Oxidative stress enhances the immune response to oxidatively modified catalase enzyme in patients with Graves' disease.

BACKGROUND: Oxidative stress is associated with several autoimmune disorders and oxidative modification of proteins that may result in autoimmune response. This study aims to evaluate the catalase (CAT) activity and the autoimmune response against the native CAT and the oxidatively modified enzyme in patients with Graves' disease (GD) and healthy controls in a comparative way. METHODS: The CAT activity was evaluated via spectrophotometric method. Using enzyme-linked immunosorbent assay, the reactivities of autoantibody toward native, malondialdehyde (MDA) and hydrogen peroxide (H2 O2 ) modified CAT were evaluated in plasmas of patients and controls. RESULTS: Reduced CAT activity was found in patients compared with controls (P < .05). It was proved that levels of IgG antibodies against MDA-modified CAT were higher than against unmodified ones (P < .001). No changes were found for the reactivities to H2 O2 -modified CAT. Positive correlation was found between the reactivity to MDA-modified CAT and the triiodothyronine level (P < .001, r = .6). CONCLUSION: Our findings incriminate the MDA in the autoantibodies reactivity to oxidatively modified CAT leading to a disturbed oxidative profile and/or the progression of GD pathology.

Fahr's syndrome in Southern Tunisia: A broad spectrum of clinical and etiological features.

AIM: We describe the clinical and etiological profile of patients with Fahr's syndrome (FS). METHODS: Charts of sixteen patients diagnosed with FS between 1999 and 2014 were retrospectively assessed. RESULTS:   The mean age at diagnosis was 44.68 years (11-67 years). The most main presenting neurological features were seizures in 6 cases, headaches in 5 cases and parkinson's syndrome in 3 cases. Psychiatric disorders were observed in 2 patients including memory loss and iritability. Hypocalcemia clinical features were observed in 7 cases. The mean value of hypocalcemia was 1.69 mmol/l. Etiologies included idiopathic hypoparathyroidism in 4 patients, pseudohypoparathyroidism in 5 cases, secondary hypoparathyroidism, isolated hypovitaminosis D and cerebral radiotherapy in one case for each and Fahr's disease in 4 patients.  Oral calcium and vitamin D substitution were started in patients with parathyroid disturbances with favorable outcome. CONCLUSION: In this report, we propose to discuss the clinical manifestations of FS, its etiologies especially parathyroid disturbances and its therapeutic modalities.

Metabolic Disorders During Prolactinomas.

The metabolic profile during prolactinoma may be subject to significant changes. We aimed to describe the different metabolic aspects in patients monitored for prolactinoma and to study the correlations between the size of the prolactinoma and the metabolic parameters. We conducted a retrospective, descriptive, and analytical study of 77 cases of prolactinomas collected and monitored at the endocrinology and diabetology department of the Hedi Chaker Hospital in Sfax between 2000 and 2017. Our patients were divided into three groups according to the size of their prolactinomas. Statistical correlations were sought between tumor size and clinical and biological parameters. The mean age of our patients was 38.3 ± 14.2 years. They were divided into 51 women (66.2%) and 26 men (33.7%). Pituitary tumor syndrome was the most common circumstance of discovery in our population (62.3%). The clinical examination revealed an average waist circumference of 95.71 cm. Android fat distribution was observed in 25 women (49%) and 12 men (46.1%). A statistically significant positive correlation was objectified between waist circumference and tumor size (r = 0.29 and P = 0.019). The average body mass index was 28.08 kg/m2. Obesity was noted in 56 cases (72.7%). Glucose tolerance disorders and hypertriglyceridemia were also more evident each time prolactinoma size increased in contrast to the level of high-density lipoprotein cholesterol which decreased with adenoma size. Our study highlighted the metabolic and hormonal repercussions of prolactinomas. Metabolic syndrome was more common in patients with larger prolactinoma. These results should guide the initial assessment and therapeutic management of prolactin adenomas.

Diagnosis and management of pituitary apoplexy: a Tunisian data.

BACKGROUND: Pituitary apoplexy (PA) is defined as the hemorrhage or the infraction of a pituitary adenoma. Aiming to determine the epidemiological, clinical, paraclinical characteristics as well as management and outcomes of PA in our population, we conducted this cross-sectional study. METHODS: This cross-sectional study was conducted at the Department of Endocrinology of Hedi chaker university hospital, Sfax. Data was collected from medical charts of patients with pituitary apoplexy admitted in our department between 2000 and 2017. RESULTS: We included 44 patients with PA. Their mean age was 50 ± 12.6 years. Among them, 31.8% had a known pituitary adenoma, and it was in all cases a macroadenoma, predominantly a prolactin secreting tumor (42.8%). A triggering factor of PA was encountered in 31.8% of cases and it was mainly: head trauma, dopamine antagonists, and hypertension. The clinical presentation of PA encompassed headaches (84.1%), visual disturbances (75%), and neurological signs (40.9%). Gonadotropin deficiency was the most frequent form of hypopituitarism noted (59.1%), followed by corticotropin deficiency (52.3%), thyrotropin deficiency (47.7%), and somatotropin deficiency (2.3%). Hormonal assessment at PA onset, concluded that 23 had a secreting adenoma: 18 prolactinomas, 3 ACTH-secreting adenomas, and 2 GH-secreting adenomas. In the 21 remaining cases, the tumor was non-functioning (47.7%). Pituitary MRI was performed in 42 cases (95.5%), revealing infraction and or hemorrhage in the pituitary gland in 33 cases; a heterogenous signal or a fluid level within the adenoma, in nine cases. Urgent administration of intra venous hydrocortisone was required in 19 cases. Mannitol administration was mandatory in a patient who had severe intracranial hypertension. Surgical management of the PA was imperative in 24 patients (54.5%): 15 suffered from severe visual impairment, 4 had an intracranial hypertension, 2 cases demonstrated an impaired consciousness, 2 patients experienced a tumor enlargement and one case had a severe Cushing's disease. Operative complications found were rhinorrhea attributable to cerebral spinal fluid leakage, insipidus diabetes associated with rhinorrhea, isolated insipidus diabetes, and hydrocephalus in one case each. Long-term follow-up concluded that headaches persisted in five cases, owing to the tenacity of a macroprolactinoma regardless of cabergoline treatment in one case, the recurrence of an adenoma in two cases and its persistence despite the medical and the surgical treatment in two patients. Concerning the visual acuity defects, only two patients had persistent diminished visual acuity at long-term follow-up. Among 25 patients, 13 were diagnosed with definitive thyrotropin deficiency. Similarly, 14 patients had persistent corticotropin deficiency (CD). Additionally, CD was de novo diagnosed in two patients. Otherwise, gonadotropin deficiency prevailed in all cases. Persistent prolactin deficiency was seen in two patients. Disappearance of the pituitary tumor was encountered in 11 out of 24 cases at long-term follow-up. Overall, surgery was associated with better outcome than conservative management. Pituitary apoplexy is a challenging condition due to its variable course, its diagnosis difficulty and management, as gaps remain to determine the best approach to treat this condition. CONCLUSIONS: To conclude, pituitary apoplexy is a challenging condition due to its variable course, its diagnosis difficulty and management, as gaps remain to determine the best approach to treat this condition. Further studies are thus needed.

Insulinoma with equivocal imaging.

Summary: A 55-year-old patient was admitted to our department for the management of a repetitive alteration of consciousness. Biological investigation results were consistent with endogenous hyperinsulinemic hypoglycemia. Insulinoma was therefore suspected. Abdominal computed tomography and endoscopic ultrasound showed no obvious pancreatic mass.Somatostatin receptor scintigraphy showed abnormal radioactive uptake in both the pancreatic tail and the uncinate process. Contrariwise, abdominal magnetic resonance imaging showed a unique lesion in the pancreas tail. The patient was then proposed for pancreatic surgery. Both intraoperative manual palpation and intraoperative ultrasonography of the pancreas showed a single corporal lesion of 1.5 cm. No lesion was found in the uncinate process. After a left pancreatectomy, the lesion was histopathologically confirmed to be a well-differentiated neuroendocrine tumor. The symptoms of the patient resolved almost immediately following the surgery. The follow-up is one and a half years to date. Learning points: The exact preoperative localization of the pancreatic mass remains the most challenging part of insulinoma diagnostic workup. The radiologist's experience is the best warrantor to a precise localization of the tumor. 111In-DTPA-octreotide uptake in the pancreatic uncinate process may be physiological and its interpretation must, therefore, be vigilant. Manual palpation along with intraoperative ultrasonography is considered as the most effective method for the localization of insulinomas during open surgery.

Case report: Management challenges of late diagnosed 17-alpha hydroxylase deficiency.

Herein we report the intriguing case of a 42-year-old woman presenting with grade three hypertension, severe hypokalemia and primary amenorrhea, which revealed to be the complete form of 17 alphahydroxylase deficiency. We also discuss the challenging therapeutic approach as well as the outcomes and the follow-up of this patient.

A novel thymidine phosphorylase mutation in a family with Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE): Molecular docking, dynamic simulation and computational investigations.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE; OMIM 603041) is a rare inherited metabolic disorder mostly caused by mutations in TYMP gene encoding thymidine phosphorylase (TP) protein that affects the mitochondrial nucleotide metabolism. TP, functionally active as a homodimer, is involved in the salvage pathway of pyrimidine nucleosides. MNGIE-like syndrome having an overlapping phenotype of MNGIE was also described and has been associated with mutations in POLG and RRM2B genes. In the present study, we report the molecular investigation of a consanguineous family including two patients with clinical features suggestive of MNGIE syndrome. Bioinformatics analyses were carried out in addition to mtDNA deletion screening and copy number quantification in the blood of the two patients. Whole exome sequencing and Sanger sequencing analyses revealed the segregation in the affected family a novel mutation c.1205T>A (p.L402Q) within the exon 9 of the TYMP gene. In addition, mtDNA analysis revealed the absence of mtDNA deletions and a decrease of the copy number in the blood of the two patients of the studied family. The p.Leu402Gln mutation was located in a conserved amino acid within the α/ß domain of the TP protein and several software supported its pathogenicity. In addition, and based on docking and molecular dynamic simulation analyses, results revealed that L402Q caused a conformational change in TP mutated structure and could therefore alter its flexibility and stability. These changes prevent also the formation of stable homodimer leading to non-functional protein with partial or complete loss of its catalytic activity.

Ganglioneuroma of adrenal gland in a patient with Turner syndrome.

A 15-year-old girl with Turner syndrome was unexpectedly found to have a left suprarenal mass. Extensive investigations showed a clinically and biochemically inapparent mass. Computed tomography disclosed a well-defined solid lesion in the left adrenal measuring 6.5 x 5 cm with minimal contrast enhancement. Laparoscopic adrenalectomy was done. Histologic examination revealed an encapsulated mass originated from the left adrenal medulla. Tumor tissue comprised abundant collagen fibers and spindloid cells admixed with mature ganglion cells. The tumor was diagnosed as left adrenal ganglioneuroma. According to literature, we report the eighth case of ganglioneuroma complicating Turner syndrome. Patients with this syndrome are predisposed to the development of neuroblastoma and related tumors. Reasons for this predisposition might relate to genetic and hormonal factors. Given that these tumors are often limited stage and of good prognosis, we recommend their screening in all patients with Turner syndrome.

A Rare Cause of Refractory Chronic Diarrhea and Cachexia: A Case Report.

VIPoma is an unusual neuroendocrine neoplasm that autonomously secretes VIP. It is associated with secretory diarrhea and electrolyte disturbances. Herein we report a case of a male patient, who was hospitalized in the Department of Endocrinology in Hedi Chaker Hospital, Sfax, Tunisia. He presented VIPoma syndrome, with hepatic metastases at diagnosis. He had a history of chronic, watery diarrhea. He was dehydrated with many electrolytic disorders as hypokalemia, hyponatremia and metabolic acidosis. Abdominal CT scan showed a heterogeneous mass in the pancreatic head with multiple hepatic lesions. A high VIP hormone level was found. Histological study of a liver biopsy revealed hepatic metastases of neuroendocrine carcinoma. The patient received analogues of somatostatin and systemic chemotherapy, with a transient symptomatic relief. Sadly the patient was lost to follow-up.

Successful Treatment of Insulin Allergy with Desensitization Therapy: A Case Report and Literature Review.

Insulin therapy is an essential treatment for type 1 and uncontrolled type 2 diabetes mellitus (DM). Hypersensitivity reactions have been described since the first administration of insulin, the same as any other therapy. Despite being a rare situation nowadays, it requires careful intra-hospital monitoring and multidisciplinary management. Here, we present a case of a 57-year-old patient with type 2 DM, an average glycemic control, and both penicillin and insulin allergy. Heunderwent a desensitization protocol which allowed successfully dismiss him with intermediate-acting insulin.

[Cardiovascular and metabolic impact of glucocorticoid substitution therapy in patients with Addison's disease]. / Répercussions métaboliques et cardiovasculaires de la substitution glucocorticoïde au cours de la maladie d'Addison.

Recent studies conducted in patients with Addison's disease (AD) highlighted that this disease, even after treatment, is a significant cause of morbi-mortality. This study aims to determine the cardiovascular and metabolic deleterious impact of long-course glucocorticoid substitution therapy. We conducted a retrospective study of 28 patients with treated Addison's disease evolving for more than 15 years. The average age of patients was 58, 53 years, with a female predominance (65%). The average follow-up period was 17, 87 years. Initial dose of hydrocortisone was 32, 5 mg/day (20.52 mg/m2) and 27, 9 mg/day (16,41mg/m2) at the time of the study. The prevalence of the metabolic syndrome (MS) in patients with AM was 35.71% after a period of treatment longer than 15 years. At the end of the follow-up period, 28.57% of patients were obese; 25% of patients had developed AH (arterial hypertension) and type 2 diabetes. The prevalence of dyslipidemia went from 3.57% to 42.85%. Only one patient had myocardial infarction at 25-year follow-up. Factors favoring the onset of MS in our study were history of disease and weight loss at the moment of diagnosis. Adjustment of substitution therapy is a challenge in patients with Addison's disease due to morbi-mortality associated with overdose. A regular follow-up and a personalized therapeutic approach are necessary to improve patients' prognosis.

A comparative study of nuclear 8-hydroxyguanosine expression in Autoimmune Thyroid Diseases and Papillary Thyroid Carcinoma and its relationship with p53, Bcl-2 and Ki-67 cancer related proteins.

PURPOSE: To investigate whether the oxidative stress is involved in the evolution of Graves' disease (GD) and Hashimoto thyroiditis (HT) into Papillary Thyroid Carcinoma (PTC), 8-hydroxy-2'-deoxyguanosine (8-OHdG) and cancer related proteins (Bcl-2, p53 and Ki-67) expressions were evaluated in these pathologies. PATIENTS AND METHODS: Immunohistochemical method was applied on 25 thyroid tissues. Allred score (AS) serving to evaluate the immunostaining is based on a scale from 0 to 8. "Negligible expression" was assigned to a score of 0 to 2, "expression" and "overexpression" were attributed to a score of 3-5 and ≥6 respectively. RESULTS: PTC cancer cells exhibited 100% 8-OHdG "overexpression" compared to 87.5% in PTC non-malignant epithelial (NME) ones (p<0.05). Higher 8-OHdG AS was found in PTC NME cells compared to GD and HT (p<0.001, p<0.05 respectively). "Overexpression" of Bcl-2 was noted in all PTC cell types. Remarkably, just like the PTC cancer and NME cells 33.3% of HT and 50% of GD patients' revealed simultaneous "overexpression" of Bcl-2 and 8-OHdG in epithelial cells. No staining was detected for p53 in all pathologies. PTC lymphoid cells exhibited 100% "overexpression" for 8-OHdG and Bcl-2 with concomitant "negligible expression" for Ki-67 in 87.5% of patients. In contrast, HT lymphoid cells showed 22.2% "expression" and GD 62.5% "expression" and 12.5% "overexpression" of Ki-67. CONCLUSIONS: Simultaneous "overexpression" of 8-OHdG and Bcl-2 in GD and HT could be considered as prognostic markers while "negligible expression" of Ki-67 in PTC lymphoid cells suggests an anergic state favoring the tumor escapes from the immune system.

[Guillain Barré syndrome and diabetic acido-ketotic decompensation during pregnancy: a case report and review of the literature]. / Syndrome de Guillain Barré et décompensation acidocétosique du diabète au cours de la grossesse: a propos d'un cas et revue de la littérature.

A 27-year-old pregnant woman was admitted to the resuscitation department with severe spontaneous acute ketoacidosis as early symptom of type 1 diabetes. The patient underwent resuscitation and insulin treatment with good clinical and biological evolution. On day 4, the patient had polyradiculoneuritis characterised by acute onset. Additional emergency examinations were negative. Lumbar cytopunction showed albuminocytologic dissociation. Electromyogram confirmed the diagnosis of Guillain Barré syndrome (GBS). The patient was treated with veinoglobulin and underwent physical rehabilitation. A dramatic improvement in neurological signs was noted. With regard to pregnancy, the patient aborted a week after being diagnosed with GBS. The association of GBS with ketotic decompensation is rare. Indeed, a few cases have been reported in the literature. This association during pregnancy was never described, hence the originality of this case study.

Proteins oxidation and autoantibodies' reactivity against hydrogen peroxide and malondialdehyde -oxidized thyroid antigens in patients' plasmas with Graves' disease and Hashimoto Thyroiditis.

The aim of this study was to evaluate proteins oxidation in plasmas of two autoimmune thyroid diseases (AITD): Graves' disease (GD) and Hashimoto Thyroiditis (HT), and to determine whether oxidative modification of thyroid antigens (T.Ag) enhanced the reactivity of autoantibodies in plasmas of AITD patients compared with the reactivity towards native T.Ag. Carbonyl and thiol groups and MDA-protein adducts were assessed spectrophotometric methods in plasmas of 74 AITD patients and 65 healthy controls. The reactivities immunoglobulin (Ig)G autoantibodies towards malondialdéhyde (MDA)-modified T.Ag, hydrogen peroxide (H2O2)-modified T.Ag, native T.Ag and native derm were checked by enzyme-linked immunosorbent assay (ELISA). Evaluation of oxidized proteins exhibited high levels of MDA bound to proteins and carbonyl groups, as well as reduced thiol level in plasmas of AITD patients by comparison to healthy controls (p < 0.05). The ELISA test showed that AITD patients' plasmas' reactivity to native T.Ag was significantly increased to the reactivity towards native derm, whereas, no differences were found in the reactivity to native T.Ag and derm in controls plasmas. In addition, treatment of T.Ag by oxidants revealed enhanced reactivity of IgG circulating autoantibodies against H2O2-oxidized T.Ag compared to native ones (p < 0.001) in plasmas of both AITD. Also, reactivity's to MDA-oxidized T.Ag in GD plasmas decreased compared to native ones (p < 0.05) and no changes were noted for HT. Pearson correlation study resulted in positive correlation between reactivity's to H2O2-oxidized T.Ag and free triodotyronine level in GD patients (r = 0.42, p < 0.05) in one hand and thyroid stimulating hormone level in HT patients in the other (r = 0.65, p < 0.001). The data suggest that high production of H2O2 probably occurred during hormone synthesis could contribute to protein oxidation in AITD and to create neoepitopes responsible for autoantibody reactivity's to H2O2-oxidized T.Ag enhancement. These results provide support to the involvement of oxidative stress in AITD development and/or exacerbation.

Lipid peroxidation, proteins modifications, anti-oxidant enzymes activities and selenium deficiency in the plasma of hashitoxicosis patients.

OBJECTIVES: The aim of this study was to explore the oxidative stress profile in hashitoxicosis (HTX) and to compare it with that of healthy subjects. PATIENTS AND METHODS: Spectrophotometric methods were used to evaluate the oxidative stress markers. The selenium level was investigated by atomic absorption. RESULTS: High levels of thiobarbituric acid reactive species (TBARS) and conjugated dienes were found in HTX patients (p = 0.034 and p = 0.043, respectively) compared with healthy controls. For antioxidant enzymes, superoxide dismutase (SOD) and catalase activities increased, whereas that of glutathione peroxidase (GPx) decreased (p = 0.000, p = 0.014, p = 0.000, respectively) compared with controls. A reduction in the level of selenium (p = 0.029) and thiol groups (p = 0.008) were shown in patients; however, levels of carbonyl group and malondialdehyde (MDA) protein adducts decreased (p = 0.000) compared with controls. Positive correlation was shown between levels of free thyroxine (FT4) and TBARS (r = 0.711, p = 0.048) and between FT4 level and SOD activity (r = 0.713, p = 0.047). Conversely, GPx activity presented a negative correlation with FT4 and free triiodothyronine (FT3) levels (r = -0.934, p = 0.001; r = -0.993, p = 0.000, respectively). In addition, GPx activity showed positive correlation with selenium level (r = 0.981, p = 0.019) and the FT3 level correlated negatively with the level of thiol groups (r = -0.892, p = 0.017). CONCLUSIONS: This study shows the presence of an oxidative stress and selenium deficiency in HTX patients and suggests that the hyperthyroid state is strongly implicated in the establishment of this disturbed oxidative profile.

Alexithymia impact on type 1 and type 2 diabetes: a case-control study.

OBJECTIVES: This paper focus on studying the prevalence of alexithymia in diabetes type 1 and type 2 and its impact on diabetes's clinical and therapeutic characteristics. We also studied the relationship between alexithymia and emotional disorders in diabetics. MATERIALS AND METHODS: The study involved a sample of 125 diabetic patients, among whom 50 had type 1 and 75 had type 2 diabetes mellitus compared with respectively 70 and 52 control subjects matched for age and sex. Alexithymia was assessed using the Toronto Alexithymia Scale, while emotional disorders were evaluated using the Hospital Anxiety and Depression Scale. RESULTS: Type 1 diabetics were more alexithymic than controls while type 2 diabetics had higher cognitive component score than control subjects. Alexithymic type 1 diabetics had a higher average of fasting blood sugar than non-alexithymic patients did (P=0.021). Moreover, with type 1 diabetes, erectile dysfunction was associated with difficulties in identifying feelings (P=0.012). We found that the presence of depression was a predictor of alexithymia in type 1 diabetes (ß=1.78, P=0.04) and the presence of psychiatric history was indicative of the presence of alexithymia in type 2 diabetes (ß=2.09, P=0.042). CONCLUSION: Given the impact of alexithymia on diabetes types 1 and 2, the detection and treatment of alexithymic subjects are important for a better prognosis of diabetic disease.

Adrenal diseases during pregnancy: pathophysiology, diagnosis and management strategies.

: Adrenal diseases--including disorders such as Cushing's syndrome, Addison's disease, pheochromocytoma, primary hyperaldosteronism and congenital adrenal hyperplasia--are relatively rare in pregnancy, but a timely diagnosis and proper treatment are critical because these disorders can cause maternal and fetal morbidity and mortality. Making the diagnosis of adrenal disorders in pregnancy is challenging as symptoms associated with pregnancy are also seen in adrenal diseases. In addition, pregnancy is marked by several endocrine changes, including activation of the renin-angiotensin-aldosterone system and the hypothalamic-pituitary-adrenal axis. The aim of this article was to review the pathophysiology, clinical manifestation, diagnosis and management of various adrenal disorders during pregnancy.

Reproductive outcomes of female patients with congenital adrenal hyperplasia due to 21-hydroxylase defi ciency.

Fertility in women with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) appears to be reduced, especially in women with the classic salt-wasting type. Several factors have been suggested to contribute to this subfertility such as androgen excess, adrenal progesterone hypersecretion, consequences of genital reconstructive surgery, secondary polycystic ovaries syndrome, and psychosexual factors. In contrast to this subfertility, pregnancies are commonly normal and uneventful. Adequate glucocorticoid therapy and improvement of surgical and psychological management could contribute to optimize fertility in CAH female patients, even among women with the classic variant. This review provides current information regarding the reproductive outcomes of women with CAH due to 21-OHD and the fertility and pregnancy issues in this population.

Complicated urinary tract infections associated with diabetes mellitus: Pathogenesis, diagnosis and management.

Diabetes mellitus has a number of long-term effects on the genitourinary system. These effects predispose to bacterial urinary tract infections (UTIs) in the patient with diabetes mellitus. Complicated UTIs are also common and potentially life-threatening conditions. They include emphysematous pyelonephritis, emphysematous pyelitis/cystitis, xanthogranulomatous pyelonephritis, renal/perirenal abscess, and renal papillary necrosis. Improved outcomes of these entities may be achieved by early diagnosis, knowledge of common predisposing factors, appropriate clinical and radiological assessment, and prompt management. Herein we review complicated UTIs associated with diabetes mellitus in terms of pathogenesis, clinical manifestations, radiological features, and current management options.