the Lynch 12 years ago, when one of my sisters, fve months of this, the cancer started syndrome. My philosophy is to not who was 46 at the time, was found to growing again and we had to switch to waste time worrying about these things; have Lynch syndrome. Ampullary cancer syndrome is an inherited condition Less than six months later, Dr. O?Reilly was supposed to be a death sentence, many of our family members underwent told me we needed to look for alternative but I?m alive thanks to the treatment I genetic testing. It turns out that my treatments because the chemotherapy received through the clinical trial. I?m mother passed on the genetic mutation had stopped working again and the forever grateful to everyone who made that causes Lynch syndrome to me and chances that more chemotherapy would this possible?the doctors, researchers, my sister and that I have passed it on to solve the problem were slim. During the year I had been under who funded the trial and the underlying Lynch syndrome dramatically increases Dr. They may also lead to the diagnosed cancer in the identification of biomarkers that identify the patients United States in 2017 (2). This is important because it could allow a patient unlikely to beneft from a particular checkpoint inhibitor to be spared continued fromp. Tese biomarkers are Hodgkin lymphoma that has not responded to treatment used for identifying those patients with lung cancer and or that has relapsed afer three or more diferent treatments. In some other cases trial showing that pembrolizumab treatment led to tumor for example, the use of durvalumab as a treatment for shrinkage in the majority of patients (176). The successes highlighted here have led to clinical trials According to the latest estimates, more than 15. Results are not available yet for most of these 1971, and this number is projected to rise to 20. It is not just cancer survivors who are afected afer a cancer diagnosis, but also their caregivers, and this population 112,370 is growing proportionally with the number of cancer of these individuals survivors. Caregivers are at risk for poor health outcomes, are children and this is ofen compounded by the fact that a subset of or adolescents caregivers are already cancer survivors themselves. Optimizing Quality of Life across the Continuum of Cancer Care One approach that can be used across the continuum of cancer care to optimize the quality of life for patients 3 Million and their families is palliative care (see sidebar on What Is Palliative Care? Several of the advances highlighted in these sections are helping As research drives advances in cancer detection, diagnosis, to reduce the short-term adverse efects of treatment as and treatment, more and more people are living longer afer well as the long-term and late efects of treatment. As a result, palliating the discussion focuses primarily on other recent advances the physical symptoms and adverse efects of cancer and that can help improve outcomes and quality of life for its treatment is becoming increasingly important.

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They rapidly dis placed traditional tobacco products such as cigars antibiotics for pneumonia purchase vantin on line amex, pipes antibiotic resistance video clip purchase vantin toronto, hand-rolled Stages of the epidemic cigarettes antibiotic 3 day dose buy vantin 100 mg visa, and snuff and by 1920 the progression of the cigarette ep were the product of choice among idemic safest antibiotic for sinus infection during pregnancy buy vantin, frst observed in developed new users. The distribution of free countries, has been conceptual cigarettes to soldiers in the First ized as a sequence of four stages and Second World Wars, combined that apply more broadly worldwide. Geographical variations However, as tobacco advertising bans take effect, teams have started using an Most of the stages of the cigarette alternative livery that alludes to the tobacco sponsor or eliminates its name entirely. Most sub-Saharan for men and women in their severity cability of the stages of the epidem African countries, with the excep and timing. Per capita and implementation of effective to the prevalence of cigarette smok consumption is fat or only begin bacco control policies also curtail ing in men generally increases ning to increase, and there is no tobacco use. Stage 3 is characterized by a fattening or downturn in smoking prevalence (and usually in per cap ita consumption), coinciding with a continuing steep increase in smok ing-attributable deaths. Several factors infuence the stage of the epidemic within a given country or region. These include the affordability and availability of cigarettes and the intensity of to bacco industry marketing efforts. Although countries (China, Bangladesh, Ne ally transitioning from stage 3 to female prevalence does not gen pal, Viet Nam, Indonesia, and the stage 4. Smoking typically begins at Convention on Tobacco Control a large proportion of the anticipated young ages, and Chinese women have reduced tobacco use in many 450 million deaths from tobacco represent a vast untapped market countries. For example, increases over the next few decades by en for the tobacco companies. Strategies to curtail the way on plain packaging (removal epidemic of all graphic branding from ciga Education about the harms of to rette packs). The widespread ap bacco use and policy interventions plication of a few powerful tobacco 86 References 1. The globalization of tobacco use: Smoking and Health: Report of the tion on Tobacco Control. Estimates of Health Service (Public Health Service Effectiveness of Tax and Price Policies global mortality attributable to smoking in Publication No. The worldwide epidemic of benzene (a cause of leukaemia), than 7000 chemical compounds, tobacco-caused diseases comes formaldehyde (an irritant and car of which many are known carcin largely from widespread smoking cinogen), carbon monoxide and cy ogens. In the contain more than 3000 chemi Bangladesh, smokeless tobacco presence of smoking, nonsmokers cals and numerous carcinogens. The potency of and also some exhaled mainstream implicated in carcinogenesis tobacco products, particularly cig smoke. Over the course products, as with many cigarette of smoking prevalence among the of a day, a smokeless tobacco user brands, usually have an ingredient 19 countries and far higher rates of may ingest twice as much nicotine that increases the pH, to promote the smoking among men than women, as a smoker. In some countries, classifed as loose leaf for chew carbonate, and sodium carbonate. Newer products include Patterns of use aged 35 years or older, the average fne-cut or powdered tobacco. Cigarettes age of initiation was generally older snuff) in teabag-like pouches, dis the Global Adult Tobacco Survey in women than men. The frst global report girls in this age range have smoked matized with substances like es based on the Global Adult Tobacco in the past month and the prevalence sences, spices, and perfumes. Menthol is often used to prevent Survey was published in 2012, of smoking among girls is approach irritation. Prevalence of current tobacco smoking among male and female adults may purchase a pre-mixed product. China Tobacco-specifc nitrosamines India are relevant to both smoking and Bangladesh smokeless tobacco use but are of Viet Nam particular prominence in the use of Philippines smokeless tobacco because poly Thailand cyclic aromatic hydrocarbons are Russian FederaHon generated by combustion and are Ukraine therefore not implicated in smoke Males Poland less tobacco carcinogenesis. These Females Egypt compounds are formed by the nitro Turkey sation of nicotine and its metabolites. These are fol lowed by Bhutan, Nepal, Sweden, reach and deposit in the bronchioles have excess risk of cancer from Sri Lanka, Sudan, Turkmenistan, and alveoli. The fgure highlights the tries according to national prevalence differing levels of carcinogens, not multiple processes that lead to un of adult smokeless tobacco use. There are both specifc smoke, and the general scheme of is believed to be smokeless tobacco and nonspecifc pathways by which Fig. The fgure begins with initia acids, and volatile aldehydes such ing prevalence was 8. Certain tobacco-relat causation who smoke daily throughout their ed nitrosamines. These variants, al variation not tested extensively to tients with tobacco-related cancers though in close proximity, appear date, such as rare population fre have an excess risk of developing to differ in their effects in terms of quencies and copy number repeats, the same type of cancer. Manhattan plot of lung cancer genome-wide association study results, overall (A) and restricted to adenocarcinoma (B) and squamous cell carcinoma (C). Findings of more malignant lesions associated with cancer risk falls after successful ces recent studies suggest that relative smokeless tobacco use. Note: For cancers of the liver, has not been typical of smokers to colon, rectum, ovary (mucinous), and date. Tobacco smoking shows that involuntary smoking, the the epidemiological evidence on inhalation of second-hand smoke by smoking and cancer comes from nonsmokers, causes cancer. At this time, the evidence linked to the increasing evidence to the global epidemic of tobacco use. Chewing tobacco has been as health is damaged by smoking proven to cause oesophageal, oral, blad ration of use in years, and women from conception onward. Smokeless initiation to promoting successful tobacco users often have pre cessation. Particular issues include cancerous oral mucosal lesions, avoiding exposure to second-hand such as leukoplakia. These white smoke and discouraging pregnant lesions tend to disappear within women from smoking. These lesions are dynamic in time, changing as the to more common in smokers who bacco industry attempts to counter also use smokeless tobacco, and control measures. Areca nut chewing is popular provisions requiring Parties to imple als are also smokers. Information about the impact of India have been formulated based For multiple sites, including lung initiatives designed to encourage on a study of the characteristics and cancer in smokers and oral cancer in individuals to cease smoking is pre needs of target groups. The circumstances involving cancer de Smokeless tobacco interventions have involved the stu velopment, and causality is proven. Tobacco control needs to include dents in interactive classroom and Thus, tobacco control provides a smokeless tobacco in its purview. Hence, taxation needs to cover non-intervention schools have been effective tobacco control policies. The risk of oral cancer ed messages to diffuse information is very high for smokeless tobacco at mass level and in small groups as users, especially if use is initiated at well as by one-to-one interaction with 94 References 1. Consequences of Smoking: A Report venting tobacco use among adolescents of the Surgeon General. Department of Health and Human National Tobacco Control Programme in Services (2010). Personal habits and in and preventing tobacco use among low Center for Chronic Disease Prevention door combustions. Reducing Tobacco Use: of Tobacco-Related Cancers and Other A Report of the Surgeon General. Department of under the Global Tobacco Surveillance Health and Human Services, Public System. Tumour types caused by Summary increases in price, and marketing drinking alcoholic beverages include bans. For renal risk has been known since the the association between alcohol cell carcinoma and non-Hodgkin beginning of the 20th century. Further known beverages are responsible for 337 400 deaths and neck cancers compared with other fruit wines, cider, and a broad worldwide, predominantly people who abstained from drink range of very diverse spirits, includ among men, with liver cancer ing for religious reasons, and that ing shochu, sake, lotus or agave accounting for the largest pro such abstainers had a markedly based spirits, and various types portion of deaths among the lower risk of these forms of cancers of country-made liquor in India. The relationship between average daily alcohol consumption and relative risk of cancer. Associations have been reported consumption and from other disease the rates of alcohol-attribut between alcohol consumption and conditions and injuries, in each case able cancer deaths and of alcohol Fig. Percentage of deaths from various forms of cancer attributable to alcohol consumption, in 2010.

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Expo sure to antibiotics for acne short term order vantin on line amex hexachlorobenzene affected the female gonad histopathologically and endocri nologically antibiotics for sinus infection not penicillin cheap 100mg vantin overnight delivery. Hexachlorobenzene induced follicular degeneration and increased atresia in rodents and primates (Sims et al antibiotics for uti not helped vantin 100mg without a prescription. The highest dose of hexa chlorobenzene used (10 mg/kg bw per day orally for 90 days) specifically reduced the numbers of primordial follicles in cynomolgus monkeys (Macaca fascicularis) (Jarrell et al antimicrobial toilet seat purchase vantin overnight delivery. The effects of hexachlorobenzene on ovarian morphology and steroidogenesis can be induced at a dose as low as 0. Decreased uterine estrogen receptor concentrations were also observed in these rats, but no change was found in uterine weight. No studies were found on the effects of hexachlorobenzene on the male reproductive system. Exposure in utero and during lactation caused neonatal mortality in rats fed diets containing 60?140 mg/kg hexa chlorobenzene (Kitchin et al. The latter effects were observed in the pups of dams treated with 10 or 50 mg/kg bw per day on days 6?16 of gestation (Andrews & Courtney, 1986). These malformations were strikingly similar to the terata associated with exposure to dioxins in utero, as noted by these authors, which raises the issue of the possible presence of traces of dioxins in technical-grade hexachlorobenzene. Both doses diminished delayed-type hypersensitivity responses in offspring tested at 40 days of age; the higher dose impaired mixed lymphocyte response to allo genic spleen cells; and, in adulthood, small changes in the relative proportion of T and B cells in the spleen were observed. Two studies were conducted to determine the effects of exposure to hexachloro benzene during development on neurobehavioural end-points. Female Sprague Dawley rats were exposed before gestation to hexachlorobenzene by gavage at a dose of 2. In assessments of behaviour during the first 20 days after birth, hexachlorobenzene exposed pups responded more quickly to negative geotaxis tests and in olfactory discrimination tests. The complexity of these effects makes it difficult to propose hypo theses about the mechanism of action, but the results demonstrate that hexachloro benzene can affect neurobehavioural function in developing rats (Goldey & Taylor, 1992). No changes were found in open-field activity at postnatal day 21; however, in tests of operant learning begun at postnatal day 150, treated animals showed decreased response rates (Lilienthal et al. In adult female rats fed hexachlorobenzene at a concentration that induced porphyria, the activity of microsomal glucuronyltransferase was increased (Graef et al. Both crude and purified hexachlorobenzene were found to increase the activity of liver enzymes in male and female Sprague-Dawley rats 4 days after an intraperitoneal injec tion of 150 mg/kg bw. The enzyme activities induced included benzphetamine N-de alkylation, ethoxyresorufin deethylation and ethoxycoumarin O-dealkylation (Franklin et al. The effect of a single dose of 200 mg/kg bw hexachlorobenzene was compared in male Syrian hamsters and male Fischer 344/N rats. In rats, the two enzyme activities were induced approximately 12 and fivefold, res pectively (Smith et al. During that time, one-third of the rats died, and the urinary porphyrin concentration increased to 100 times the control level. It was further noted that, whereas the animals that died began wasting 5 days after cessation of intake of hexachlorobenzene, when relatively minor disturbances in porphyrins were found, the survivors developed major porphyrin disturbances without wasting; the deaths were therefore not correlated with porphyria (Rozman et al. Microsomal cytochrome P450 was induced to a greater extent in male than in female Fischer rats, while cytochrome b5 was induced only in males. Aminopyrine-N-de methylase activity doubled in animals of each sex after treatment, while that of Ah hydroxylase was 16 times the control value in females and 1. After hexachlorobenzene treatment, the phospholipid content of microsomal membranes in liver was increased, while the cholesterol content was unchanged. Ana lysis of the phospholipid pattern showed that hexachlorobenzene interfered with the bio synthesis of phospholipids containing choline. Hexachlorobenzene showed more pronounced features of a phenobarbital type inducer in males than in females (Cantoni et al. Taken together, these results indicate that hexachlorobenzene is a weak agonist for the Ah receptor and suggest that some of its effects are mediated by its interaction with this gene-regu latory protein (Hahn et al. After 42 days, the mice were injected a second time with 75 mg/kg bw hexachlorobenzene and killed 20 days later. In wild-type mice, the hepatic uroporphyrin concentration ranged from 70 to 310 nmol/g of liver, whereas in null mice it was < 1 nmol/g of liver. This study also showed that hexachlorobenzene did not increase hepatic microsomal uroporphy rinogen oxidation in Cyp1a2(-/-) mice (Sinclair et al. Female B6-Ahb mice (Ah receptor, approximately 30?70 fmol/mg of cytosolic protein) and B6-Ahd mice (Ah receptor, undetectable) were pretreated with iron at 500 mg/kg bw (given as iron dextran) and then fed a diet containing 0 or 200 mg/kg hexachlorobenzene for up to 17 weeks. Urinary excretion of porphyrins was increased after 7 weeks of hexachlorobenzene treatment in B6-Ahb mice, and by 15 weeks was over 200 times greater than that of mice given only iron. In B6-Ahd mice, porphyrin excretion did not begin to increase until after 13 weeks, and after 15 weeks was only six times greater than that of controls. Similar differences were seen in the hepatic porphyrin concentrations at 15 weeks: B6-Ahb, 1110 393; B6-Ahd, 17. The activity of the enzyme was only slightly inhibited in the absence of iron, and was not inhibited in the absence of hexachlorobenzene. While there is a marked sex difference in hexachlorobenzene-induced porphyria (see above), the induction of oxidation of uroporphyrinogen I to uroporphyrin I by hepatic microsomes was not correlated with the sex difference in porphyria deve lopment. Hexachlorobenzene was found to be a potent inducer of malic enzyme gene expression in the liver of female Wistar rats exposed to 1 g/kg bw by gavage for 9?15 days. No changes in T4 or T3 concentrations were found in rat liver, and the activities of other thyroid hormone-responsive enzymes were not found to be increased. In contrast, in brown adipose tissue of male Wistar rats given 1 g/kg bw hexachlorobenzene by gavage for 30 days, the activities of malic enzyme, glucose-6-phosphate dehydrogenase and L-glycerol-3-phosphate dehydro genase were decreased in both euthyroid and thyriodectomized rats (Alvarez et al. Administration of 1 g/kg bw hexachlorobenzene to rats for 10 days caused a 50% reduction in epidermal growth factor receptor?ligand binding (Randi et al. The expression was localized to the centrilobular region, with the most intense staining nearest the central vein. Evaluation of porphyrin fluorescence also revealed centrilobular accumulation, with average concentrations of porphyrin of 0. The results were compared with those for 28 control workers who had not been exposed. The 28 controls were men working in other companies in the same geographical region and of the same median age, but without detectable serum concentrations of hexachlorobenzene. In the exposed group, there was no correlation between the occurrence of micronuclei and age, current smoking, length of employment at the factory or hexa chlorobenzene concentration in serum. The authors noted that it was not possible to identify a particular factor that might account for the difference in the frequency of micronuclei (da Silva Augusto et al. In a study from one laboratory, hexachlorobenzene induced alkali-labile sites in human hepatocytes and micronuclei in rat and human hepatocytes in vitro. A total of 23 preneoplastic and neo plastic lesions obtained from these mice were analysed for mutations of Ha-ras at codon 61, since these often occur at high frequency in the livers of mice treated with carci nogens. Only two mutations were found: an A > T transversion in a focus of altered cells and a C > A transversion in a trabecular-cell carcinoma (Rumsby et al. The experi mental results indicate that hexachlorobenzene induces hypothyroidism in rats through its main metabolite, pentachlorophenol, and through tetrachlorohydroquinone. Displacement of hormones from serum carriers by these metabolites could be a factor in the induction of the observed hypothyroidism. In addition, hexachlorobenzene increases the metabolism of T4 by inducing glucuronosyl transferase and decreases type-1 deiodinase activity. Therefore, the decreased T4 concentrations in serum of rats after exposure to hexachlorobenzene may be due to a combined effect of displacement of T4 from carriers, increased glucuronidation of T4 and enhanced bile flow. The mechanism of thyroid tumour development in hamsters is probably due to effects similar to those in rats. The hexachlorobenzene poisoning incident in Turkey demonstrated that hexachlorobenzene can produce porphyria in humans. The acquired porphyria was more frequent and more severe in women, and the effects of the exposure may be exacerbated by estrogens. There is evidence for a role of the Ah receptor in some but not all of the effects of hexachlorobenzene in the liver. Some results suggest that oxidative biotransformation may be related to the porphyrinogenic action of hexachlorobenzene. Iron accumulation in subcellular organelles such as lysosomes and iron seques tration have been reported in hexachlorobenzene-exposed animals. The iron in hepatocyte lysosomes associated with porphyria may result in oxidative damage. Female rats are more sensitive to the induction of porphyria than males, and mice are less sensitive than rats.

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