Metabolism of glioma and IDH1/IDH2 mutations

Many known oncogenic signaling pathways involved in gliomagenesis have strong consequences on tumor cell metabolism, and promote the switch from oxidative phosphorylation to aerobic glycolysis, for ATP generation. However, the interest on metabolism has been recently renewed by the discovery of recurrent mutation of IDH1 genes by systematic sequencing of a glioblastoma series. IDH1 encodes the cytoplasmic NADP dependent isocitrate dehydrogenase 1 that catalyzes the oxidative decarboxylation of isocitrate into α-ketoglutarate. IDH1, more rarely IDH2, is mutated in 40% of gliomas (roughly 70% of low-grade gliomas, 50% of grade III, and 5 to 10% of primary glioblastomas). IDH1/IDH2 mutations are associated with genomic profile, being present in nearly all the 1p19q codeleted gliomas, and virtually absent in gliomas with EGFR amplification. It is a strong and independent predictor of survival, whatever grade considered. IDH1/IDH2 mutation results in a new enzymatic activity transforming α-ketoglutarate into 2-hydroxyglutarate (2-HG). The oncometabolite 2-HG accumulates in the cell and acts as a competitive inhibitor of many α-ketoglutarate dependent cellular reactions. The cellular consequences of this mutation offer potential targets for the development of novel therapeutics.     

Diaphragm rupture in a liver transplant patient under chronic immunosuppressive therapy with sirolimus: rare complication after liver transplantation

A diaphragm rupture is a very rare event. A variety of conditions such as coughing, delivery, and vigorous exercise causing a sudden increase of the intra-abdominal pressure can result in diaphragm rupture [1]. The diagnosis can be difficult because of non-specific symptoms and no history of blunt or penetrating trauma. Due to anatomical reasons, diaphragmatic lesions in the left side are more common than those in the right side. Chronic immunosuppressive therapy in transplanted patients, especially with antiproliferative drugs such as mTOR inhibitor, has been considered as a risk factor for the development of incisional hernia [2, 3]. We present the case of diaphragm rupture in a liver transplant patient under chronic immunosuppressive therapy with sirolimus.     

Hemifacial spasm can be the presenting symptom of a fourth ventricle tumour. A short case-illustrated review and pathogenetic considerations

In this short case-illustrated review we aimed to analyse the possible nuances of hemifacial spasm (HFS) as the presenting symptom of a tumour of the fourth ventricle. The issue is remarkable since HFS can be secondary to a fourth ventricle tumour, even when no other neurological signs are reported. In addition, the possible presentation with only upper facial muscle involvement, as in the presented case, can be deceitful because this is characteristic of the benign and much more frequent “typical” form. Based on our intra-operative data and on the previously reported cases, we think that pathogenesis could be referable to the facial nerve nucleus involvement and that clinical nuances could be related to the specific somatotropy of the nucleus under the fourth ventricle floor that, as in our case, can be infiltrated by tumour. Resolution of the disorder can usually be obtained after the complete resection of the tumour that in the reported case resulted a subependymoma (WHO grade I), so far never described in literature associated with HFS.     

Spontaneous cure in a case of Tinea nigra

The authors report a case (in Itajai, Santa Catarina State, Brazil) of tinea nigra in a 4-year-old female child which spontaneously healed. We discuss the clinical and epidemiological aspects of the mycosis and this rare case of spontaneous healing.     

Prognostic impact of the isocitrate dehydrogenase 1 single‐nucleotide polymorphism rs11554137 in malignant gliomas

BACKGROUND.

The IDH1 gene, which encodes isocitrate dehydrogenase 1, is frequently mutated in gliomas and acute myeloid leukemia. The single‐nucleotide polymorphism (SNP) (reference SNP no. rs11554137:C>T) located on IDH1 codon 105 has been associated with a poor outcome in patients with acute myeloid leukemia but has not been investigated in patients with gliomas.

METHODS.

The IDH1 codon 105 SNP was genotyped first in a series of 952 patients with grade 2 through 4 gliomas and was correlated with outcomes and tumor genomic profile. Then, it was genotyped in 2 validations sets of 306 patients with glioblastoma (GBM) and 591 patients with glioma.

RESULTS.

The minor allele codon 105 glycine (GGT) SNP (IDH1^105GGT) was identified in 98 of 952 patients (10.3%) and was not associated with the codon 132 (IDH1¹³²) mutation. Patients who had GMB with the IDH1^105GGT variant had a poorer outcome than patients without the variant (median overall survival [OS], 10.7 months vs 15.5 months; P = .001; median progression‐free survival [PFS], 6.4 months vs 8.5 months; P = .003). The prognostic impact was confirmed in an independent validation set of 306 GBMs from the same center (median PFS, 6.8 months vs 9.7 months; P = .006; median OS, 13.9 months vs 18.8 months; P = .0187). In the second validation cohort (591 grade 2‐4 gliomas), a significant association was observed between IDH1^105GGT and an adverse prognosis for the overall series and for patients with World Health Organization grade 3 gliomas, but the difference did not reach significance in patients with GBM.

CONCLUSIONS.

Taken together, the current data strongly suggested an association between the SNP rs11554137:C>T polymorphism and adverse outcomes in patients with malignant glioma. A single‐nucleotide polymorphism (SNP) located on codon 105 of the isocitrate dehydrogenase 1 (IDH1) gene (reference SNP rs11554137) is analyzed in 3 independent series of patients with gliomas. The SNP rs11554137 is independent of the occurrence of somatic mutation on IDH1 codon 132, but, per se, has a prognostic impact in malignant gliomas. Cancer 2013. © 2012 American Cancer Society.     

Dynamic medium containing kit ligand and follicle-stimulating hormone promotes follicular survival, activation, and growth during long-term in vitro culture of caprine preantral follicles

The aim of this study was to evaluate the effects of a dynamic medium containing kit ligand (KL) and follicle-stimulating hormone (FSH) on the in vitro culture of caprine preantral follicles for 16 days. Ovarian fragments were cultured in α-MEM(+) containing or not containing KL (50 ng/ml) and/or FSH (50 ng/ml) added during the first (days 0-8) and/or second half (days 8-16) of the culture period. Noncultured (control) and cultured fragments were processed for histological and ultrastructural evaluation. After 1 day of culture, only the treatments performed with KL or FSH maintained a percentage of normal follicles similar to that of the control. After 16 days, all treatments using KL until day 8 (KL/KL, KL/FSH, and KL/FSH+KL) and only FSH during the entire culture period (FSH/FSH) showed higher rates of follicular survival compared to α-MEM(+) alone. After 1 and 8 days, the treatments initially cultured with KL increased the percentage of follicular activation in comparison to α-MEM(+) alone and other treatments. The highest follicular diameter after 16 days was observed in follicles cultured with KL until day 8 followed by FSH (KL/FSH). Furthermore, this treatment promoted, as early as after 1 day of culture, an increase in oocyte growth compared to α-MEM(+) alone. Ultrastructural analysis confirmed the integrity of follicles cultured in KL/FSH after 16 days. In conclusion, a dynamic medium containing KL and FSH maintained follicular integrity and promoted follicular activation and growth during the long-term in vitro culture of caprine preantral follicles.     

Re-Assembled Botulinum Neurotoxin Inhibits CNS Functions without Systemic Toxicity

The therapeutic potential of botulinum neurotoxin type A (BoNT/A) has recently been widely recognized. BoNT/A acts to silence synaptic transmission via specific proteolytic cleavage of an essential neuronal protein, SNAP25. The advantages of BoNT/A-mediated synaptic silencing include very long duration, high potency and localized action. However, there is a fear of possible side-effects of BoNT/A due to its diffusible nature which may lead to neuromuscular blockade away from the injection site. We recently developed a "protein-stapling" technology which allows re-assembly of BoNT/A from two separate fragments. This technology allowed, for the first time, safe production of this popular neuronal silencing agent. Here we evaluated the re-assembled toxin in several CNS assays and assessed its systemic effects in an animal model. Our results show that the re-assembled toxin is potent in inhibiting CNS function at 1 nM concentration but surprisingly does not exhibit systemic toxicity after intraperitoneal injection even at 200 ng/kg dose. This shows that the re-assembled toxin represents a uniquely safe tool for neuroscience research and future medical applications.     

Inherited thrombophilia and venous thromboembolism

The term thrombophilia includes any inherited and acquired disorders associated with an increased tendency to venous thromboembolism (VTE). Inherited thrombophilia is one of the main determinants of VTE, and the presence of inherited thrombophilic defects exposed carriers to increased risks for VTE compared with noncarriers. There is no clear relationship between clinical manifestations and the type of underlying thrombophilic defect. Thus, the diagnosis of inherited thrombophilia has to be established on a laboratory basis. Carriers of thrombophilic defects may experience thrombosis at a younger age than noncarriers. However, a first thrombotic manifestation that occurs late in life may also be an expression of thrombophilia and this remains in many cases the only etiopathogenetic explanation for the event. Screening of family members of symptomatic probands has the potential to identify still asymptomatic carriers who may benefit from more appropriate thromboprophylaxis during high-risk situations for VTE. Women of fertile age who belong to these thrombophilic families might receive the greatest advantage from screening. Many inherited thrombophilic disorders can be considered risk factors for recurrent VTE, especially if more than one defect is present in the same patient. More intensive or prolonged duration of VTE treatment might be requested for the prevention of recurrent VTE in the most severe thrombophilic conditions. The availability of new methods for the assessment of thrombin generation in terms of endogenous thrombin potential are very promising tools for the identification of those carriers of inherited thrombophilia who will develop thrombosis or who will encounter recurrence of VTE.     

Evaluation of the Effects of Cigarette Smoking on Testosterone Levels in Adult Men

IntroductionCigarette smoking is highly prevalent among men. Many studies have evaluated the effect of cigarette smoking on levels of male reproductive hormones; however, the findings still remain controversial.AimTo evaluate the influence of cigarette smoking on serum levels of total testosterone (TT), free testosterone (FT), bioavailable testosterone (BT), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH).MethodsA total of 255 men (90 smokers and 165 nonsmokers), aged 30 to 70 years, were investigated. Weight and height were obtained and body mass index (BMI) was calculated. Also, waist circumference and hip circumference were measured and waist-to-hip ratio was obtained. Fasting blood samples were drawn for determination of plasmatic glucose levels and serum levels of total cholesterol, high-density lipoprotein cholesterol (HDL-c), triglycerides, albumin, prolactin, TT, SHBG, LH, and FSH. The values of low-density lipoprotein cholesterol (LDL-c) were determined by Friedwald equation and the values of FT and BT were calculated from TT, SHBG, and albumin. Statistical significance was set at P ≤ 0.05.Main Outcome MeasuresThe influence of smoking on levels of TT, FT, and BT.ResultsNo significant difference was observed in the mean values of TT (P = 0.580), FT (P = 0.869), BT (P = 0.933), SHBG (P = 0.279), LH (P = 0.573), and FSH (P = 0.693) in the different levels of pack-years when compared to nonsmokers. Moreover, after multivariate logistic regression, no association between increased pack-years of smoking and increased odds ratio for occurrence of low hormones and SHBG levels was observed.ConclusionIn this study, smokers and nonsmokers had similar mean values of androgens, gonadotropins and SHBG. However, it is necessary to standardize pack-years of smoking in order to elucidate the influence of cigarette smoking on sex hormone levels, as well as to minimize differences among studies and to confirm our results. Halmenschlager G, Rossetto S, Lara GM, and Rhoden EL. Evaluation of the effects of cigarette smoking on testosterone levels in adult men. J Sex Med 2009;6:1763–1772.     

Tinea nigra in geographical forms of "heart" and "parrot beak"

Through a photographic essay, we identified similarities between hyperchromic maculas of two cases of Tinea Nigra with images of a heart-shaped mangrove called "Coeur de Voh", located on the French island of New Caledonia (Oceania) and of a rock formation called "Parrot Beak" located on Cabe?udas Beach, Itajaí, Santa Catarina State (Brazil).