RESUMO
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe adverse reactions to drugs that cause a life-threatening eruption of mucocutaneous blistering and epithelial sloughing. While the acute complications of SJS/TEN are well described, it is increasingly recognized that survivors may develop delayed sequelae, some of which can be associated with significant morbidity. Studies of long-term SJS/TEN outcomes mostly focus on mucocutaneous and ocular complications. However, other internal organs, such as the respiratory tract and gastrointestinal tract, can be affected. Psychological sequelae are also frequent following the trauma of widespread epidermal necrolysis. An appreciation of the 'chronic' phase of SJS/TEN is needed by clinicians caring for individuals who have survived the acute illness. This review aims to provide an update on the breadth and range of sequelae that can affect patients in the months and years following an acute episode of SJS/TEN.
Assuntos
Síndrome de Stevens-Johnson/complicações , Adulto , Assistência ao Convalescente , Pré-Escolar , Doença Crônica , Doenças do Sistema Digestório/etiologia , Doenças do Sistema Digestório/terapia , Oftalmopatias/etiologia , Oftalmopatias/terapia , Feminino , Doenças Urogenitais Femininas/etiologia , Doenças Urogenitais Femininas/terapia , Humanos , Nefropatias/etiologia , Nefropatias/terapia , Pneumopatias/etiologia , Pneumopatias/terapia , Masculino , Doenças Urogenitais Masculinas/etiologia , Doenças Urogenitais Masculinas/terapia , Doenças da Boca/etiologia , Doenças da Boca/terapia , Equipe de Assistência ao Paciente , Dermatopatias/etiologia , Dermatopatias/terapia , Síndrome de Stevens-Johnson/prevenção & controle , Sobreviventes , Doenças Dentárias/etiologia , Doenças Dentárias/terapiaAssuntos
Síndrome de Stevens-Johnson/terapia , Corticosteroides/uso terapêutico , Adulto , Assistência ao Convalescente , Analgesia/métodos , Curativos Biológicos , Procedimentos Clínicos , Ciclosporina/uso terapêutico , Oftalmopatias/terapia , Feminino , Doenças Urogenitais Femininas/terapia , Hidratação/métodos , Previsões , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Ativação Linfocitária , Masculino , Doenças Urogenitais Masculinas/terapia , Doenças da Boca/terapia , Apoio Nutricional/métodos , Prognóstico , Doenças Respiratórias/terapia , Higiene da Pele/métodos , Testes de Irritação da Pele/métodos , Síndrome de Stevens-Johnson/etiologia , Síndrome de Stevens-Johnson/patologiaRESUMO
Summary Drug reaction with eosinophilia and systemic symptoms (DRESS) describes a severe medication-induced adverse reaction, which has cutaneous, haematological and solid-organ features. It is one of the triad of life-threatening drug hypersensitivity dermatoses, along with acute generalized exanthematous pustulosis (AGEP) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). In this article, we discuss several controversies that surround DRESS, including problems with nomenclature and the lack of consensus in diagnostic criteria.
Assuntos
Toxidermias , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Eosinofilia , Diagnóstico Diferencial , Toxidermias/classificação , Toxidermias/patologia , Eosinofilia/induzido quimicamente , Eosinofilia/patologia , Humanos , Índice de Gravidade de Doença , Terminologia como Assunto , Fatores de TempoAssuntos
Antivirais/efeitos adversos , Toxidermias/etiologia , Hepatite C Crônica/tratamento farmacológico , Oligopeptídeos/efeitos adversos , Prolina/análogos & derivados , Inibidores de Proteases/efeitos adversos , Toxidermias/epidemiologia , Feminino , Hepatite C Crônica/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prolina/efeitos adversos , Reino Unido/epidemiologiaRESUMO
Hyperbilirubinaemia is the most common condition requiring evaluation and treatment in newborns. A study in the NEJM 2006 suggested that current guidelines for the treatment of hyperbilirubinaemia in otherwise healthy infants should be relaxed. Prompted by this we performed a retrospective review of review of all term infants who received phototherapy between 1998 and 2006 (total number births = 56,894) in the National Maternity Hospital, Holles Street. 1441 infants received phototherapy during this time period (2.5%). Of those that were of term gestation (n=539), only 9% of those infants receiving phototherapy had peak total serum bilirubin (TSB) exceeding 400 umol. Twenty six percent of infants who received phototherapy had a peak TSB that never exceeded 250 umol/l. There were no cases of kernicterus. Review of the Coombs status revealed that 27% of those undergoing phototherapy in the lowest TSB range were Coombs positive. Seven Coombs positive infants had peak TSB >400 umol/l (14%). Four Coombs positive infants received exchange transfusions. Following this study we would concur with the opinion of Newman et al that current guidelines for the treatment of hyperbilirubinaemia in otherwise healthy infants could be relaxed.
Assuntos
Hiperbilirrubinemia Neonatal/terapia , Fototerapia/métodos , Padrões de Prática Médica/estatística & dados numéricos , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Irlanda , Masculino , Estudos RetrospectivosRESUMO
Intravenous immunoglobulin (IVIG) is indicated for use in Rhesus and ABO hemolytic disease of the newborn (HDN) to reduce the need for exchange transfusion, to decrease hospital stay and the duration of phototherapy. 11 infants received IVIG and the effect of IVIG on the total serum bilirubin (TSB) level, and its effect on the rate of rise of TSB was quantified. There was a statistically significant decrease in bilirubin levels before and after treatment with IVIG from 234 to 219 micromol/L (p = 0.001). In addition, the rate of change in bilirubin level significantly altered from an upward to a downward trend. (p = 0.001). The Number Needed to Treat (NNT) to prevent an exchange transfusion was 2.75--comparable with the recent systematic review of IVIG with a NNT of 2.7.
Assuntos
Bilirrubina/sangue , Eritroblastose Fetal/tratamento farmacológico , Imunoglobulinas Intravenosas/uso terapêutico , Eritroblastose Fetal/sangue , Eritroblastose Fetal/terapia , Transfusão Total , Feminino , Idade Gestacional , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Recém-Nascido , Injeções Intravenosas , Masculino , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Leptin is a peptide hormone produced by adipose tissue which acts centrally to decrease appetite and increase energy expenditure. Although leptin increases norepinephrine turnover in thermogenic tissues, the effects of leptin on directly measured sympathetic nerve activity to thermogenic and other tissues are not known. We examined the effects of intravenous leptin and vehicle on sympathetic nerve activity to brown adipose tissue, kidney, hindlimb, and adrenal gland in anesthetized Sprague-Dawley rats. Intravenous infusion of mouse leptin over 3 h (total dose 10-1,000 microg/kg) increased plasma concentrations of immunoreactive murine leptin up to 50-fold. Leptin slowly increased sympathetic nerve activity to brown adipose tissue (+286+/-64% at 1,000 microg/kg; P = 0.002). Surprisingly, leptin infusion also produced gradual increases in renal sympathetic nerve activity (+228+/-63% at 1,000 microg/kg; P = 0.0008). The effect of leptin on sympathetic nerve activity was dose dependent, with a threshold dose of 100 microg/kg. Leptin also increased sympathetic nerve activity to the hindlimb (+287+/-60%) and adrenal gland (388+/-171%). Despite the increase in overall sympathetic nerve activity, leptin did not increase arterial pressure or heart rate. Leptin did not change plasma glucose and insulin concentrations. Infusion of vehicle did not alter sympathetic nerve activity. Obese Zucker rats, known to possess a mutation in the gene for the leptin receptor, were resistant to the sympathoexcitatory effects of leptin, despite higher achieved plasma leptin concentrations. These data demonstrate that leptin increases thermogenic sympathetic nerve activity and reveal an unexpected stimulatory effect of leptin on overall sympathetic nerve traffic.
Assuntos
Proteínas/farmacologia , Sistema Nervoso Simpático/fisiologia , Potenciais de Ação/efeitos dos fármacos , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/inervação , Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/inervação , Animais , Glicemia/metabolismo , Modelos Animais de Doenças , Hemodinâmica/efeitos dos fármacos , Membro Posterior/efeitos dos fármacos , Membro Posterior/inervação , Insulina/sangue , Rim/efeitos dos fármacos , Rim/inervação , Leptina , Masculino , Obesidade/genética , Proteínas/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Zucker , Sistema Nervoso Simpático/efeitos dos fármacosRESUMO
The overall objective of the guideline is to provide up-to-date, evidence-based recommendations for the diagnosis and management of the full spectrum of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and SJS-TEN overlap in adults during the acute phase of the disease. The document aims to.
Assuntos
Gerenciamento Clínico , Guias de Prática Clínica como Assunto , Síndrome de Stevens-Johnson , Adulto , Diagnóstico Diferencial , Prática Clínica Baseada em Evidências , Humanos , Gravidade do Paciente , Pele/patologia , Síndrome de Stevens-Johnson/diagnóstico , Síndrome de Stevens-Johnson/fisiopatologia , Síndrome de Stevens-Johnson/terapia , Reino UnidoRESUMO
Glucose and fructose enter mammalian cells via facilitated diffusion, a process regulated by five glucose transporter isoforms (GLUT1-5) at the plasma membrane. The tissue-specific pattern of GLUT isoform expression likely reflects differing needs for glucose transport by various tissues. Myocytes must respond expeditiously to increased metabolic demand. A basal isoform, GLUT1, and the insulin-regulatable glucose transporter, GLUT4, have been demonstrated in human myocytes. GLUT3 has a high affinity for glucose, but its presence in human myocardium has not been clearly established. The purpose of this study was to determine whether GLUT3 protein is present in human cardiac myocytes. We examined rapidly frozen myocardial tissue from the explanted heart of seven patients undergoing cardiac transplantation, from the heart of a young, previously healthy male organ donor, from the heart of a 67-year-old woman without known cardiac disease who had a fatal stroke, and from the heart of six human fetuses. GLUT3 protein was detected by immunoblots and localized by light and electron microscopy immunohistochemistry. The presence of GLUT3 protein was verified in myocardial tissue by both immunoblots and immunohistochemistry. Light and electron microscopy confirmed that GLUT3 was in cardiac myocytes. GLUT3 was also demonstrated as a 48 kDa protein in fetal myocardium, which was present at 10 weeks, increased at 15 weeks, then decreased at 20 weeks of gestation. GLUT3 is present in human adult and fetal myocardium. Human myocardial GLUT3 regulation and its role in myocardial glucose uptake remain to be elucidated.
Assuntos
Proteínas de Transporte de Monossacarídeos/análise , Miocárdio/metabolismo , Proteínas do Tecido Nervoso , Idoso , Criança , Feminino , Feto/metabolismo , Idade Gestacional , Transportador de Glucose Tipo 3 , Humanos , Immunoblotting , Imuno-Histoquímica , Técnicas In Vitro , Masculino , Músculo Esquelético/metabolismo , Pericárdio/metabolismoRESUMO
INTRODUCTION: The goal of this study was to define the kinetics of glucose transport from maternal blood to placenta to fetus using real time imaging. METHODS: Positron emission tomography (PET) imaging of the glucose-tracer [(18)F]fluorodeoxyglucose (FDG) was used to temporally and spatially define, in vivo, the kinetics of glucose transport from maternal blood into placentae and fetuses, in the late gestational gravid rat. Computed tomography (CT), with intravenous contrast, co-registered to the PET images allowed anatomic differentiation of placentae from fetal and maternal tissues. RESULTS: FDG was rapidly taken up by placentae and subsequently appeared in fetuses with minimal temporal lag. FDG standardized uptake values in placentae and fetuses approached that of maternal brain. In both anesthetized and awake dams, one quarter of the administered FDG ultimately was accrued in the collective fetuses and placentae. Accordingly, kinetic modeling demonstrated that the placentae had very high avidity for FDG, 2-fold greater than that of the fetus and maternal brain, when accounting for the fact that fetal FDG necessarily must first be taken up by placentae. Consistent with this, placental expression of glucose transporter 1 exceeded that of all other tissues. DISCUSSION: Fetal and placental tissues place a substantial glucose metabolic burden on the mother, owing to very high avidity of placentae for glucose coupled with the large relative mass of fetal and placental tissues. CONCLUSIONS: The placenta has a tremendous capacity to uptake and transport glucose. PET/CT imaging is an ideal means to study metabolite transport kinetics in the fetoplacental unit.
Assuntos
Glucose/metabolismo , Placenta/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada por Raios X/métodos , Animais , Disponibilidade Biológica , Feminino , Fluordesoxiglucose F18/farmacocinética , Imagem Multimodal , Gravidez , Ratos , Ratos Sprague-Dawley , Distribuição TecidualRESUMO
To determine whether leptin has insulin sensitizing effects in normal rodents, we measured plasma glucose and insulin concentrations in male Sprague-Dawley rats treated with leptin or vehicle by continuous s.c. infusion for 48 h. In additional experiments, we examined the acute effect of i.v. leptin upon insulin sensitivity under conditions of clamped glycemia. Subcutaneous leptin was administered at 10.0 and 1.0 microg/h. To avoid confounding effects of differences in food intake, both leptin- and vehicle-treated rats were fasted during the 48-h period of infusion. Infusion of leptin, 10 microg/h, significantly reduced both plasma glucose and insulin. Leptin, 1.0 microg/h, also decreased plasma glucose and insulin, although the effects on insulin did not achieve statistical significance. Leptin at either dose did not alter body weight or epididymal fat mass compared with vehicle treated controls. Leptin, 10 microg/h, decreased circulating insulin-like growth factor-1 levels. No differences in GLUT-4 content in either in brown or epididymal fat were observed as a result of leptin-treatment. Leptin, 10 microg/h, significantly decreased urine osmolality, increased water intake, and reduced renal potassium excretion compared with vehicle-infused rats. In additional rats, we measured the acute effect of i.v. leptin on insulin sensitivity determined as whole body glucose utilization during hyperinsulinemic glucose clamps performed at glucose targets of 60 and 90 mg/100 ml. Glucose utilization was increased by 29% during the last 135 min of glycemia clamped at 60 mg/100 ml (P < 0.05) and by 30% during the last 135 min of glycemia clamped at 90 mg/dl (P < 0.01) in rats infused with leptin compared with vehicle. In summary, leptin increased insulin sensitivity in normal rats both under fasting conditions and in the presence of hyperinsulinemia at clamped glucose. These effects did not appear dependent on altered body weight. Leptin also altered salt and water metabolism under fasting conditions resulting in increased water intake and more dilute urine.
Assuntos
Resistência à Insulina/fisiologia , Proteínas Musculares , Proteínas/farmacologia , Tecido Adiposo Marrom/química , Animais , Glicemia/análise , Glicemia/metabolismo , Peso Corporal/fisiologia , Epididimo/química , Glucose/metabolismo , Transportador de Glucose Tipo 4 , Hiperinsulinismo/sangue , Hiperinsulinismo/fisiopatologia , Bombas de Infusão Implantáveis , Insulina/sangue , Fator de Crescimento Insulin-Like I/análise , Fator de Crescimento Insulin-Like I/metabolismo , Leptina , Masculino , Proteínas de Transporte de Monossacarídeos/análise , Proteínas de Transporte de Monossacarídeos/metabolismo , Proteínas/administração & dosagem , Proteínas/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Equilíbrio HidroeletrolíticoRESUMO
Body weight is tightly regulated physiologically. The recent discovery of the peptide hormone leptin has permitted more detailed evaluation of the mechanisms responsible for control of body fat. Leptin is almost exclusively produced by adipose tissue and acts in the CNS through a specific receptor and multiple neuropeptide pathways to decrease appetite and increase energy expenditure. Leptin thus functions as the afferent component of a negative feedback mechanism to control adipose tissue mass. Increasing evidence suggests that leptin may have wider actions influencing autonomic, cardiovascular, and endocrine function. Intravenous leptin increases norepinephrine turnover and sympathetic nerve activity to thermogenic brown adipose tissue. Studies from our laboratory suggest that leptin also increases sympathetic nerve activity to kidney, hindlimb, and adrenal gland. However, systemic administration of leptin does not acutely increase arterial pressure or heart rate in anesthetized animals. Thus, longer-term exposure to hyperleptinemia may be necessary for full expression of the expected pressor effect of renal sympathoexcitation. Alternatively, leptin may have additional cardiovascular actions to oppose sympathetically mediated vasoconstriction. Leptin in high doses increases renal sodium and water excretion, apparently through a direct tubular action. In addition, leptin appears to increase systemic insulin sensitivity, even in the absence of weight loss. Although we are at an early stage of understanding, we speculate that abnormalities in the actions of leptin may have implications for the sympathetic, cardiovascular, and renal changes associated with obesity.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Rim/efeitos dos fármacos , Proteínas/farmacologia , Sistema Nervoso Simpático/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Animais , Humanos , Insulina/metabolismo , Secreção de Insulina , Leptina , Obesidade/fisiopatologiaRESUMO
The purpose of this study is to determine whether dystrophin-deficient mdx mice are more susceptible to muscle injury and functional impairment than normal C57 mice when allowed to exercise voluntarily on mouse wheels. The mdx mice were significantly impaired when compared to controls as shown by functional, contractile and morphometric responses. The distance young mdx mice ran was 67-78% of young C57 mice, while adult mdx mice ran 31-48% of adult controls. After exercise the slow, oxidative soleus of young and adult mdx mice exhibited hypertrophy with no changes in strength or fatiguability, while the young C57 mice increased strength and the adults became less fatiguable. In the adult mdx mice the fast EDL, which is primarily glycolytic, exhibits slight hypertrophy with a loss of strength, while the young exhibit no changes. These results indicate that the mdx mouse adapts differently than the C57 mouse to even moderate exercise.
Assuntos
Camundongos Endogâmicos mdx/fisiologia , Atividade Motora/fisiologia , Músculo Esquelético/fisiologia , Adaptação Fisiológica/fisiologia , Fatores Etários , Animais , Peso Corporal , Creatina Quinase/sangue , Camundongos , Camundongos Endogâmicos C57BL , Contração Muscular/fisiologia , Fadiga Muscular/fisiologia , Fatores de TempoRESUMO
We investigated the use of intravenously injected fluorescent dextran molecules (FDx) as a histological marker of sarcolemmal injury. Using fluorescent microscopy, uptake of FDx (average MW 10 kD) was assessed in sections of quadriceps muscles from three models: 1) normal (C57BL/10SnJ) mice, 2) normal mice run downhill (0, 3, and 7 days post exercise), and 3) non-exercised mdx (dystrophin-deficient) mice. These were compared to serial sections stained with hematoxylin and eosin (H&E). In control muscles, strong fluorescence was seen between fibers (intercellular). Intracellular FDx was observed within cells of the quadriceps from normal mice run downhill at days 0 and 3 post exercise, but not at day 7. On H&E staining, muscle pathology was not observed until day 3, with regeneration by day 7. Intracellular FDx was also observed within mdx muscles, particularly in fibers that appeared pre-necrotic on H&E stained sections. FDx appears to be useful as a histological marker of changes in sarcolemmal integrity associated with muscle injury from eccentric exercise or muscle disease.
Assuntos
Biomarcadores , Dextranos , Fluoresceína-5-Isotiocianato/análogos & derivados , Fibras Musculares Esqueléticas/patologia , Sarcolema/patologia , Animais , Creatina Quinase/sangue , Estudos de Avaliação como Assunto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Condicionamento Físico AnimalRESUMO
Glycolysis is increased in cancer cells compared with normal cells. It has been shown that glucose enters cells via a family of five functional glucose transporters (GLUT). However, GLUT expression appears to be altered in human breast cancer, which may serve as a selective advantage and facilitate the metastatic potential of these cells. The relationship of GLUT isoform expression and breast cancer cell invasiveness has not been adequately addressed. Thus, the purpose of this study was to investigate whether an association exists between GLUT expression and human breast cancer cell invasiveness. Invasiveness of the human breast cancer lines MCF-7, MDA-MB-435 and MDA-MB-231 was measured using an in vitro assay and compared with cellular GLUT isoform expression, assessed by Western blot analysis and verified by immunohistochemistry in a poorly differentiated human ductal breast cancer. Cell surface GLUT-1 expression was associated with the invasive ability of MCF-7 (2.0 + 0.02%), MDA-MB-435 (6.4 +/- 0.4%), and MDA-MB-231 (19.3 +/- 2.0%). However, GLUT-2 and GLUT-5 were inversely associated with invasiveness; GLUT-3 expression was variable; and GLUT-4 was undetected. In a poorly differentiated human ductal breast cancer, in situ GLUT-1 staining was intense. GLUT-1 expression was associated with the in vitro invasive ability of human breast cancer cells which was validated in situ. If this relationship is found to exist in a larger number of human breast cancer tissues, it may be possible to develop diagnostic and therapeutic strategies based on targeted GLUT isoform expression.
Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteínas de Transporte de Monossacarídeos/metabolismo , Western Blotting , Feminino , Regulação Neoplásica da Expressão Gênica , Transportador de Glucose Tipo 1 , Humanos , Imuno-Histoquímica , Proteínas de Transporte de Monossacarídeos/genética , Invasividade Neoplásica , Células Tumorais CultivadasRESUMO
This article explains how animal models can be utilized to develop rehabilitation approaches to minimize the pathophysiology of neuromuscular diseases (NMD). Homologous animal models can be used to understand the pathogenesis of each NMD and the effect of physical interventions. Much of the current work using animals has been conducted to show how gene therapy could be used to ameliorate these diseases. Although we applaud this work, animal models should also be used to determine how the phenotypic expression of the disease can be modified by such physical interventions as exercise, stretching, and immobilization. Methods that can be experimentally applied to animals but not to humans can be used to determine the underlying causes of the pathologic process and to identify potential therapies for NMD.
Assuntos
Modelos Animais de Doenças , Doenças Neuromusculares/fisiopatologia , Doenças Neuromusculares/reabilitação , Medicina Física e Reabilitação/métodos , Animais , Humanos , Doenças Neuromusculares/etiologia , Doenças Neuromusculares/genética , Fenótipo , Reprodutibilidade dos TestesRESUMO
ADAR2 transgenic mice misexpressing the RNA editing enzyme ADAR2 (Adenosine Deaminase that act on RNA) show characteristics of overeating and experience adult onset obesity. Behavioral patterns and brain changes related to a possible addictive overeating in these transgenic mice were explored as transgenic mice display chronic hyperphagia. ADAR2 transgenic mice were assessed in their food preference and motivation to overeat in a competing reward environment with ad lib access to a running wheel and food. Metabolic activity of brain and peripheral tissue were assessed with [(18) F] fluorodeoxyglucose positron emission tomography (FDG-PET) and RNA expression of feeding related genes, ADAR2, dopamine and opiate receptors from the hypothalamus and striatum were examined. The results indicate that ADAR2 transgenic mice exhibit, (1) a food preference for diets with higher fat content, (2) significantly increased food intake that is non-distractible in a competing reward environment, (3) significantly increased messenger RNA (mRNA) expressions of ADAR2, serotonin 2C receptor (5HT2C R), D1, D2 and mu opioid receptors and no change in corticotropin-releasing hormone mRNAs and significantly reduced ADAR2 protein expression in the hypothalamus, (4) significantly increased D1 receptor and altered bioamines with no change in ADAR2, mu opioid and D2 receptor mRNA expression in the striatum and (5) significantly greater glucose metabolism in the hypothalamus, brain stem, right hippocampus, left and right mid brain regions and suprascapular peripheral tissue than controls. These results suggest that highly motivated and goal-oriented overeating behaviors of ADAR2 transgenic mice are associated with altered feeding, reward-related mRNAs and hyperactive brain mesolimbic region.