Poor creativity in frontotemporal dementia: A window into the neural bases of the creative mind

Background

The prefrontal cortex (PFC) supports functions critical for creative thinking. Damage to the PFC is expected to impair creativity. Yet, previous works suggested the emergence of artistic talent in patients with frontotemporal lobar degeneration (FTLD), which was interpreted as increased creativity.

Objective

We designed a study in patients with frontal variant (fv) of FTLD in order to verify whether: (1) creativity is impaired after frontal degeneration, (2) poor creativity is associated with frontal dysfunctions, and (3) poor creativity is related to hypoperfusion in specific PFC regions.

Materials and methods

Three groups of subjects were enrolled in the study: fvFTLD patients (n = 17), non-demented Parkinson's disease (PD) patients (n = 12) and healthy controls (n = 17). Participants performed a standardized test of creativity, the Torrance Test of Creative Thinking (TTCT) and tests assessing frontal functions. Brain perfusion was correlated to fvFTLD patients’ performance in the TTCT.

Results

Patients with fvFTLD were strongly impaired in all dimensions of the TTCT, compared to PD patients and controls. Disinhibited and perseverative responses were observed only in fvFTLD patients, leading to “pseudo-creative” responses. Poor creativity was positively correlated with several frontal tests. Poor creativity was also correlated with prefrontal hypoperfusion, particularly in the frontal pole.

Conclusions

Poor creativity is associated with fvFTLD. The results also suggest that the integrity of the PFC (in particular frontopolar) is strongly associated with creative thinking. The emergence of artistic talent in patients with fvFTLD is explained by the release of involuntary behaviors, rather than by the development of creative thinking.     

Predictive Factors for Ipsilateral Recurrence After Nephron-sparing Surgery in Renal Cell Carcinoma

Background

Ipsilateral recurrence after nephron-sparing surgery (NSS) is rare, and little is known about its specific determinants.

Objective

To determine clinical or pathologic features associated with ipsilateral recurrence after NSS performed for renal cell carcinoma (RCC).

Design, setting, and participants

We analysed 809 NSS procedures performed at eight academic institutions for sporadic RCCs retrospectively.

Measurements

Age, gender, indication, tumour bilaterality, tumour size, tumour location, TNM stage, Fuhrman grade, histologic subtype, and presence of positive surgical margins (PSMs) were assessed as predictors for recurrence in univariate and multivariate analysis by using a Cox proportional hazards regression model.

Results and limitations

Among 809 NSS procedures with a median follow-up of 27 (1–252) mo, 26 ipsilateral recurrences (3.2%) occurred at a median time of 27 (14.5–38.2) mo. In univariate analysis, the following variables were significantly associated with recurrence: pT3a stage (p = 0.0489), imperative indication (p < 0.01), tumour bilaterality (p < 0.01), tumour size >4 cm (p < 0.01), Fuhrman grade III or IV (p = 0.0185), and PSM (p < 0.01). In multivariate analysis, tumour bilaterality, tumour size >4 cm, and presence of PSM remained independent predictive factors for RCC ipsilateral recurrence. Hazard ratios (HR) were 6.31, 4.57, and 11.5 for tumour bilaterality, tumour size >4 cm, and PSM status, respectively. The main limitations of this study included its retrospective nature and a short follow-up.

Conclusions

RCC ipsilateral recurrence risk after NSS is significantly associated with tumour size >4 cm, tumour bilaterality (synchronous or asynchronous), and PSM. Careful follow-up should be advised in patients presenting with such characteristics.     

DNA polymerase kappa microsatellite synthesis: Two distinct mechanisms of slippage‐mediated errors

Microsatellite tandem repeats are frequent sites of strand slippage mutagenesis in the human genome. Microsatellite mutations often occur as insertion/deletion of a repeat motif (unit‐based indels), and increase in frequency with increasing repeat length after a threshold is reached. We recently demonstrated that DNA polymerase κ (Pol κ) produces fewer unit‐based indel errors within dinucleotide microsatellites than does polymerase δ. Here, we examined human Pol κ's error profile within microsatellite alleles of varying sequence composition and length, using an in vitro HSV‐tk gap‐filling assay. We observed that Pol κ displays relatively accurate synthesis for unit‐based indels, using di‐ and tetranucleotide repeat templates longer than the threshold length. We observed an abrupt increase in the unit‐based indel frequency when the total microsatellite length exceeds 28 nucleotides, suggesting that extended Pol κ protein–DNA interactions enhance fidelity of the enzyme when synthesizing these microsatellite alleles. In contrast, Pol κ is error‐prone within the HSV‐tk coding sequence, producing frequent single‐base errors in a manner that is highly biased with regard to sequence context. Single‐nucleotide errors are also created by Pol κ within di‐ and tetranucleotide repeats, independently of the microsatellite allele length and at a frequency per nucleotide similar to the frequency of single base errors within the coding sequence. These single‐base errors represent the mutational signature of Pol κ, and we propose them a mechanism independent of homology‐stabilized slippage. Pol κ's dual fidelity nature provides a unique research tool to explore the distinct mechanisms of slippage‐mediated mutagenesis.Environ. Mol. Mutagen., 2012. © 2012 Wiley Periodicals, Inc.     

Re-localisation of a biopsy site in endoscopic images and characterisation of its uncertainty

Endoscopy guided probe-based optical biopsy is a new method for detecting sites for tissue biopsy and treatment. After detection, it can be useful to provide a visual aid in the endoscopic images to the endoscopist for example for guidance of forceps to the biopsy sites detected optically. A new method for re-localisation of these sites during the endoscopic examination is presented in this paper. It makes use of a sequence of endoscopic images, where the biopsy site location is known, in order to derive the same number of epipolar lines as images in the sequence projected onto a subsequent target image where the re-localised biopsy site needs to be computed. The location of the re-localised biopsy site is found by minimisation of the sum of squared distances to the epipolar lines. The method also determines analytically the uncertainty of the re-localised biopsy site. This provides the endoscopist with a confidence region around the re-localised biopsy site and a measure of the re-localisation precision. Simulations confirmed that the analytical uncertainty has the potential to be a good estimation of the experimental uncertainty. The method was tested on a physical phantom and on real data from four patients with eight sequences of images acquired during gastroscopy. The re-localisation precision and accuracy were estimated at 1 millimetre or better, which is sufficient for re-localisation of optical biopsy sites.     

Leishmania antimony resistance: what we know what we can learn from the field

Leishmania is the causative agent of various forms of leishmaniasis, a significant cause of morbidity and mortality. The clinical manifestations of the disease range from self-healing cutaneous and mucocutaneous skin ulcers to a fatal visceral form named visceral leishmaniasis or kala-azar. In the absence of any effective vaccine, the only means to treat and control leishmaniasis is affordable medication. The treatment choice is essentially directed by economic considerations; therefore, for a large majority of countries, chemotherapy relies only on the use of cheaper antimonial compounds. The emergence of antimonial therapy failure in India linked to proven parasite resistance has stressed questions about selective factors as well as transmission risk of drug resistance. Unfortunately, in most parts of the world, the frequency of parasite antimony resistance linked to treatment failure is unknown because of a lack of information on Leishmania antimony susceptibility. This information is crucial for addressing the risk of selection and transmission of drug-resistant parasites, particularly in areas where antimony is the only chemotherapeutic alternative. However, the poor knowledge about factors that favor selection of resistant parasites, the multiplicity of the agents that can play a role in the in vivo antileishmanial activity of antimony, and the lack of a standard protocol to diagnose and survey parasite resistance all contribute to insufficient monitoring of antimony resistance. In this review, we discuss on the factors potentially involved in the selection of antimony resistance in the field and discuss on the methods available for its diagnosis.     

A high-dose of fentanyl induced delayed anxiety-like behavior in rats. Prevention by a NMDA receptor antagonist and nitrous oxide (N(2)O)

Postoperative negative affects such as anxiety need to be better understood and treated to improve patient recovery. The present study evaluates the effect of a single exposure to a high-dose of opioid (4 × 100 μg/kg fentanyl injections in 15 min intervals resulting in a total dose of 400 μg/kg), as used for surgery in humans, on anxiety-like behavior (ALB) in rats. First, the level of anxiety was evaluated 24-h after a high-dose of fentanyl using an elevated plus-maze apparatus. Second, the preventive effect of BN2572, a N-methyl-d-aspartate receptor (NMDA-R) antagonist, and 50% nitrous oxide (N₂O), a gas with NMDA-R antagonist properties, was assessed. A significant increase in ALB was observed in fentanyl‐treated rats. Interestingly, fentanyl-induced ALB was prevented by BN2572, suggesting a NMDA-dependant pathway. Fentanyl-induced ALB was also prevented by a single 50% N₂O exposure. The present study provides evidence that deleterious outcomes of opioid use, referred to as “post-opioid syndrome”, include not only pain hypersensitivity as previously described, but also negative affects such as anxiety. Since N₂O prevents elements of this post-opioid syndrome, we speculate that N₂O could be a good therapeutic agent to facilitate postoperative rehabilitation.     

Immunocytochemical evidence for the existence of substance P receptor (NK1) in serotonin neurons of rat and mouse dorsal raphe nucleus

In addition to its neurotransmitter/modulator role in pain perception, substance P (SP) is involved in a regulation of mood, as antagonists of its neurokinin-1 receptor (NK1r) have been found to have antidepressant-like effects in humans. In rodents, treatment with NK1r antagonists has been shown to increase the firing of dorsal raphe nucleus (DRN) serotonin (5-hydroxytryptamine, 5-HT) neurons and to induce a desensitization of their 5-HT1A autoreceptors, suggesting local interactions between the SP and 5-HT systems. To search for the presence of NK1r on 5-HT neurons of the DRN, we used light and electron microscopic immunocytochemistry, as well as confocal microscopy, after single- and double-labelling of NK1r and of the biosynthetic enzyme of 5-HT, tryptophan hydroxylase (TpOH). A significant number of 5-HT (TpOH-positive) cell bodies and dendrites endowed with NK1r were thus demonstrated in the caudal part of rat and mouse DRN. As visualized by electron microscopy after gold immunolabelling, NK1r was mostly cytoplasmic in 5-HT neurons, while predominating on the plasma membrane in the case of TpOH-negative dendrites. The proportion of NK1r observed on the plasma membrane of 5-HT neurons was, however, slightly higher in mouse than rat. Thus, in both rat and mouse DRN, a subpopulation of 5-HT neurons is endowed with NK1r receptors and may be directly involved in the antidepressant-like effects of NK1r antagonists. These 5-HT neurons represent a new element in the neuronal circuitry currently proposed to account for the role of SP in mood regulation.     

Cutaneous mucormycosis

Mucormycosis is an aggressive invasive fungal infection that occurs rarely in immunocompetent but frequently in immunocompromised patients. We present a case of a 68‐year‐old patient with cutaneous mucormycosis due to Rhizopus pusillus. He was initially hospitalized for invasive pulmonary aspergillosis and diabetes mellitus secondary to acute graft‐versus‐host treatment with glucocorticoids after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia. Treatment with liposomal amphotericin B and posaconazole was initiated but the patient developed septic shock with multiple organ failure and died 5 days later. The risk factors, clinical presentation, treatment, and prognosis of cutaneous mucormycosis in hematopoietic stem cell and solid organ transplant patients are discussed.     

Naive antibody gene-segment frequencies are heritable and unaltered by chronic lymphocyte ablation

A diverse antibody repertoire is essential for an effective adaptive immune response to novel molecular surfaces. Although past studies have observed common patterns of V-segment use, as well as variation in V-segment use between individuals, the relative contributions to variance from genetics, disease, age, and environment have remained unclear. Using high-throughput sequence analysis of monozygotic twins, we show that variation in naive V(H) and D(H) segment use is strongly determined by an individual's germ-line genetic background. The inherited segment-use profiles are resilient to differential environmental exposure, disease processes, and chronic lymphocyte depletion therapy. Signatures of the inherited profiles were observed in class switched germ-line use of each individual. However, despite heritable segment use, the rearranged complementarity-determining region-H3 repertoires remained highly specific to the individual. As it has been previously demonstrated that certain V-segments exhibit biased representation in autoimmunity, lymphoma, and viral infection, we anticipate our findings may provide a unique mechanism for stratifying individual risk profiles in specific diseases.