Sex differences in discrimination behavior and orbitofrontal engagement during context-gated reward prediction.

Animals, including humans, rely on contextual information to interpret ambiguous stimuli. Impaired context processing is a hallmark of several neuropsychiatric disorders, including schizophrenia, autism spectrum disorders, post-traumatic stress disorder, and addiction. While sex differences in the prevalence and manifestations of these disorders are well established, potential sex differences in context processing remain uncertain. Here, we examined sex differences in the contextual control over cue-evoked reward seeking and its neural correlates, in rats. Male and female rats were trained in a bidirectional occasion-setting preparation in which the validity of two auditory reward-predictive cues was informed by the presence, or absence, of a visual contextual feature (LIGHT: X+/DARK: X-/LIGHT: Y-/DARK: Y+). Females were significantly slower to acquire contextual control over cue-evoked reward seeking. However, once established, the contextual control over behavior was more robust in female rats; it showed less within-session variability (less influence of prior reward) and greater resistance to acute stress. This superior contextual control achieved by females was accompanied by an increased activation of the orbitofrontal cortex (OFC) compared to males. Critically, these behavioral and neural sex differences were specific to the contextual modulation process and not observed in simple, context-independent, reward prediction tasks. These results indicate a sex-biased trade-off between the speed of acquisition and the robustness of performance in the contextual modulation of cued reward seeking. The different distribution of sexes along the fast learning ↔ steady performance continuum might reflect different levels of engagement of the OFC, and might have implications for our understanding of sex differences in psychiatric disorders.

A novel, ataxic mouse model of ataxia telangiectasia caused by a clinically relevant nonsense mutation.

Ataxia Telangiectasia (A-T) and Ataxia with Ocular Apraxia Type 1 (AOA1) are devastating neurological disorders caused by null mutations in the genome stability genes, A-T mutated (ATM) and Aprataxin (APTX), respectively. Our mechanistic understanding and therapeutic repertoire for treating these disorders are severely lacking, in large part due to the failure of prior animal models with similar null mutations to recapitulate the characteristic loss of motor coordination (i.e., ataxia) and associated cerebellar defects. By increasing genotoxic stress through the insertion of null mutations in both the Atm (nonsense) and Aptx (knockout) genes in the same animal, we have generated a novel mouse model that for the first time develops a progressively severe ataxic phenotype associated with atrophy of the cerebellar molecular layer. We find biophysical properties of cerebellar Purkinje neurons (PNs) are significantly perturbed (e.g., reduced membrane capacitance, lower action potential [AP] thresholds, etc.), while properties of synaptic inputs remain largely unchanged. These perturbations significantly alter PN neural activity, including a progressive reduction in spontaneous AP firing frequency that correlates with both cerebellar atrophy and ataxia over the animal's first year of life. Double mutant mice also exhibit a high predisposition to developing cancer (thymomas) and immune abnormalities (impaired early thymocyte development and T-cell maturation), symptoms characteristic of A-T. Finally, by inserting a clinically relevant nonsense-type null mutation in Atm, we demonstrate that Small Molecule Read-Through (SMRT) compounds can restore ATM production, indicating their potential as a future A-T therapeutic.

Giant Condyloma Acuminata (Buschke-Lowenstein Tumor): Review of an Unusual Disease and Difficult to Manage.

Giant condyloma acuminatum (GCA) or Buschke-Loewenstein tumor is a rare disease, with an estimated prevalence of 0.1%. It was initially described in 1896 by Buschke and later in 1925 by Buschke and Loewenstein. Classic condyloma acuminata (CCA) and squamous cell carcinoma (SCC) were initially described as different entities. These three entities are currently considered to correspond to the same spectrum of different but not exclusive malignant transformations, associated with multiple risk factors such infection by human papilloma virus (HPV), immunodeficiencies, poor hygiene, multiple sexual partners, and chronic genital infections. HPV subtypes 6 and 11 are associated with 90% of GCA. It presents as a cauliflower-like tumor in the genital region with bad odor, bleeding, and local infection, differential diagnosis with multiple conditions should be considered, and sexually transmitted diseases should always be investigated. GCA has a higher rate of malignant transformation than CCA and tends to infiltrate adjacent soft tissues. The therapeutic approach is controversial but is considered that the resection with free edges is the gold standard and can be combined with adjuncts. The recurrence rate is high. Overall mortality is 21% and is associated with morbidity caused by recurrences. Imiquimod cream 5% has recently shown good results as monotherapy and in combination with ablative and surgical treatments. The quality of life is diminished in patients with this condition. In this review, we address the different aspects of this rare entity including the therapeutic approach.

Squamous Cell Carcinoma of the Nail, an Underdiagnosed and Underestimated Entity: A Series of Two Cases.

The nail apparatus is a complex area with great functional and cosmetic importance. The appearance of tumors is rare, frequently misdiagnosed with delaying the diagnosis. A series of cases is presented, where squamous cell carcinoma of nail apparatus underwent resection and reconstructive surgery in a relatively short time from their diagnosis, with a good oncological, functional, and cosmetic result.