Persistent cortical activity: mechanisms of generation and effects on neuronal excitability

Local cortical networks in the prefrontal cortex and visual cortex are capable of spontaneously generating sustained activity for periods of seconds or longer. This sustained activity is generated through recurrent excitation between pyramidal cells that is controlled by feedback inhibition and can have both a rapid onset and a rapid offset. The period of activity is associated with a marked increase in neuronal responsiveness to the intracellular injection of current pulses, especially those of smaller amplitude. Independently mimicking the depolarization, increase in membrane conductance and increase in noise associated with sustained activity revealed that the depolarization is largely responsible for the increase in neuronal responsiveness, although an increase in membrane noise also facilitates responses to small inputs. These results indicate that the persistent activity associated with the performance of working memory tasks may be generated largely through recurrent networks. They also suggest that feedback pathways, such as those involved in selective attention, may exert a powerful influence on neuronal responsiveness through synaptic bombardment.     

Operating characteristics of two independent sample design in phase I trials in paediatric oncology

PurposeThe European medicines agency (EMEA) has stated that the degree of pre-treatment could modify the patient’s tolerance to new treatments in paediatric oncology. It is current practice to divide a phase I trial into two groups to identify the maximum tolerated dose (MTD) in each group separately. The aim of this study was to investigate the relevance of this approach.MethodsWe reanalysed a large phase I trial of Irinotecan that included 80 children (32 heavily pretreated patients and 48 less heavily pretreated). An extended simulation study was performed to investigate the robustness of the conclusions in the context of small sample sizes. Dose recommendations were studied according to scenarios with group differences, as measured by odds ratio (OR), ranging from 1 (no difference) to 10 (large difference) and sample sizes increasing from 20 × 2 to 60 × 2 patients.ResultsThis study shows a high risk of misidentification of the MTD in each of the two groups, regardless of the group difference. With a group difference corresponding to OR = 8 and balanced sample sizes (20 × 2 patients), the same MTD was identified in 11% of the simulations. Even with larger sample sizes (40 × 2 patients), this figure reached 24% for OR = 3. There is also a very high risk of identifying two different MTD (52% for 40 × 2 patients) although the risk is similar in both groups.ConclusionsTwo independent sample designs in paediatric phase I trials should be avoided or reserved to limited situations when there is a strong rationale possibly based on adult data.     

Bin Beitrag zur Kenntnis des Blinzelreflexes

Ohne ZusammenfassungMeinem hochverehrten Lehrer, dem Herrn Hofrat Professor Sigmund Exner erlaube ich mir, an dieser Stelle meinen besten Dank für die freundliche Mühewaltung in Bezug auf diese Arbeit auszudrücken.     

KDM1A inactivation causes hereditary food-dependent Cushing syndrome

PurposeThis study aimed to investigate the genetic cause of food-dependent Cushing syndrome (FDCS) observed in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) and adrenal ectopic expression of the glucose-dependent insulinotropic polypeptide receptor. Germline ARMC5 alterations have been reported in about 25% of PBMAH index cases but are absent in patients with FDCS.MethodsA multiomics analysis of PBMAH tissues from 36 patients treated by adrenalectomy was performed (RNA sequencing, single-nucleotide variant array, methylome, miRNome, exome sequencing).ResultsThe integrative analysis revealed 3 molecular groups with different clinical features, namely G1, comprising 16 patients with ARMC5 inactivating variants; G2, comprising 6 patients with FDCS with glucose-dependent insulinotropic polypeptide receptor ectopic expression; and G3, comprising 14 patients with a less severe phenotype. Exome sequencing revealed germline truncating variants of KDM1A in 5 G2 patients, constantly associated with a somatic loss of the KDM1A wild-type allele on 1p, leading to a loss of KDM1A expression both at messenger RNA and protein levels (P = 1.2 × 10^–12 and P < .01, respectively). Subsequently, KDM1A pathogenic variants were identified in 4 of 4 additional index cases with FDCS.ConclusionKDM1A inactivation explains about 90% of FDCS PBMAH. Genetic screening for ARMC5 and KDM1A can now be offered for most PBMAH operated patients and their families, opening the way to earlier diagnosis and improved management.     

Impact of body mass index on the oncological outcomes of patients treated with radical nephroureterectomy for upper tract urothelial carcinoma

Purpose

To evaluate the association between body mass index (BMI) and oncological outcomes in patients treated with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC).

Methods

We retrospectively reviewed 237 consecutive patients treated with RNU for UTUC at our institution between 1990 and 2012. Univariable and multivariable cox regression models investigated the association of BMI with disease recurrence, cancer-specific mortality, and overall mortality.

Results

From the 237 patients, 104 (44%) had a BMI < 25 kg/m², 88 (37%) had a BMI between 25 and 29.9 kg/m², and 45 (19%) had a BMI ≥ 30 kg/m² at the time of surgery. Within a median follow-up of 44 months (IQR: 24–79), 53 patients (22.4%) experienced a disease recurrence, 85 patients (35.9%) had bladder recurrence, and 44 patients (18.6%) died from the disease. The 5 year recurrence-free and cancer-specific survival rates were, respectively, 32 and 56% for BMI ≥ 30 kg/m², 45 and 74% for patients with BMI 25–29.9 kg/m², and 69 and 81% for patients with BMI < 25 kg/m². In multivariable analyses that adjusted for the effects of the standard clinico-pathological features, BMI ≥ 30 kg/m² was associated with a higher risk of disease recurrence (HR 3.23; 95% CI 2.3–6.6, p < 0.001) and cancer-specific mortality (HR 3.84; 95% CI 2.8–6.5; p < 0.001).

Conclusions

Obesity was independently associated with higher risks of disease recurrence and cancer-specific mortality in patients treated with RNU for UTUC.

     

Involvement of right piriform cortex in olfactory familiarity judgments

Previous studies have shown activation of right orbitofrontal cortex during judgments of odor familiarity. In the present study, we sought to extend our knowledge about the neural circuits involved in such a task by exploring the involvement of the right prefrontal areas and limbic/primary olfactory structures. Fourteen right-handed male subjects were tested using fMRI with a single functional run of two olfactory conditions (odor detection and familiarity judgments). Each condition included three epochs. During the familiarity condition, subjects rated whether odors were familiar or unfamiliar. During the detection condition, participants decided if odors were present. When contrasting the familiarity with the detection conditions, activated areas were found mainly in the right piriform cortex (PC) and hippocampus, the left inferior frontal gyrus and amygdala, and bilaterally in the mid-fusiform gyrus. Further analyses demonstrated that the right PC was more strongly activated than the left PC. This result supports the notion that the right PC is preferentially involved in judgments of odor familiarity.     

Sonography of suspected acute appendicitis in children: Evaluation of the progress in performance of senior residents

Purpose

The objective of this study was to evaluate the progress in performance of senior residents in diagnosing acute appendicitis.