Impaired phosphocreatine metabolism in white adipocytes promotes inflammation.

The mechanisms promoting disturbed white adipocyte function in obesity remain largely unclear. Herein, we integrate white adipose tissue (WAT) metabolomic and transcriptomic data from clinical cohorts and find that the WAT phosphocreatine/creatine ratio is increased and creatine kinase-B expression and activity is decreased in the obese state. In human in vitro and murine in vivo models, we demonstrate that decreased phosphocreatine metabolism in white adipocytes alters adenosine monophosphate-activated protein kinase activity via effects on adenosine triphosphate/adenosine diphosphate levels, independently of WAT beigeing. This disturbance promotes a pro-inflammatory profile characterized, in part, by increased chemokine (C-C motif) ligand 2 (CCL2) production. These data suggest that the phosphocreatine/creatine system links cellular energy shuttling with pro-inflammatory responses in human and murine white adipocytes. Our findings provide unexpected perspectives on the mechanisms driving WAT inflammation in obesity and may present avenues to target adipocyte dysfunction.

Characteristics of pain in patients with pituitary adenomas: A cross-sectional study.

BACKGROUND: This study determines the prevalence and particularities of headache and pain with neuropathic characteristics (NC) in a large French group of patients with pituitary adenoma (PA). METHODS: Analysis of validated self-administered questionnaires, radiological characteristics and treatment strategies of PA was performed. RESULTS: Of the 221 sent questionnaires, 146 could be used for statistical analysis, 50% of which were completed by women. Among responders, 58.9% had pain: 30.1% migraine, 15.7% pain with NC and 13.1% other types of pain. Migraine was more common in patients with PA than in the general population (30.1% vs. 21.3%, p = .010) and attacks received appropriate treatment for less than 20% of these patients. Furthermore, the prevalence of chronic migraine was much higher than in the general population (6.8% vs. 2.2%, p = .003). Neuropathic pain was also more frequent in PA patients than in the general population (15.8% vs. 6.9%, p < .001). Neuropathic pain was most often located in the extremities and was frequently described as an 'electric shock', 'numbness', or 'pins-and-needles'. Multivariate analyses linked migraine to younger age, anxiety, pain with NC, and a visible tumour on MRI, regardless of its invasiveness or secretory nature. CONCLUSIONS: Migraine headaches and neuropathic pain are more frequent and disabling in PA patients than in the general population. Both types of pain are comorbid in PA patients and are poorly treated. Migraine is associated with the presence of a tumour. Thus, biological mechanisms of this relationship need to be characterized to design optimal treatments for these individuals. SIGNIFICANCE: Migraine headaches and neuropathic pain are more common in PA patients than in the general population and are generally poorly treated. A systematic screening for migraine should be done by physicians in daily practice to provide adequate therapeutics.

Assessment of oro-dental manifestations in a series of acromegalic patients, the AcroDent study.

OBJECTIVE: The dental and periodontal impact of GH/IGF-1 hypersecretion has been poorly investigated until now. Our aim is to precisely describe the oro-dental state of acromegalic patients and to study the impact of GH/IGF-1 hypersecretion on patients' reported oral health-related quality of life (OHRQoL). METHODS: After collecting characteristics of their disease, acromegalic patients answered the GOHAI questionnaire assessing their OHRQoL, the AcroQoL questionnaire and then benefited from a complete stomatological and radiological examination (orthopantomogram systematically, retro-alveolar radiography or Cone Beam CT if necessary). RESULTS: In total, 29 patients aged 59.1 ± 16.0 years were included. The average DMFT index (sum of Decayed, Missing and Filled Teeth per patient) was 19.0 ± 7.8. 16/29 patients had a gingivitis and 18/29 a mild to moderate chronic periodontitis, but no case of severe chronic periodontitis was found, probably because the frequency of a protective thick gingival biotype was increased (9/29). No case of generalized gingival hypertrophy or diffuse hypercementosis was observed. According to the Add-GOHAI score, only 8/26 patients had a satisfactory OHRQoL. This parameter was correlated to the acromegaly-specific quality of life according to the AcroQoL score. Interestingly, 11/29 patients had bulky oral bony outgrowths (OBO), such as large maxillary or mandibular tori and multiple vestibular exostosis. CONCLUSIONS: The unsatisfactory OHRQoL reported by acromegalic patients contrasts with a rather good objective oro-dental state and annual oral examination seems relevant in this population. Finally, we report that huge OBO could be helpful signposts for the diagnosis of acromegaly.

Re-treatment With Adjuvant Radioactive Iodine Does Not Improve Recurrence-Free Survival of Patients With Differentiated Thyroid Cancer.

Introduction: Loco regional persistence or recurrence of differentiated thyroid cancer (DTC) is frequent despite initial thyroidectomy and radioactive iodine therapy (RAI). The aim of this study was to analyze the impact of a complementary adjuvant RAI (Ad-RAI) on disease recurrence following re-operation on patients with locally persistent or recurrent DTC. Patients and Methods: A retrospective study of 85 patients with DTC was conducted. All patients were initially treated with total thyroidectomy and RAI, and re-operated for a locally persistent or recurrent disease. Propensity score was calculated to predict the impact of Ad-RAI on survival after reoperation, and to reduce the bias of the limited sample size and the prognostic tests. Results: 49 (58%) patients were re-treated with Ad-RAI after re-operation while 36 (42%) were only followed up. Disease recurrence after re-treatment (re-operation ± Ad-RAI) was detected in 31 patients (36.5%). In multivariate analysis, age >55 years (HR: 3.9 [1.6; 9.5]; p < 0.00001) was the main poor prognostic factor for recurrence-free survival. Three parameters independently influenced the decision to administer ad-RAI: low number of previous RAI administrations, Nx before re-operation, and pTg > 30 µg/l. These parameters were incorporated in the Propensity score calculation. If ad-RAI tended to improve recurrence-free survival (median survival 17.4 vs. 10.9 months), adjustment using the Propensity score removed any difference between the groups (p = 0.54), confirming the limited value of ad-RAI. Conclusion: In patients with locally persistent or recurrent DTC, age is the main independent prognostic factor. Adjuvant RAI does not improve recurrence-free survival of DTC patients.

Age, thyroglobulin levels and ATA risk stratification predict 10-year survival rate of differentiated thyroid cancer patients.

INTRODUCTION: Differentiated thyroid cancer (DTC) is the most common of endocrine cancers. Many studies have focused on recurrence-free survival of DTC patients, however, few studies have addressed overall survival rates. Given its very good prognosis, estimating overall or long-term survival in patients with DTC seems rational. So far, neither the impact of pre- and post-ablation thyroglobulin, nor that of initial American Thyroid Association (ATA) risk stratification on long-term disease-specific survival, have been sufficiently studied. OBJECTIVE: The aim of this study was to determine the factors that influence long-term disease-specific survival and thyroglobulin levels in patients with DTC who have been previously treated with thyroidectomy and radioactive iodine (RAI) remnant ablation. PATIENTS AND METHODS: This observational retrospective study included 1093 patients who were treated for DTC between 1995 and 2010 and are still monitored in our tertiary center. Only patients who needed RAI ablation after thyroidectomy were included in this study. Patients who were treated with RAI following rhTSH stimulation, patients who presented positive anti-thyroglobulin antibodies, and patients who had micro-cancers were excluded. Pre-ablation stimulated thyroglobulin (Pre-ablation sTg) was measured after thyroid hormone withdrawal (THW), just before RAI. RESULTS: According to ATA standards, 29 patients (2.7%) were classified as high-risk patients. Initial ATA high-recurrence risk rating (HR 21.9; 95% CI: 8.5-56.3), age>55 years (HR 23.8; 95%-CI: 7.5-75.3) and pre-ablation sTg≥30 µg/l (HR 8.4; 95% CI: 4.6-15.3) significantly impacted ten-year survival. Moreover, age over 45 years, ATA moderate-risk and follicular DTC were also significant. Ten-year survival was lower in ATA high-risk patients (51% vs 95% and 93% for the low and intermediate risk; p<10-7), patients older than 55 years (82% vs 98%; p<10-7), and in patients with pre-ablation sTg≥30 (78% vs 95%; p<10-7). Three rates of long-term survival were distinguished: excellent (survival rate of 99% in patients<55 years with pre-ablation sTg <30µg/l) representing 59% of the cohort, moderate (survival rate of 94.5% in patients <55 years with pre-ablation sTg ≥30µg/l or ≥55 years with pre-ablation sTg <30 µg/l) representing 38% of the cohort, and low (survival rate of 49% in patients ≥55 years with pre-ablation sTg ≥30µg/l) representing 3% of the cohort. CONCLUSION: Initial ATA high-risk classification, age over 55 years old and pre-ablation sTg ≥30 µg/l are the main negative factors that influence the ten-year survival in DTC. We suggest three categories of overall survival rates. Patients older than 55 years with pre-ablation sTg ≥30 µg/l have the worst survival rate.

Comparison of microbiological results obtained from per-wound bone biopsies versus transcutaneous bone biopsies in diabetic foot osteomyelitis: a prospective cohort study.

Transcutaneous bone biopsy (TCB) is the gold standard for taking microbiological specimens in diabetic foot osteomyelitis (DFO), but this technique is not widely used in diabetic foot care centers. We aimed to evaluate the reliability of per-wound bone biopsy (PWB) cultures by comparing them with concomitant TCB cultures obtained through healthy skin. This is a prospective monocentric study including patients seen in consultation for clinical and radiological diabetic foot osteomyelitis with positive probe-bone tests between April 2015 and May 2018. Two bone biopsies were performed on each consenting patient: TCB through a cutaneous incision in healthy skin, and PWB, after careful debridement of the wound. A total of 46 paired cultures were available from 43 eligible patients. Overall, 16 (42%) of the PWB and TCB pairs had identical culture results, but the TCB cultures were sterile in 8 (17%) cases. For 38 paired cultures with positive TCB, the correlation between PWB results and TCB results was 58.4%. PWB revealed all microorganisms found in the transcutaneous specimen in 26/38 samples (68.5%). In patients with DFO, the culture results of specimens taken by per-wound biopsies did not correlate well with those obtained by TCB. PWB should be reserved for cases where the transcutaneous biopsy is sterile or not feasible.

Stimulated Thyroglobulin and Thyroglobulin Reduction Index Predict Excellent Response in Differentiated Thyroid Cancers.

CONTEXT: Despite its good prognosis, differentiated thyroid cancer (DTC) is characterized by high rates of disease persistence and recurrence. Estimation of long-term remission (excellent response) thanks to specific parameters could help to individualize the active surveillance schedule. OBJECTIVE: Evaluation of the ability of stimulated thyroglobulin (Tg) and Tg reduction index (TRI) to predict long-term remission in patients with DTC managed by thyroidectomy and radioactive iodine (RAI) remnant ablation. PATIENTS AND INTERVENTIONS: Observational retrospective study of 1093 patients treated for DTC between 1995 and 2010. Preablation stimulated thyroglobulin (presTg) was measured under thyroid hormone withdrawal just before RAI. Recombinant human TSH-stimulated thyroglobulin (sTg) was measured at first evaluation of the initial management 6 to 12 months after RAI. TRI was calculated based on pre-Tg and sTg. RESULTS: After univariate and multivariate analyses, lymph node invasion (N1, OR = 2.08; 95% CI, 1.19 to 3.64), presTg (OR = 4.04; 95% CI, 2.56 to 6.38), sTg (OR = 2.62; 95% CI, 2.05 to 3.34), and TRI (OR = 0.43; 95% CI, 0.21 to 0.88) were identified as independent prognostic factors influencing the rate of disease persistence or recurrence after the initial management. Receiver operating characteristic analysis identified presTg cutoff (<10 µg/L) to predict excellent response, with a negative predictive value of 94%, and validated for higher stages (T3/T4, N1). Furthermore, sTg <1 µg/L predicts excellent response. TRI >60% for the entire cohort and 62.5% for locally advanced disease (T3/T4, N1) was sensitive predictor for excellent response. CONCLUSION: This study identifies presTg, sTg, and TRI as highly sensitive predictors of excellent response in patients with DTC and subsequently disease-free status. The cutoff of such parameters is also adapted for patients with higher tumor stages (T3/T4, N1).

Liver X Receptors: A Possible Link between Lipid Disorders and Female Infertility.

A close relationship exists between cholesterol and female reproductive physiology. Indeed, cholesterol is crucial for steroid synthesis by ovary and placenta, and primordial for cell structure during folliculogenesis. Furthermore, oxysterols, cholesterol-derived ligands, play a potential role in oocyte maturation. Anomalies of cholesterol metabolism are frequently linked to infertility. However, little is known about the molecular mechanisms. In parallel, increasing evidence describing the biological roles of liver X receptors (LXRs) in the regulation of steroid synthesis and inflammation, two processes necessary for follicle maturation and ovulation. Both of the isoforms of LXRs and their bona fide ligands are present in the ovary. LXR-deficient mice develop late sterility due to abnormal oocyte maturation and increased oocyte atresia. These mice also have an ovarian hyper stimulation syndrome in response to gonadotropin stimulation. Hence, further studies are necessary to explore their specific roles in oocyte, granulosa, and theca cells. LXRs also modulate estrogen signaling and this could explain the putative protective role of the LXRs in breast cancer growth. Altogether, clinical studies would be important for determining the physiological relevance of LXRs in reproductive disorders in women.

Cymbopogon citratus and Cymbopogon giganteus essential oils have cytotoxic effects on tumor cell cultures. Identification of citral as a new putative anti-proliferative molecule.

Cymbopogon species are used as traditional remedies in Burkina Faso for treating several diseases. We aimed to study the effects of their essential oils on cancer cell lines. For that purpose, Cymbopogon citratus (DC.) Stapf. and Cymbopogon giganteus Chiov. were studied for their essential oils after various chemical extractions. Antioxidant, potential anti-inflammatory action (inhibition of lipoxygenase) and cytotoxic activities were also tested on various prostate cancer and glioblastoma cell lines. Thirty-three compounds were identified in the essential oil of C. giganteus: Limonene (19.33%), Mentha-1(7),8-dien-2-ol cis (17.34%), Mentha-1(7),8-dien-2-ol trans (13.95%), trans-Mentha-2,8-diene-para-ol 1 (13.91%) and Mentha-2,8-diene-1-ol, cis-para (8.10%) were the most abundant. C. citratus essential oil contained 15 compounds and the major ones were geranial/citral A (48.18%) and neral/citral B (34.37%). Essential oil of C. citratus showed the highest ability to scavenge DPPH+ radicals (approximately 68% at 8 mg/mL) while C. giganteus exhibited the highest capability to reduce ABTS+ (0.59µmolET/g). The essential oil of C. citratus was the most effective on prostate cell lines LNCaP (IC50 = 6.36 µg/ml) and PC-3 (IC50 = 32.1 µg/ml), and on glioblastoma cell lines (SF-767 (IC50 = 45.13 µg/ml) and SF-763 (IC50 = 172.05 µg/ml). Interestingly, the activity of essential oil of C. citratus was statistically equal to that of its major component, citral. Combination of both oils showed antagonist, additive, indifferent and synergistic effects on LNCaP, PC-3, SF-767 and SF-763 cell lines, respectively. In conclusion, plants from the traditional medicine in Burkina Faso could be of interest for identifying new compounds, such as citral, for the treatment of prostate cancer and glioblastoma.

LXRs, SHP, and FXR in Prostate Cancer: Enemies or Ménage à Quatre With AR?

Androgens and androgen receptor (AR, NR3C4) clearly play a crucial role in prostate cancer progression. Besides, the link between metabolic disorders and the risk of developing a prostate cancer has been emerging these last years. Interestingly, "lipid" nuclear receptors such as LXRα/NR1H3 and LXRß/NR1H2 (as well as FXRα/NR1H4 and SHP/NR0B2) have been described to decrease the lipid metabolism, while AR increases it. Moreover, these former orphan nuclear receptors can regulate androgen levels and modulate AR activity. Thus, it is not surprising to find such receptors involved in the physiology of prostate. This review is focused on the roles of liver X receptors (LXRs), farnesoid X receptor (FXR), and small heterodimeric partner (SHP) in prostate physiology and their capabilities to interfere with the androgen-regulated pathways by modulating the levels of active androgen within the prostate. By the use of prostate cancer cell lines, mice deficient for these nuclear receptors and human tissue libraries, several authors have pointed out the putative possibility to pharmacologically target these receptors. These data open a new field of research for the development of new drugs that could overcome the castration resistance in prostate cancer, a usual phenomenon in patients.

The prognostic influence of the proliferative discordance in metastatic pancreatic neuroendocrine carcinoma revealed by peptide receptor radionuclide therapy: Case report and review of literature.

RATIONALE: Pancreatic neuroendocrine tumors (pNET) are rare slowly growing tumors with a high metastatic potential. Peptide receptor radionuclide therapy (PRRT) with radiolabeled analogues has been developed as a new tool for the management of metastatic well-differentiated (grade 1 and 2) neuroendocrine tumors expressing somatostatin receptor (SSTR2). Chemotherapy is the mainstay in the management of grade 3 (G3) unresectable pancreatic neuroendocrine carcinoma (pNEC). To date, no study has evaluated the efficacy of PRRT in such tumors. DIAGNOSES AND INTERVENTIONS: We describe a case of a progressive G3 pNEC with huge liver metastases successfully treated with PRRT (Lu DOTATATE). OUTCOMES: Complete remission was obtained for 3 years. Indeed, the mitotic index was low (as G2 tumors) but with a very high Ki-67 index (45%-70%). Such discordance between the proliferative markers should consider the use of PRRT before chemotherapy in unresectable metastatic G3 tumors expressing SSTR2. LESSONS: This case supports the hypotheses highlighting the heterogeneity of G3 pNEC. The latter should be subdivided into 2 distinct categories: proliferation-discordant (well differentiated) and concordant (poorly differentiated) NEC. PRRT could be suggested for the former group before the conventional chemotherapy.

Time course of Graves' orbitopathy after total thyroidectomy and radioiodine therapy for thyroid cancer.

The risk of cancer is relatively higher in Graves' patients presenting simultaneously with thyroid nodules. Radioiodine (RAI) therapy recommended in high-risk differentiated thyroid carcinoma may be associated with worsening of a pre-existing Graves' orbitopathy (GO) or developing a new onset. The impact of RAI therapy in patients with differentiated thyroid cancer on the course of a pre-exisiting GO has not been specifically investigated.The aim of this study is to assess the influence of RAI treatment administered for differentiated thyroid cancer on the course of a pre-existing GO.This is a retrospective multicenter study including 35 patients from the University Hospital of Clermont-Ferrand (7 patients) and Lyon-Est (6 patients) in France and from a literature review published as case reports or studies (22 patients).Seven patients exhibited a worsened pre-existing GO after total thyroidectomy followed by RAI treatment for thyroid cancer. Older men, those who initially presented with a lower clinical score of GO before RAI therapy, received higher doses of I especially when prepared with recombinant thyroid-stimulating hormone, and/or not prepared with glucocorticoids during RAI are at a higher risk to worsen their GO.This study is the first and complete study collection. We describe worsening of GO in 20% of patients after RAI treatment for thyroid cancer and determine a pool of predictive factors.

Infundibuloneurohypophysitis Associated With Sjögren Syndrome Successfully Treated With Mycophenolate Mofetil: A Case Report.

Hypophysitis is an inflammatory disorder of the pituitary gland and corticosteroids are usually recommended as the first-line treatment. Hypophysitis related to primary Sjögren syndrome (pSS) is uncommon. We describe the unusual case of a patient with infundibuloneurohypophysitis associated with pSS successfully treated with mycophenolate mofetil (MMF).We describe a case of a 60-year-old man with a medical history of pSS presented with central diabetes insipidus and panhypopituitarism. Magnetic resonance imaging (MRI) revealed a thickening of the pituitary stalk and intense enhancement of the posterior pituitary, pituitary stalk, and hypothalamus. We diagnosed infundibuloneurohypophysitis associated with pSS. Hormonal replacement was started immediately and MMF was introduced without corticosteroids. After 9 months of treatment, MRI of the pituitary revealed a complete regression of the nodular thickening of the pituitary stalk, with normal enhancement and appearance of the pituitary. The pituitary axes had completely recovered, whereas the diabetes insipidus was partially restored. Our findings suggest that MMF is an effective alternative to corticosteroids for the treatment of lymphocytic hypophysitis associated with an autoimmune disease. Furthermore, this report could contribute to extend the spectrum of the neurological and endocrinological manifestations of pSS.

Amiodarone-Induced Thyrotoxicosis Recurrence After Amiodarone Reintroduction.

Reintroduction of amiodarone in patients with a history of amiodarone-induced thyrotoxicosis (AIT) is rarely used. To date, the risk of AIT recurrence after amiodarone reintroduction is unpredicted. The aim of the study was to evaluate the risk of AIT recurrence. Retrospectively, from 2000 to 2011, all euthyroid patients with a history of AIT with amiodarone reintroduction were included. Type and severity of the first AIT, amiodarone chronology, and thyroid function evolution after reintroduction of amiodarone were investigated: 46 of 172 patients with AIT history needed amiodarone reintroduction. At first AIT episode, the mean age was 62.2 ± 16 years with male gender predominance; 65% of patients were classified as type 1 AIT. AIT recurred in 14 patients (30%), 12 patients developed hypothyroidism (26%), and 20 patients remained euthyroid (44%). Characteristics of type 1 AIT during the first episode, namely briefer exposure period to amiodarone and longer duration of treatment to normalize thyroid hormones, were predictive of AIT recurrence; 73% of patients (8 of 11) with previous episode of type 1 AIT, who did not receive a preventive thioamide treatment, developed a second episode of AIT. Thioamide preventive treatment could be useful to prevent type 1 AIT recurrence. In conclusion, AIT recurrence after amiodarone reintroduction is 4 times more frequent in patients with type 1 AIT history. Thyroid ablation before amiodarone reintroduction in patients with a history of type 1 AIT is preferred. Preventive thioamide treatment could be suggested in patients with type 1 AIT history pending for surgery.

Acute and Chronic Pheochromocytoma-Induced Cardiomyopathies: Different Prognoses?: A Systematic Analytical Review.

Pheochromocytoma and paraganglioma (PPG) are rare and late-diagnosed catecholamine secreting tumors, which may be associated with unrecognized and/or severe cardiomyopathies. We performed a computer-assisted systematic search of the electronic Medline databases using the MESH terms "myocarditis," "myocardial infarction," "Takotsubo," "stress cardiomyopathy," "cardiogenic shock", or "dilated cardiomyopathy," and "pheochromocytoma" or "paraganglioma" from 1961 to August 2012. All detailed case reports of cardiomyopathy due to a PPG, without coronary stenosis, and revealed by acute symptoms were included and analyzed. A total of 145 cases reports were collected (49 Takotsubo Cardiomyopathies [TTC] and 96 other Catecholamine Cardiomyopathies [CC]). At initial presentation, prevalence of high blood pressure (87.7%), chest pain (49.0%), headaches (47.6%), palpitations (46.9%), sweating (39.3%), and shock (51.0%) were comparable between CC and TTC. Acute pulmonary edema (58.3% vs 38.8%, P = 0.03) was more frequent in CC. There was no difference in proportion of patients with severe left ventricular systolic dysfunction (LV Ejection Fraction [LVEF] < 30%) at initial presentation between both groups (P = 0.15). LVEF recovery before (64.9% vs 40.8%, P = 0.005) and after surgical resection (97.7% vs 73.3%, P = 0.001) was higher in the TTC group. Death occurred in 11 cases (7.6%). In multivariate analysis, only TTC was associated with a better LV recovery (0.15 [0.03-0.67], P = 0.03). Pheochromocytoma and paraganglioma can lead to different cardiomyopathies with the same brutal and life-threatening initial clinical presentation but with a different recovery rate. Diagnosis of unexplained dilated cardiomyopathy or TTC should lead clinicians to a specific search for PPG.

Leydig cell tumor in a patient with 49,XXXXY karyotype: a review of literature.

49,XXXXY pentasomy or Fraccaro's syndrome is the most severe variant of Klinefelter's syndrome (KS) affecting about 1/85000 male births. The classical presentation is the triad: mental retardation, hypergonadotropic hypogonadism and radio ulnar synostosis. Indeed, the reproductive function of Fraccaro's syndrome is distinguished from KS. Besides, Leydig cell tumors are described in cases of KS, but never documented in the Klinefelter variants.We describe a young adult of 22 years old who presented with hyper gonadotropic hypogonadism, delayed puberty and bilateral micro-cryptorchidism. Chromosomal pentasomy was confirmed since infancy. Bilateral orchidectomy revealed a unilateral well-circumscribed Leydig cell tumor associated with bilateral Leydig cell hyperplasia.Inspired from reporting the first case of Leydig cell tumor in a 49,XXXXY patient, we summarize the particularities of testicular function in 49,XXXXY from one side, and the risk and mechanisms of Leydig cell tumorigenesis in Klinefelter variants on the other side. The histological destructions in 49,XXXXY testes and hypogonadism are more profound than in Klinefelter patients, with early Sertoli, Leydig and germ cell destruction. Furthermore, the risk of Leydigioma development in KS and its variants remains a dilemma. We believe that the risk of Leydigioma is much higher in KS than the general population. By contrast, the risk could be lower in the Klinefelter variants with more than 3 supplementary X chromosomes, owing to an earlier and more profound destruction of Leydig cells rendering them irresponsive to chronic Luteinizing hormone (LH) stimulation.

Enolase is regulated by Liver X Receptors.

Enolase is a glycolytic enzyme known to inhibit cholesteryl ester hydrolases (CEHs). Cholesteryl ester loading of macrophages, as occurs during atherosclerosis, is accompanied by increased Enolase protein and activity. Here, we describe that J774 macrophages treated with LXR agonists exhibit reduced Enolase transcript and protein abundance. Moreover, we show that this reduction is further potentiated by activation of the LXR/RXR heterodimer with the RXR ligand 9-cis retinoic acid. Enolase levels are also reduced in vivo following activation of LXRs in the intestine, but not in the liver. This effect is lost in Lxrαß-/- mice. In aggregate, our study identified Enolase as a new target of LXRs in vivo, which may promote cholesterol mobilization for subsequent efflux.

Liver X receptors interfere with the deleterious effect of diethylstilbestrol on testicular physiology.

Liver X receptors LXRα (NR1H3) and LXRß (NR1H2) are transcription factors belonging to the nuclear receptor superfamily, activated by specific oxysterols, oxidized derivatives of cholesterol. These receptors are involved in the regulation of testis physiology. Lxr-deficient mice pointed to the physiological roles of these nuclear receptors in steroid synthesis, lipid homeostasis and germ cell apoptosis and proliferation. Diethylstilbestrol (DES) is a synthetic estrogen considered as an endocrine disruptor that affects the functions of the testis. Various lines of evidences have made a clear link between estrogens, their nuclear receptors ERα (NR3A1) and ERß (NR3A2), and Lxrα/ß. As LXR activity could also be regulated by the nuclear receptor small heterodimer partner (SHP, NR0A2) and DES could act through SHP, we wondered whether LXR could be targeted by estrogen-like endocrine disruptors such as DES. For that purpose, wild-type and Lxr-deficient mice were daily treated with 0.75 µg DES from days 1 to 5 after birth. The effects of DES were investigated at 10 or 45 days of age. We demonstrated that DES induced a decrease of the body mass at 10 days only in the Lxr-deficient mice suggesting a protective effect of Lxr. We defined three categories of DES-target genes in testis: those whose accumulation is independent of Lxr; those whose accumulation is enhanced by the lack of both Lxrα/ß; those whose accumulation is repressed by the absence of Lxrα/ß. Lipid accumulation is also modified by neonatal DES injection. Lxr-deficient mice present different lipid profiles, demonstrating that DES could have its effects in part due to Lxrα/ß. Altogether, our study shows that both nuclear receptors Lxrα and Lxrß are not only basally important for testicular physiology but could also have a preventive effect against estrogen-like endocrine disruptors.

Aggressive silent GH pituitary tumor resistant to multiple treatments, including temozolomide.

Temozolomide (TMZ) has been proposed as a therapeutic option in aggressive pituitary tumors. Among the published cases, GH expressing tumors were rare. We describe a patient with initially benign silent GH adenoma that transformed into an aggressive GH secreting tumor resistant to usual therapy. MGMT expression was high and the MGMT promoter was unmethylated. Before this aggressive course, patient received three cycles of TMZ; no response was observed. Four cases of GH aggressive tumor treated by TMZ have been reported. Response to TMZ was observed in one of these four patients. Predictive factors of failure of TMZ remain unclear.