Clinical and demographic aspects of Paget disease of bone: A multicentric study from Turkey.

OBJECTIVE: Paget disease of bone (PDB) is a metabolic bone disease that has been rarely reported in the Eastern countries. This study aimed to evaluate the clinical and demographic characteristics of patients with PDB followed up at endocrinology clinics in Turkey. METHODS: An invitation was sent to tertiary endocrinology clinics to complete a survey on the demographic, clinical, radiological, and laboratory parameters, as well as treatment modalities of patients with PDB. This study enrolled clinically and radiologically proven 185 patients with PDB from 18 endocrinology centers based in 10 cities of Turkey. RESULTS: This cohort of PDB had female preponderance (women/men: 105/80) with a mean age, during diagnosis, of 57±10 years. Most of the patients (59.6%) were symptomatic at diagnosis. Bone pain and headache were the predominant clinical symptoms. Polyostotic disease was observed in 67.5% (n=125) of patients. Frequently affected bones were skull (41.6%), pelvis (53.5%), spine (41%), and femur (25.4%). Moreover, 17 patients with skull involvement had hearing loss. Mean serum alkaline phosphatase (ALP) level (552±652 IU/L; range: 280-5762 IU/L) was over the normal reference cutoff with normal serum calcium levels. Intravenous bisphosphonates (zoledronic acid, 5 mg; pamidronate, 60-90 mg) were the most used drugs (75%) for the treatment of PDB. Most of the patients (87.1%) treated with intravenous bisphosphonates responded well, with a decrease in serum ALP level (117±114 IU/L) in the 12th month of therapy. Furthermore, 16 patients relapsed after the second year of therapy; 3 patients did not respond to the initial intravenous bisphosphonate treatment. CONCLUSION: The patients with PDB followed up by endocrinology clinics of Turkey exhibited polyostotic disease with classical clinical, radiological, and biochemical features and women's predominance with good response to intravenous bisphosphonate therapy.

Retro-and orthonasal olfactory function in relation to olfactory bulb volume in patients with hypogonadotrophic hypogonadism / Função olfativa retro e ortonasal em relação ao volume do bulbo olfatório em pacientes com hipogonadismo hipogonadotrófico

Abstract Introduction: Idiopathic hypogonadotrophic hypogonadism with an olfactory deficit is defined as Kallmann syndrome and is distinct from normosmic idiopathic hypogonadotrophic hypogonadism. Objective: Because olfactory perception not only consists of orthonasally gained impressions but also involves retronasal olfactory function, in this study we decided to comprehensively evaluate both retronasal and orthonasal olfaction in patients with idiopathic hypogonadotrophic hypogonadism. Methods: This case-control study included 31 controls and 45 idiopathic hypogonadotrophic hypogonadism patients. All participants whose olfactory and taste functions were evaluated with orthonasal olfaction (discrimination, identification and threshold), retronasal olfaction, taste function and olfactory bulb volume measurement. The patients were separated into three groups according to orthonasal olfaction: anosmic idiopathic hypogonadotrophic hypogonadism, hyposmic idiopathic hypogonadotrophic hypogonadism and normosmic idiopathic hypogonadotrophic hypogonadism. Results: Discrimination, identification and threshold scores of patients with Kallmann syndrome were significantly lower than controls. Threshold scores of patients with normosmic idiopathic hypogonadotrophic hypogonadism. were significantly lower than those of controls, but discrimination and identification scores were not significantly different. Retronasal olfaction was reduced only in the anosmic idiopathic hypogonadotrophic hypogonadism group compared to controls. Identification of bitter, sweet, sour, and salty tastes was not significantly different when compared between the anosmic, hyposmic, and normosmic idiopathic hypogonadotrophic hypogonadism groups and controls. Olfactory bulb volume was lower bilaterally in all patient groups when compared with controls. The olfactory bulb volume of both sides was found to be significantly correlated with threshold, discrimination and identification scores in idiopathic hypogonadotrophic hypogonadism patients. Conclusion: 1) There were no significant differences in gustatory function between controls and idiopathic hypogonadotrophic hypogonadism patients; 2) retronasal olfaction was reduced only in anosmic patients but not in orthonasally hyposmic participants, possibly indicating presence of effective compensatory mechanisms; 3) olfactory bulb volumes were highly correlated with olfaction scores in the hypogonadotrophic hypogonadism group. The current results indicate a continuum from anosmia to normosmia in idiopathic hypogonadotrophic hypogonadism patients.

Resumo Introdução: O hipogonadismo hipogonadotrófico idiopático com déficit olfatório é definido como síndrome de Kallmann e é distinto de hipogonadismo hipogonadotrófico idiopático normósmico. Objetivo: Pelo fato de a percepção olfativa não apenas consistir em impressões obtidas ortonasalmente, mas também envolver a função olfativa retronasal, neste estudo decidimos avaliar de maneira abrangente o olfato retronasal e ortonasal em pacientes com hipogonadismo hipogonadotrófico idiopático. Método: Este estudo caso-controle incluiu 31 controles e 45 pacientes com hipogonadismo hipogonadotrófico idiopático. Todos os participantes tiveram as funções olfativas e de paladar avaliadas com olfação ortonasal (discriminação, identificação e limiar), olfação retronasal, função do paladar e medida do volume do bulbo olfatório. Os pacientes foram separados em três grupos de acordo com a olfação ortonasal: hipogonadismo hipogonadotrófico idiopático anósmico, hipogonadismo hipogonadotrófico idiopático hipósmico e hipogonadismo hipogonadotrófico idiopático normósmico. Resultados: Os escores de discriminação, identificação e limiar de pacientes com síndrome de Kallmann foram significativamente menores do que os controles. Os escores dos limiares de pacientes com hipogonadismo hipogonadotrófico idiopático normósmico foram significativamente menores do que os dos controles, mas os escores de discriminação e identificação não foram significativamente diferentes. A olfação retronasal foi reduzida apenas no grupo hipogonadismo hipogonadotrófico idiopático anósmico em comparação com os controles. A identificação de gostos amargos, doces, azedos e salgados não foi significativamente diferente quando comparada entre os grupos e controles de hipogonadismo hipogonadotrófico idiopático anósmicos, hipósmicos e normósmicos. O volume do bulbo olfatório foi menor bilateralmente em todos os grupos de pacientes quando comparado com os controles. O volume do bulbo olfatório de ambos os lados foi significativamente correlacionado com os escores de limiar, discriminação, identificação em pacientes com hipogonadismo hipogonadotrófico idiopático. Conclusão: 1) Não houve diferenças significativas na função gustativa entre controles e pacientes com hipogonadismo hipogonadotrófico idiopático; 2) A olfação retronasal foi reduzida apenas em pacientes anosmáticos, mas não em participantes ortonasalmente hipósmicos, possivelmente indicou presença de mecanismos compensatórios efetivos; 3) Os volumes do bulbo olfatório foram altamente correlacionados com os escores de olfação no grupo hipogonadismo hipogonadotrófico. Os resultados atuais indicam um contínuo da anosmia à normosmia em pacientes com hipogonadismo hipogonadotrófico idiopático.

Retro- and orthonasal olfactory function in relation to olfactory bulb volume in patients with hypogonadotrophic hypogonadism.

INTRODUCTION: Idiopathic hypogonadotrophic hypogonadism with an olfactory deficit is defined as Kallmann syndrome and is distinct from normosmic idiopathic hypogonadotrophic hypogonadism. OBJECTIVE: Because olfactory perception not only consists of orthonasally gained impressions but also involves retronasal olfactory function, in this study we decided to comprehensively evaluate both retronasal and orthonasal olfaction in patients with idiopathic hypogonadotrophic hypogonadism. METHODS: This case-control study included 31 controls and 45 idiopathic hypogonadotrophic hypogonadism patients. All participants whose olfactory and taste functions were evaluated with orthonasal olfaction (discrimination, identification and threshold), retronasal olfaction, taste function and olfactory bulb volume measurement. The patients were separated into three groups according to orthonasal olfaction: anosmic idiopathic hypogonadotrophic hypogonadism, hyposmic idiopathic hypogonadotrophic hypogonadism and normosmic idiopathic hypogonadotrophic hypogonadism. RESULTS: Discrimination, identification and threshold scores of patients with Kallmann syndrome were significantly lower than controls. Threshold scores of patients with normosmic idiopathic hypogonadotrophic hypogonadism. were significantly lower than those of controls, but discrimination and identification scores were not significantly different. Retronasal olfaction was reduced only in the anosmic idiopathic hypogonadotrophic hypogonadism group compared to controls. Identification of bitter, sweet, sour, and salty tastes was not significantly different when compared between the anosmic, hyposmic, and normosmic idiopathic hypogonadotrophic hypogonadism groups and controls. Olfactory bulb volume was lower bilaterally in all patient groups when compared with controls. The olfactory bulb volume of both sides was found to be significantly correlated with threshold, discrimination and identification scores in idiopathic hypogonadotrophic hypogonadism patients. CONCLUSION: 1) There were no significant differences in gustatory function between controls and idiopathic hypogonadotrophic hypogonadism patients; 2) retronasal olfaction was reduced only in anosmic patients but not in orthonasally hyposmic participants, possibly indicating presence of effective compensatory mechanisms; 3) olfactory bulb volumes were highly correlated with olfaction scores in the hypogonadotrophic hypogonadism group. The current results indicate a continuum from anosmia to normosmia in idiopathic hypogonadotrophic hypogonadism patients.

Functional characterization of AVPR2 mutants found in Turkish patients with nephrogenic diabetes insipidus.

Diabetes insipidus is a rare disorder characterized by an impairment in water balance because of the inability to concentrate urine. While central diabetes insipidus is caused by mutations in the AVP, the reason for genetically determined nephrogenic diabetes insipidus can be mutations in AQP2 or AVPR2 After release of AVP from posterior pituitary into blood stream, it binds to AVPR2, which is one of the receptors for AVP and is mainly expressed in principal cells of collecting ducts of kidney. Receptor activation increases cAMP levels in principal cells, resulting in the incorporation of AQP2 into the membrane, finally increasing water reabsorption. This pathway can be altered by mutations in AVPR2 causing nephrogenic diabetes insipidus. In this study, we functionally characterize four mutations (R68W, ΔR67-G69/G107W, V162A and T273M) in AVPR2, which were found in Turkish patients. Upon AVP stimulation, R68W, ΔR67-G69/G107W and T273M showed a significantly reduced maximum in cAMP response compared to wild-type receptor. All mutant receptor proteins were expressed at the protein level; however, R68W, ΔR67-G69/G107W and T273M were partially retained in the cellular interior. Immunofluorescence studies showed that these mutant receptors were trapped in ER and Golgi apparatus. The function of V162A was indistinguishable from the indicating other defects causing disease. The results are important for understanding the influence of mutations on receptor function and cellular trafficking. Therefore, characterization of these mutations provides useful information for further studies addressing treatment of intracellularly trapped receptors with cell-permeable antagonists to restore receptor function in patients with nephrogenic diabetes insipidus.

Olfactory and gustatory functions in patients with non-complicated type 1 diabetes mellitus.

The aim of this study was to evaluate any possible relationship between diabetic state and olfactory and gustatory functions in patients with non-complicated diabetes mellitus type 1 (T1D), and also to present evidence of the association between olfactory and gustatory scores and HbA1c values and disease durations. The study included 39 patients with non-complicated T1D and 31 healthy controls. Clinical characteristics such as age, gender, duration of disease, education levels and biochemical analyses (fasting blood glucose, urea, creatinine, total cholesterol, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein (HDL-C), triglyceride, HbA1c, C-peptide, postprandial blood glucose) were measured. Subjective olfactory and gustatory tests were performed for all participants. There were no significant differences in olfactory tests between the two groups (odor thresholds 8.63 ± 0.91 vs. 8.55 ± 0.57, p = 0.66; odor discrimination 12.97 ± 0.80 vs. 12.74 ± 0.79, p = 0.24; odor identification 13.81 ± 0.98 vs. 13.72 ± 0.89, p = 0.69; TDI score 35.34 ± 1.94 vs. 34.97 ± 1.4, p = 0.37). There were also no significant differences in gustatory tests between the two groups (bitter 3.45 ± 0.51 vs. 3.44 ± 0.50, p = 0.90; sweet 3.32 ± 0.48 vs. 3.38 ± 0.49, p = 0.60; salty 3.13 ± 0.72 vs. 3.10 ± 0.72, p = 0.88; total score of taste 13.16 ± 1.61 vs. 13.13 ± 1.22, p = 0.92). Comparison of gustatory and olfactory scores according to disease duration of type 1 diabetes mellitus patients revealed that there were no differences between groups (all p > 0.05). T1D without complications may not be associated with olfactory and gustatory dysfunction according to subjective testing. We also found that gustatory and olfactory functions may not be related with HbA1c values and disease duration in non-complicated T1D.

Serum SIRT1 level is higher in male patient with isolated hypogonadotropic hypogonadism: the first study in human / El nivel de serum SIRT1 es mayor en pacientes masculinos con hipogonadismo hipogonadotrópico: el primer estudio en humanos

Objective. Our aim is to compare the serum SIRT1 levels between patients with hypogonadotropic hypogonadism and healthy subjects. Material and method. Twenty-five male patients diagnosed with isolated hypogonadotropic hypogonadism (IHH) and thirty healthy male as a control group were included in the study. Serum SIRT1, hormone levels and biochemical parameters, age, body mass index and insulin resistance were compared in both groups. Results. Mean serum SIRT1 levels in patient and control group were 20.1±11.7ng/ml and 12.8±7.1ng/ml, respectively. Difference between both groups was statistically significant (p=0.02). The difference of Homeostasis Model Assessment-Insulin Resistance index (HOMA-IR) between two groups was also statistically significant. Patient group had more insulin resistance than the control group and it was statistically significant (mean HOMA-IR 2.66±1.57 vs. 1.38±0.43; p=0.002). Conclusions. This is the first human study that investigates SIRT1 levels and its relation with metabolic and hormonal parameters. We demonstrated that serum SIRT1 levels in patients with IHH were significantly higher than controls, and there is a negative correlation between testosterone and SIRT1 levels. The reason for elevated SIRT1 levels may be a compensation mechanism against both hypogonadotropic hypogonadism and insulin resistance. To understand the relation between SIRT1 and androgen deficiency, further large-scale randomized control studies are needed (AU)

Objetivo. Nuestro objetivo es comparar los niveles séricos de SIRT1 en pacientes con hipogonadismo hipogonadotrópico (IHH) y en sujetos sanos. Material y método. Veinticinco pacientes masculinos con IHH y 30 hombres como grupo control fueron incluidos en el estudio. Se determinaron los niveles séricos de SIRT1, los niveles hormonales y los parámetros bioquímicos en ambos grupos y se compararon los niveles séricos de SIRT1, testosterona, gonadrotropinas, la edad, el índice de masa corporal y la resistencia a la insulina. Resultados. Los niveles promedio de SIRT1 en los pacientes y el grupo control fueron de 20,1±11,7 y 12,8±7,1ng/ml, respectivamente. La diferencia entre los 2 grupos fue estadísticamente significativa (p=0,02). La diferencia del Homeostasis model assessment-insulin resistance index (HOMA-IR) entre los grupos también fue estadísticamente significativa. El grupo de pacientes tuvo mayor resistencia a la insulina que el grupo control y también fue estadísticamente significativa (HOMA-IR promedio 2,66±1,57 vs. 1,38±0,43; p=0,002). Conclusiones. Este es el primer estudio en humanos que mide los niveles séricos de SIRT1 y su relación con parámetros hormonales y metabólicos en pacientes con IHH. Nosotros demostramos que los niveles séricos de SIRT1 en pacientes con IHH fueron significativamente más altos que en el grupo control. También hay una correlación negativa entre los niveles de testosterona y los niveles de SIRT1. Los mecanismos compensatorios del IHH y la resistencia a la insulina pueden ser la principal razón de los niveles elevados de SIRT1. Para entender la relación entre los niveles de SIRT1 y la deficiencia androgénica se necesitan estudios aleatorizados con mayor número de pacientes (AU)

The value of combined elevation of D-dimer and neopterin as a predictive parameter for early stage acute mesenteric ischemia: An experimental study.

Background The diagnosis of acute mesenteric ischemia is variable. Early diagnosis is important for reducing the mortality and morbidity rates. Aim This experimental study aims to investigate the diagnostic utility of D-dimer and neopterin as a marker for the early stage of acute mesenteric ischemia caused by occlusion of superior mesenteric artery. Methods The levels of D-dimer and neopterin were measured using an animal acute mesenteric ischemia model in 21 male rabbits. Superior mesenteric artery occlusion (Group 1, n = 14) and control (Group 2, n = 7) groups were identified. Blood samples at different times are collected from each rabbits. Blood samples from superior mesenteric artery occlusion group were taken 30 min after anesthesia but before laparotomy, 1, 2, and 3 h after superior mesenteric artery ligation. Blood samples from control group were taken 1 h before, 1 and 3 h after anesthesia and laparotomy. The D-dimer and neopterin levels of each blood sample were measured. Results The probability of acute mesenteric ischemia was found to be 36 times higher when the D-dimer level was over 0.125 ng/L, whereas the probability was 19.2 times higher when the neopterin level was over 1.25 nmol/L. Conclusions In this experimental study, the combined elevation of two significant markers, D-dimer and neopterin, may be helpful for the early diagnosis of acute mesenteric ischemia.

Is There Any Effect on Smell and Taste Functions with Levothyroxine Treatment in Subclinical Hypothyroidism?

Subclinical hypothyroidism has been accused for coronary heart disease, lipid metabolism disorders, neuropsychiatric disorders, infertility or pregnancy related problems with various strength of evidence. Currently there is insufficient knowledge about olfaction and taste functions in subclinical hypothyroidism. Aim of the present study is to investigate the degree of smell and taste dysfunction in patients with subclinical hypothyroidism. 28 subclinical hypothyroid patients, and 31 controls enrolled in the prospective study in Istanbul, Turkey. Subclinical hypothyroid patients were treated with L-thyroxine for 3 months. Psychophysiological olfactory testing was performed using odor dispensers similar to felt-tip pens ("Sniffin' Sticks", Burghart, Wedel, Germany). Taste function tests were made using "Taste Strips" (Burghart, Wedel, Germany) which are basically tastant adsorbed filter paper strip. Patients scored lower on psychophysical olfactory tests than controls (odor thresholds:8.1±1.0 vs 8.9±1.1, p = 0.007; odor discrimination:12.4±1.3 vs 13.1±0.9, p = 0.016; odor identification:13.1±0.9 vs 14.0±1.1, p = 0.001; TDI score: 33.8±2.4 vs 36.9±2.1, p = 0.001). In contrast, results from psychophysical gustatory tests showed only a decreased score for "bitter" in patients, but not for other tastes (5.9±1.8 vs 6.6±1.0, p = 0.045). Three month after onset of treatment olfactory test scores already indicated improvement (odor thresholds:8.1±1.0 vs 8.6±0.6, p<0.001; odor discrimination:12.4±1.31 vs 12.9±0.8, p = 0.011; odor identification:13.1±0.9 vs 13.9±0.8, p<0.001; TDI scores:33.8±2.4 vs 35.5±1.7, p<0.001) respectively. Taste functions did not differ between groups for sweet, salty and, sour tastes but bitter taste was improved after 3 months of thyroxin substitution (patients:5.9±1.8 vs 6.6±1.2, p = 0.045). Correlation of changes in smell and taste, with thyroid function test were also evaluated. TSH, fT4 were found have no correlation with smell and taste changes with treatment. However bitter taste found positively correlated with T3 with treatment(r: 0.445, p: 0.018). Subclinical hypothyroid patients exhibited a significantly decreased olfactory sensitivity; in addition, bitter taste was significantly affected. Most importantly, these deficits can be remedied on average within 3 months with adequate treatment.

Identification of a Novel Deletion in AVP-NPII Gene in a Patient with Central Diabetes Insipidus.

Central Diabetes Insipidus (CDI) is caused by a deficiency of antidiuretic hormone and characterized by polyuria, polydipsia and inability to concentrate urine. Our objective was to present the results of the molecular analyses of AVP-neurophysin II (AVP-NPII) gene in a large familial neurohypophyseal (central) DI pedigree. A male patient and his family members were analyzed and the prospective clinical data were collected. The proband applied to hospital for eligibility to be a recruit in Armed Forces. The patient had severe polyuria (20 L/day), polydipsia (20.5 L/day), fatique, and deep thirstiness. CDI was confirmed with the water deprivation-desmopressin test according to an increase in urine osmolality from 162 mOsm/kg to 432 mOsm/kg after desmopressin acetate injection. To evaluate the coding regions of AVP-NPII gene, polymerase chain reactions were performed and amplified regions were submitted to direct sequence analysis. We detected a heterozygous three base pair deletion at codon 69-70 (207_209delGGC) in exon 2, which lead to a deletion of the amino acid alanine. A three-dimensional protein structure prediction was shown for the deleted AVP-NPII and compared with the wild type. The three base pair deletion may yield an abnormal AVP precursor in neurophysin moiety, but further functional analyses are needed to understand the function of the deleted protein.

Evaluation of electrocardiographic parameters in patients with diabetes insipidus.

BACKGROUND: There is limited data regarding the effect of altered serum osmolality on cardiac electrical activity. The aim of the present study is to evaluate the electrocardiographic (ECG) effects of diabetes insipidus (DI) and any related hyperosmolality in a population of young patients with DI and without any known cardiovascular disease or risk factors. METHODS: Twelve-lead ECG's of 44 consecutive untreated young male patients (age: 21.8 ± 2.9 years) who had been referred to endocrinology clinic and diagnosed as DI based on water deprivation test were retrospectively evaluated. A total of 30 age-matched (21.9 ± 2.4 years) healthy males were selected as control group and ECG's of these controls were obtained for comparison with ECG's of DI patients. All ECG parameters were measured and compared. RESULTS: Duration of QRS complex was significantly shorter in patients with DI compared with controls (85.2 ± 12.0 vs. 94.0 ± 10.6 ms, p: 0.001). P wave dispersion (PWD) of patients with DI was significantly higher compared with controls (31.9 ± 9.9 vs. 26.5 ± 10.6 ms, p: 0.03) and it was significantly correlated with serum osmolality and serum sodium level (r = - 0.36, p: 0.02 and r: - 0.35, p: 0.02, respectively). CONCLUSIONS: DI patients without any cardiovascular disease or risk factors displayed significantly shorter QRS duration and increased p wave dispersion compared with controls.

Effects of valsartan treatment on serum ghrelin level and left ventricular mass index in patients with untreated primary hypertension.

OBJECTIVE: In the present study, left ventricular hypertrophy and serum ghrelin concentration in patients with primary hypertension and effects of angiotensin receptor blocker valsartan on these parameters were determined. METHODS: Thirty-seven patients and 30 age and body mass index matched healthy controls were followed up prospectively. Serum ghrelin level was measured by enzyme immunoassay (EIA). Left ventricular mass was determined by transthoracic echocardiography. Left ventricular mass index (LVMI) was calculated by dividing the left ventricular mass to body surface area. All patients were started treatment with oral valsartan 80 mg. Follow-up visits were performed every 4 weeks, and the dosage was doubled in subjects with insufficient blood pressure reduction. At the end of the 12th week all measurements were repeated in the patient group. All data were recorded in the computer using SPSS for Windows software. Mann-Whitney U, Student t, Wilcoxon and t tests were used for statistical analyses. RESULTS: At baseline, mean serum ghrelin level was significantly lower in the patients group (14.9 ng/mL) compared to healthy controls (42.1 ng/mL) (p<0.05). After a 12-week antihypertensive treatment of patients, serum ghrelin concentration increased while LVMI decreased (p<0.05, for both). No significant correlation was found between Δ-ghrelin level and Δ-LVMI (r=0.155, p=0.368). CONCLUSION: Low circulating level of ghrelin in patients with hypertension and its increase after antihypertensive treatment suggest that this peptide need to be explored in the mechanism and complications of hypertension.

A large deletion of the AVPR2 gene causing severe nephrogenic diabetes insipidus in a Turkish family.

X-linked nephrogenic diabetes insipidus (NDI) is a rare hereditary disease caused by mutations in arginine vasopressin type 2 receptor (AVPR2) and characterized by the production of large amounts of urine and an inability to concentrate urine in response to the antidiuretic hormone vasopressin. We have identified a novel 388 bp deletion starting in intron 1 and ending in exon 2 in the AVPR2 gene in a patient with NDI and in his family. We have revealed that this mutation is a de novo mutation for the mother of the proband patient. Prospective clinical data were collected for all family members. The water deprivation test confirmed the diagnosis of diabetes insipidus. The patient has severe symptoms like deep polyuria nocturia, polydipsia, and fatigue. He was given arginine vasopressin treatment while he was a child. However, he could not get well due to his nephrogenic type of illness. Both of his nephews have the same complains in addition to failure to grow. We have sequenced all exons and intron-exon boundaries of the AVPR2 gene of all family members. The analyses of bioinformatics and comparative genomics of the deletion were done via considering the DNA level damage. AVPR2 gene mutation results in the absence of the three transmembrane domains, two extracellular domains, and one cytoplasmic domain. Three-dimensional protein structure prediction was shown. We concluded that X-linked NDI and severity of illness in this family is caused by a novel 388 bp deletion in the AVPR2 gene that is predicted to truncate the receptor protein, and also this deletion may lead to dysfunctioning in protein activity and inefficient or inadequate binding abilities.

Mitotane-induced hyperlipidemia: a retrospective cohort study.

Limited data are available about mitotane-nduced hyperlipidemia. We retrospectively analyzed lipid data in 38 patients with adrenocortical carcinoma (ACC) who received mitotane therapy with emphasis on HDL cholesterol (HDL-c) and clinical predictors of lipid changes. At baseline, the mean levels of HDL-c, LDL-c, and triglycerides were 53.3 mg/dL, 114.4 mg/dL, and 149 mg/dL, respectively. HDL-c, LDL-c, and triglyceride concentrations significantly increased with mitotane therapy to a mean HDL peak (HDL-P) of 86.3 mg/dL (P < 0.001), a mean LDL peak of 160.1 mg/dL (P < 0.001), and a mean triglyceride peak (Tg-P) of 216.7 mg/dL (P = 0.042). HDL-P positively correlated with mitotane concentration (r = 0.52, P < 0.001), while LDL-P levels and Tg-P did not. Gender, body mass index, cortisol overproduction, baseline levels of HDL-c, and triglyceride did not predict change in HDL-c. Similar changes were noticed in subgroup analysis after excluding patients who were using lipid-lowering agents. In conclusion, in ACC patients, mitotane caused significant increases in HDL-c that may counteract the deleterious atherosclerotic effects of LDL-c and Tg rise. Understanding the mechanism of HDL change may lead to the discovery of novel HDL-c-elevating drugs.

Adrenocortical carcinoma: clinical outcomes and prognosis of 330 patients at a tertiary care center.

OBJECTIVE: Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. Herein, we describe the clinical features and outcomes for a large series of ACC patients. DESIGN AND METHODS: Retrospective review of ACC patients seen at The University of Texas MD Anderson Cancer Center from 1998 through 2011. RESULTS: A total of 330 patients with median age at diagnosis of 48.5 years; 12 (3.6%) patients were under 18 years. Hormonally functioning tumors represented 41.8% (n=138) of all cases. Surgical resection for the primary tumor was done in 275 (83.3%) patients (45 at MD Anderson (16.4%)). For those who had surgical resection, the median local-recurrence-free time was 1.04 years. Factors associated with local recurrence included positive surgical margins (P=0.007) and advanced disease stage (P=0.026). Median overall survival time for all patients was 3.21 years. Median survival times were 24.1, 6.08, 3.47, and 0.89 years for stages I, II, III, and IV respectively. In multivariable analysis, older age, functioning tumors, and higher disease stage remained significant prognostic factors associated with poor survival. CONCLUSION: ACC prognosis remains poor with the use of currently available treatments. Older age, functioning tumors, and incomplete resections are clinical factors associated with poor survival. Surgical expertise is important to achieve complete resections and to improve outcome.

A retrospective cohort analysis of the efficacy of adjuvant radiotherapy after primary surgical resection in patients with adrenocortical carcinoma.

CONTEXT: Adrenocortical carcinoma (ACC) is a rare malignancy with high recurrence and mortality rates. The role of adjuvant radiation therapy (RT) to improve outcome remains unclear. OBJECTIVE: The aim of this study was to evaluate the impact of adjuvant RT on overall survival and recurrence rates of ACC patients. DESIGN: We conducted a retrospective cohort study of select ACC patients who were seen at The University of Texas MD Anderson Cancer Center (MDACC) between 1998 and 2011. All patients in this study underwent primary tumor resection and received adjuvant RT within 3 months of primary surgical resection prior to referral to the MDACC. We compared patients who had surgery and adjuvant RT with patients who had surgery alone. RESULTS: Baseline characteristics and adjuvant mitotane use were not significantly different between the adjuvant RT group (n = 16) and the non-RT group (n = 32). Local recurrence occurred in seven patients (43.8%) who received RT and 10 patients (31.3%) in the control group. At 5 yr, the estimated local recurrence-free rate (95% confidence interval) was 53% (32-87%) in the RT group and 67% (52-86%) in the non-RT group (P = 0.53). The distributions of time to distant recurrence and recurrence-free survival were not significantly different between the two groups. Using a multivariate Cox proportional hazards model for overall survival, the hazard ratio for RT use was 1.593 (95% confidence interval, 0.707-3.589; P = 0.26) after adjusting for stage and adjuvant mitotane therapy. CONCLUSIONS: ACC has high rates of recurrence. In our study, RT did not improve clinical outcomes in patients who received their initial care in the community. We believe there is a need for a collaborative, multicenter, prospective randomized trial to evaluate the role of adjuvant treatments (both mitotane and RT) to assess their impact on recurrence patterns and survival.

Mutations in the AVPR2, AVP-NPII, and AQP2 genes in Turkish patients with diabetes insipidus.

The aim of this study was to identify mutations in three different genes, the arginine-vasopressin-neurophysin II (AVP-NPII) gene, the arginine-vasopressin receptor 2 (AVPR2) gene, and the vasopressin-sensitive water channel aquaporin-2 (AQP2) gene in Turkish patients affected by central diabetes insipidus or nephrogenic diabetes insipidus. This study included 15 patients from unrelated families. Prospective clinical data were collected for all patients including the patients underwent a water deprivation-desmopressin test. The coding regions of the AVPR2, AQP2, and AVP-NPII genes were amplified by polymerase chain reaction and submitted to direct sequence analysis. Of the 15 patients with diabetes insipidus referred to Gulhane Military Medical Academy, Department of Endocrinology and Metabolism, eight patients have AVPR2 mutations, five patients have AQP2 mutations and two patients have AVP-NPII mutations. Of the patients, which have AVPR2 mutations, one is compound heterozygous for AVPR2 gene. Seven of these mutations are novel. Comparison of the clinical outcomes of these mutations may facilitate in understanding the functions of AVP-NPII, AQP2, and AVPR2 genes in future studies.

Heart rate variability of young men with idiopathic hypogonadotropic hypogonadism.

BACKGROUND: There is little data available regarding the effects of male sex hormones on cardiac autonomic function. The aim of this study is to evaluate the association between hormones of male hypothalamo-pitiutary-gonadal axis and cardiac autonomic function by comparing heart rate variability (HRV) parameters of young male idiopathic hypogonadotropic hypogonadism patients with those of healthy controls. METHODS: The study consisted of 22 male idiopathic hypogonadotropic hypogonadism patients (mean age 20.8+/-1.2years) and the same number of age-matched healthy male controls (mean age 21.0+/-1.5years). A 24-hour Holter monitoring was performed to assess the time and frequency-domain parameters. The HRV parameters of patients and control groups were compared, and possible associations between levels of tested hormones and HRV parameters were evaluated. RESULTS: The standard deviation of all NN intervals (SDNN), standard deviation of the averages of NN intervals in all 5min segments (SDANN), power in low frequency range (LF, ms(2)) and power in high frequency range (HF, ms(2)) values of patients were significantly lower compared to those of controls (147.47+/-56.16 vs. 193.63+/-40.89; 138.31+/-57.64 vs. 190.15+/-43.94; 397.8+/-236.7 vs. 491.5+/-208.4; and 133.6+/-97.4 vs. 198.5+/-91.6 respectively; p<0.05 for all). Significant negative correlations were observed between serum FSH, LH and testosterone levels and most of the HRV parameters. CONCLUSIONS: Deficiency in the male hypothalamo-pituitary-gonadal axis seems to adversely affect cardiac autonomic modulation with increased sympathetic and decreased parasympathetic components of HRV.

Evaluation of vascular reactivity of young male hypogonadotrophic hypogonadism patients.

We aimed to study the vascular reactivity of young male hypogonadal hypogonadism patients without any cardiovascular risk factors and compare these findings with the ones of age-matched healthy controls. Study population consisted of 26 young male hypogonadotrophic hypogonadism patients (20.9 +/- 1.3 years) and 25 age-matched healthy male controls (21.8 +/- 2.9 years, P = NS). In addition to detailed hormonal analysis, each subject underwent ultrasound study of right brachial artery. Vessel diameter was measured at rest, during reactive hyperemia [endothelium-dependent flow-mediated vasodilation (FMD)] and after sublingual nitroglycerin administration (endothelium-independent vasodilation). Both flow-mediated and endothelium-independent sublingual nitroglycerin mediated dilatation values of patients were higher compared to controls (12.98 +/- 10.76% vs. 7.92 +/- 1.96%, P = 0.003 and 21.44 +/- 10.36% vs. 14.72 +/- 3.57%, P = 0.023, respectively). Linear regression analysis revealed that only serum HDL levels (relative risk 2.94, 95% CI 0.12-0.66, P = 0.006) and baseline vessel diameter (relative risk -2.77, 95% CI -17.73 to -2.70, P = 0.009) were found to be independently associated with FMD values. Endogenous male sex hormones seem to exert negative effects on vascular reactivity parameters and much of their effects are indirect that is by the way of alteration on lipid profile.