17alpha-hydroxylase deficiency : biochemical and molecular findings in two sisters and their family.

OBJECTIVE: To search for molecular changes in two Argentinian sisters with a clinical and biochemical diagnosis of 17alpha-hydroxylase deficiency. SUBJECTS: Both patients had 46 XX karyotype, with sexual infantilism, primary amenorrhea, and hypertension. Other member of the first degree family did not have this deficiency. HORMONAL RESULTS: The patients showed high levels of gonadotrophins and progesterone along with very low cortisol and androgen levels. Basal levels of corticosterone were very high, but aldosterone was normal. Both steroids had a high response after adrenocorticotropic hormone (ACTH) stimulation, with no changes in 17-hydroxyl progesterone and cortisol levels. Progesterone, corticosterone, and aldosterone decreased with the dexamethasone test, without modifications in 17-hydroxyl progesterone and cortisol levels. A corticosterone/aldosterone ratio was calculated from the results of the stimulation test; the ratios were similar in both patients. On administration of the ACTH test, both parents and one sister (S2) showed a marked response in corticosterone levels, their corticosterone/aldosterone ratios were also similar to each other and similar to the patients. MOLECULAR RESULTS: Molecular studies in the cytochrome P450 17 (CYP17) gene showed that exon 8 had a 4 bp duplication at codon 480 (CATC) in the two patients and their mother and in exon 1, a C to T transition at codon 96 was identified, changing CGG into TGG in the two patients, S2, and their father. CONCLUSIONS: Both patients were shown to be compound heterozygous, carrying different alleles in exon 1 and exon 8, inherited from their father and mother, respectively. The molecular results obtained on S2 confirmed the heterozygosity suggested by the stimulated hormonal test and corticosterone/aldosterone ratio.     

Dopaminergic Modulation of Probabilistic Reasoning and Overconfidence in Errors: A Double-Blind Study

Introduction:

Reasoning biases such as jumping to conclusions (JTC) and overconfidence in errors have been well replicated in patients with delusions. However, their relation to dopaminergic activity, central to pathophysiologic models of psychosis, has not yet been investigated. This study aimed to examine the effects of a dopaminergic agonist (l-dopa) and a dopaminergic antagonist (haloperidol) on the JTC bias and overconfidence in errors after single-dose administration in healthy individuals.

Methods:

The study used a randomized, double-blind, placebo-controlled, 3-way crossover design. Participants were 36 healthy individuals aged 18–36 years. The variables of interest were draws to decision and probability threshold to decision on a computerized variant of the beads task and the number of high-confident incorrect responses on a visual memory task.

Results:

There were no significant effects of substance on draws to decision and probability threshold to decision. A significant effect emerged for high-confident incorrect responses in the memory task; pairwise comparisons indicated a significant reduction of the number of high-confident incorrect responses after administration of haloperidol vs l-dopa and placebo.

Conclusions:

This is the first study to investigate the direct effects of dopaminergic drugs on reasoning biases. The JTC bias and overconfidence in errors showed a differential pattern of dopaminergic modulation, suggesting that they represent different facets of reasoning abnormalities that interact with each other to produce delusions in susceptible individuals.Key words: delusions, schizophrenia, reasoning biases, metacognition, jumping to conclusions, liberal acceptance     

A Critical Role for Thioredoxin-Interacting Protein in Diabetes-Related Impairment of Angiogenesis

Impaired angiogenesis in ischemic tissue is a hallmark of diabetes. Thioredoxin-interacting protein (TXNIP) is an exquisitely glucose-sensitive gene that is overexpressed in diabetes. As TXNIP modulates the activity of the key angiogenic cytokine vascular endothelial growth factor (VEGF), we hypothesized that hyperglycemia-induced dysregulation of TXNIP may play a role in the pathogenesis of impaired angiogenesis in diabetes. In the current study, we report that high glucose–mediated overexpression of TXNIP induces a widespread impairment in endothelial cell (EC) function and survival by reducing VEGF production and sensitivity to VEGF action, findings that are rescued by silencing TXNIP with small interfering RNA. High glucose–induced EC dysfunction was recapitulated in normal glucose conditions by overexpressing either TXNIP or a TXNIP C247S mutant unable to bind thioredoxin, suggesting that TXNIP effects are largely independent of thioredoxin activity. In streptozotocin-induced diabetic mice, TXNIP knockdown to nondiabetic levels rescued diabetes-related impairment of angiogenesis, arteriogenesis, blood flow, and functional recovery in an ischemic hindlimb. These findings were associated with in vivo restoration of VEGF production to nondiabetic levels. These data implicate a critical role for TXNIP in diabetes-related impairment of ischemia-mediated angiogenesis and identify TXNIP as a potential therapeutic target for the vascular complications of diabetes.     

Aprotinin reduces oxidative stress induced by pneumoperitoneum in rats

Background

Ischemia–reperfusion injury induced by pneumoperitoneum is a well-studied entity, which increases oxidative stress during laparoscopic operations. The reported anti-inflammatory action of aprotinin was measured in a pneumoperitoneum model in rats for the first time in this study.

Materials and methods

A total of 60 male Albino Wistar rats were used in our protocol. Prolonged pneumoperitoneum (4 h) was applied, causing splanchnic ischemia and a period of reperfusion with a duration of 60 or 180 min followed. Several cytokines and markers of oxidative stress were measured in liver, small intestine, and lungs to compare the aprotinin group with the control group. Tissue inflammation was also evaluated and compared between groups using a five-scaled histopathologic score.

Results

In aprotinin group values of biochemical markers (tumor necrosis factor α, interleukin 6, endothelin 1, C reactive protein, pro-oxidant–antioxidant balance, and carbonyl proteins) were lower in all tissues studied. Statistical significance was greater in liver and lungs (P < 0.05). Histopathologic examination revealed significant difference between control and aprotinin groups in all tissues examined. Aprotinin groups showed mild to moderate lesions, while in control groups severe to very severe inflammation was present. Aprotinin subgroup with prolonged reperfusion period (180 min) showed milder lesions in all tissues than the rest of the groups.

Conclusions

Aprotinin reduced inflammatory response and oxidative stress induced by pneumoperitoneum in liver, small intestine, and lungs.     

TMPRSS2-ERG Fusions Are Strongly Linked to Young Patient Age in Low-grade Prostate Cancer

Based on next-generation sequencing of early-onset prostate cancer (PCa), we earlier demonstrated that PCa in young patients is prone to rearrangements involving androgen-regulated genes—such as transmembrane protease, serine 2 (TMPRSS2)–v-ets avian erythroblastosis virus E26 oncogene homolog (ERG) fusion—and provided data suggesting that this situation might be caused by increased androgen signaling in younger men. In the same study, an accumulation of chromosomal deletions was found in cancers of elderly patients. To determine how age-dependent molecular features relate to cancer phenotype, an existing data set of 11 152 PCas was expanded by additional fluorescence in situ hybridization analyses of phosphatase and tensin homolog (PTEN), 6q15 and 5q21. The results demonstrate that the decrease in TMPRSS2–ERG fusions with increasing patient age is limited to low-grade cancers (Gleason ≤3 + 4) and that the significant increase in the deletion frequency with age was strictly limited to ERG-negative cancers for 6q15 and 5q21 but to ERG-positive cancers for PTEN. These data suggest that the accumulation of non–androgen-linked genomic alterations with advanced patient age may require an appropriate microenvironment, such as a positive or negative ERG status. The strong link of ERG activation to young patient age and low-grade cancers may help to explain a slight predominance of low-grade cancers in young patients.     

Applanation resonance tonometry for intraocular pressure in humans

Glaucoma is a group of diseases associated with optic nerve damage and loss of visual field. The aetiology is not completely understood, but one of the major risk factors is elevated intraocular pressure (IOP). Reliable methods for measuring the IOP are therefore important. The aim of the study was to investigate the ability of the applanation resonance tonometry (ART) system, based on continuous force and area recording, to measure IOP in humans. Both the phase of initial indentation (IOPIndentation) and the phase when the sensor was removed (IOPRemoval) from the cornea were analysed. The Goldmann applanation tonometry (GAT) was used as reference method. The study included 24 healthy volunteers with normal IOP and 24 patients with elevated IOP. The correlation and standard deviation (SD) between IOPIndentation and IOPGAT was R = 0.92 (p < 0.001), SD = 3.6 mmHg, n = 104, and between IOPRemoval and IOPGAT R = 0.94 (p < 0.001), SD = 3.1 mmHg, n = 104. In conclusion, resonance sensor technology has made it possible to introduce a new multi-point method for measuring IOP, and the method is relevant for measuring IOP in humans. The study indicates that with further development towards elimination of position dependence, the ART has the potential to become a useful clinical instrument for IOP measurement.