Differential effects of chronic stress in young-adult and old female mice: cognitive-behavioral manifestations and neurobiological correlates.

Stress-related psychopathology is highly prevalent among elderly individuals and is associated with detrimental effects on mood, appetite and cognition. Conversely, under certain circumstances repeated mild-to-moderate stressors have been shown to enhance cognitive performance in rodents and exert stress-inoculating effects in humans. As most stress-related favorable outcomes have been reported in adolescence and young-adulthood, this apparent disparity could result from fundamental differences in how aging organisms respond to stress. Furthermore, given prominent age-related alterations in sex hormones, the effect of chronic stress in aging females remains a highly relevant yet little studied issue. In the present study, female C57BL/6 mice aged 3 (young-adult) and 20-23 (old) months were subjected to 8 weeks of chronic unpredictable stress (CUS). Behavioral outcomes were measured during the last 3 weeks of the CUS protocol, followed by brain dissection for histological and molecular end points. We found that in young-adult female mice, CUS resulted in decreased anxiety-like behavior and enhanced cognitive performance, whereas in old female mice it led to weight loss, dysregulated locomotion and memory impairment. These phenotypes were paralleled by differential changes in the expression of hypothalamic insulin and melanocortin-4 receptors and were consistent with an age-dependent reduction in the dynamic range of stress-related changes in the hippocampal transcriptome. Supported by an integrated microRNA (miRNA)-mRNA expression analysis, the present study proposes that, when confronted with ongoing stress, neuroprotective mechanisms involving the upregulation of neurogenesis, Wnt signaling and miR-375 can be harnessed more effectively during young-adulthood. Conversely, we suggest that aging alters the pattern of immune activation elicited by stress. Ultimately, interventions that modulate these processes could reduce the burden of stress-related psychopathology in late life.

Alterations in the expression of a neurodevelopmental gene exert long-lasting effects on cognitive-emotional phenotypes and functional brain networks: translational evidence from the stress-resilient Ahi1 knockout mouse.

Many psychiatric disorders are highly heritable and may represent the clinical outcome of early aberrations in the formation of neural networks. The placement of brain connectivity as an 'intermediate phenotype' renders it an attractive target for exploring its interaction with genomics and behavior. Given the complexity of genetic make up and phenotypic heterogeneity in humans, translational studies are indicated. Recently, we demonstrated that a mouse model with heterozygous knockout of the key neurodevelopmental gene Ahi1 displays a consistent stress-resilient phenotype. Extending these data, the current research describes our multi-faceted effort to link early variations in Ahi1 expression with long-term consequences for functional brain networks and cognitive-emotional phenotypes. By combining behavioral paradigms with graph-based analysis of whole-brain functional networks, and then cross-validating the data with robust neuroinformatic data sets, our research suggests that physiological variation in gene expression during neurodevelopment is eventually translated into a continuum of global network metrics that serve as intermediate phenotypes. Within this framework, we suggest that organization of functional brain networks may result, in part, from an adaptive trade-off between efficiency and resilience, ultimately culminating in a phenotypic diversity that encompasses dimensions such as emotional regulation and cognitive function.

Neural mechanisms underlying stress resilience in Ahi1 knockout mice: relevance to neuropsychiatric disorders.

The Abelson helper integration site 1 (AHI1) gene has a pivotal role in brain development. Studies by our group and others have demonstrated association of AHI1 with schizophrenia and autism. To elucidate the mechanism whereby alteration in AHI1 expression may be implicated in the pathogenesis of neuropsychiatric disorders, we studied Ahi1 heterozygous knockout (Ahi1(+/-)) mice. Although their performance was not different from wild-type mice on tests that model classical schizophrenia-related endophenotypes, Ahi1(+/-) mice displayed an anxiolytic-like phenotype across different converging modalities. Using behavioral paradigms that involve exposure to environmental and social stress, significantly decreased anxiety was evident in the open field, elevated plus maze and dark-light box, as well as during social interaction in pairs. Assessment of core temperature and corticosterone secretion revealed a significantly blunted response of the autonomic nervous system and the hypothalamic-pituitary-adrenal axis in Ahi1(+/-) mice exposed to environmental and visceral stress. However, response to centrally acting anxiogenic compounds was intact. On resting-state functional MRI, connectivity of the amygdala with other brain regions involved in processing of anxiogenic stimuli and inhibitory avoidance learning, such as the lateral entorhinal cortex, ventral hippocampus and ventral tegmental area, was significantly reduced in the mutant mice. Taken together, our data link Ahi1 under-expression with a defect in the process of threat detection. Alternatively, the results could be interpreted as representing an anxiety-related endophenotype, possibly granting the Ahi1(+/-) mouse relative resilience to various types of stress. The current knockout model highlights the contribution of translational approaches to understanding the genetic basis of emotional regulation and its associated neurocircuitry, with possible relevance to neuropsychiatric disorders.

CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice.

Attention-deficit hyperactivity disorder (ADHD) is a common childhood-onset psychiatric disorder characterized by inattention, impulsivity and hyperactivity. ADHD exhibits substantial heritability, with rare monogenic variants contributing to its pathogenesis. Here we demonstrate familial ADHD caused by a missense mutation in CDH2, which encodes the adhesion protein N-cadherin, known to play a significant role in synaptogenesis; the mutation affects maturation of the protein. In line with the human phenotype, CRISPR/Cas9-mutated knock-in mice harboring the human mutation in the mouse ortholog recapitulated core behavioral features of hyperactivity. Symptoms were modified by methylphenidate, the most commonly prescribed therapeutic for ADHD. The mutated mice exhibited impaired presynaptic vesicle clustering, attenuated evoked transmitter release and decreased spontaneous release. Specific downstream molecular pathways were affected in both the ventral midbrain and prefrontal cortex, with reduced tyrosine hydroxylase expression and dopamine levels. We thus delineate roles for CDH2-related pathways in the pathophysiology of ADHD.

Tumor involvement of the facial nerve.

Tumors involving the facial nerve are rare and challenging in both diagnosis and treatment. In this paper we report 18 cases of benign and malignant neoplasms involving the temporal portion of the facial nerve. The selection of those patients with facial paralysis who require detailed evaluation is discussed. Often, despite thorough evaluation of these patients, a preoperative diagnosis is unavailable or erroneous. An occasional patient may require surgical exposure of the nerve from the middle cranial fossa to the parotid gland.

Characteristics of clients attending confidential versus anonymous testing clinics for human immunodeficiency virus.

OBJECTIVES: To compare risk behavior between subjects attending anonymous and confidential clinics for human immunodeficiency virus testing, and to assess whether anonymous testing results in a higher accrual of persons at risk for HIV. METHODS: An anonymous questionnaire that addressed sociodemographic and risk behavior aspects was administered to 140 subjects attending an anonymous clinic and 124 attending a confidential clinic in the Tel Aviv area. A logistic regression analysis was used to compare the effects of various behavioral factors on the probability of attending each clinic. RESULTS: Chronological age, age at first sexual intercourse, and the percent of married subjects were similar in both clinics. However, there was a significant difference in the sex ratio and in educational attainment (85.0% versus 55.6% were males, P < 0.001; and 58% vs. 34% had over 12 years of education, P < 0.001, in the anonymous and confidential clinics respectively). There was a striking difference between the two clinics with regard to sexual experience characteristics: of the subjects reaching the anonymous clinic 21.4% were homosexual and 10.0% bisexual versus a total of 2.6% in the confidential clinic. A logistic regression analysis, comparing the effects of various behavioral factors on the probability of attending each clinic, showed that gender (male), high education, homosexuality, number of partners and sexual encounter with sex workers were the strongest predictors for selecting anonymous HIV examination. CONCLUSIONS: Individuals at high risk for HIV, such as homosexuals and bisexuals, prefer to attend an anonymous clinic.

Cerebral venous thrombosis in the mediterranean area in children.

Cerebral Venous Sinus (sinovenous) Thrombosis (CSVT) is a serious and rare disorder, increasingly recognized and diagnosed in pediatric patients. The etiology and pathophisiology has not yet been completely clarified, and unlike adults with CSVT, management in children and neonates remains controversial. However, morbidity and mortality are significant, highlighting the continued need for high-quality studies within this field. The following review will highlight aspects of CSVT in the mediteranian area in children.

Toxin compartmentation and delivery in the Cnidaria: the nematocyst's tubule as a multiheaded poisonous arrow.

With the aid of dialysis and ion exchange chromatography, a new polypeptide toxin was purified from the tentacles of the Mediterranean jellyfish Rhopilema nomadica. The amino acid sequence of the N-terminal segment of the new toxin revealed that it is a phospholipase A2 (PhA2) toxin closely resembling those previously isolated from reptile and hymenopterous venoms. The occurrence of a PhA2 toxin in the jellyfish tentacles may explain both their local (dermanecrotic) and systemic (cardiac-respiratory) effects upon human envenomation. We used an antibody raised against the above toxin as a probe to explore, for the first time, the site of toxin allocation in cnidarian nematocysts and its morphological route of delivery. Our immunocytochemical approach revealed that the toxin is stored on the outer ("cytoplasmic") surface of the inverted tubule folded in the capsule of the resting nematocyst. During discharge the toxin is translocated to the internal surface surrounding the lumen of the everting tubule, and its delivery via extended spirally arrayed barbs is apparently propelled by the high hydrostatic pressure of the capsule. This is a unique example where subcellular translocation and transfer of a polypetide is driven by mechanical forces.

Comparison between transillumination and the roentgenogram in diagnosing paranasal sinus disease.

The reliability of transillumination versus roentgenogram to diagnose maxillary and frontal paranasal sinus disease was assessed in 52 subjects with rhinitis and/or asthma. Two different otolaryngologists transilluminated the sinuses while the roentgenograms were evaluated by a radiologist and a third otolaryngologist. Patients filled in questionnaires of symptoms. There was excellent agreement (p < 0.001) between otolaryngologists regarding transillumination of the frontal sinuses but not the maxillary sinuses. Similarly, transillumination of the frontal sinuses correlated well with the roentgenograms. This was not true for transillumination of the maxillary sinuses. Although pain in the upper teeth related well to the presence of frontal disease, sinus headache was a frequent complaint but not useful as a predictor of sinus disease. Even though transillumination of the frontal paranasal sinus has some predictive value, the technique of transillumination has limited usefulness as a diagnostic tool and is not an adequate substitute for roentgenogram.

Advanced colorectal carcinoma: redefining the role of oral ftorafur.

The therapeutic performance, effect on quality of life and cost effectiveness of an orally administered medication in a home care setting were examined prospectively in a group of 61 patients presenting with advanced colorectal carcinoma. A regimen of daily ftorafur capsules (370 mg/m2) and leucovorin tablets (20 mg/m2) was offered to 35 symptomatic patients with poor performance status; the standard in-hospital i.v. protocol of 5-fluouracil and leucovorin was given to the remaining 26 patients. Follow-up and survival analysis indicated that there was no compromise in survival associated with home care and oral chemotherapy. There were statistically significant advantages in terms of reduced toxicity and improved Karnofsky performance status in this group. Home care was approximately 70% less expensive. A home treatment program based on oral ftorafur may be the most desirable option for all patients with advanced colorectal carcinoma.