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Hyperthermic intrathoracic chemotherapy (HITHOC) adjunct to surgery for Malignant Pleural Mesothelioma (MPM) has no definite role. The primary objective of this pilot-trial was to evaluate the feasibility for future large studies. The study design was a prospective randomized three-centric pilot trial. We recruited patients diagnosed with MPM and prospectively assigned them to two groups: Group A: Video Assisted Thoracic Surgery (VATS) talc pleurodesis or Group B: Video-assisted P/D plus HITHOC. From November-2011 to July-2017 24 males and 3 females, with a median age of 68-years were enrolled (recruitment rate 5 patients/year). Preoperative stage was I-II, and 18 had epithelioid type. 14 patients were in the Group A. Operative mortality was 0. Follow-up ranged 6-80 months. The median overall survival time started to diverge at 20 months, being 19 months (95% CI 12-25) in Group A and 28 months (95% CI 0-56) in Group B. Survival rate for the epithelioid type was 15 months (95% CI 0-34) in Group A and 45 months (95% CI 0-107) in the Group B. These findings suggest that video-assisted P/D plus HITHOC may improve survival time in MPM patients undergoing surgical treatment and support the need for a larger multicenter randomized clinical trial., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (© 2023 The Authors.)

Mutations in the synaptic scaffolding protein SHANK3 are a major cause of autism and are associated with prominent intellectual and language deficits. However, the neural mechanisms whereby SHANK3 deficiency affects higher-order socio-communicative functions remain unclear. Using high-resolution functional and structural MRI in adult male mice, here we show that loss of Shank3 ( Shank3B -/- ) results in disrupted local and long-range prefrontal and frontostriatal functional connectivity. We document that prefrontal hypoconnectivity is associated with reduced short-range cortical projections density, and reduced gray matter volume. Finally, we show that prefrontal disconnectivity is predictive of social communication deficits, as assessed with ultrasound vocalization recordings. Collectively, our results reveal a critical role of SHANK3 in the development of prefrontal anatomy and function, and suggest that SHANK3 deficiency may predispose to intellectual disability and socio-communicative impairments via dysregulation of higher-order cortical connectivity. SIGNIFICANCE STATEMENT Mutations in the synaptic scaffolding protein SHANK3 are commonly associated with autism, intellectual, and language deficits. Previous research has linked SHANK3 deficiency to basal ganglia dysfunction, motor stereotypies, and social deficits. However, the neural mechanism whereby Shank3 gene mutations affects cortical functional connectivity and higher-order socio-communicative functions remain unclear. Here we show that loss of SHANK3 in mice results in largely disrupted functional connectivity and abnormal gray matter anatomy in prefrontal areas. We also show that prefrontal connectivity disruption is tightly linked to socio-communicative deficits. Our findings suggest that SHANK3 is a critical orchestrator of frontocortical function, and that disrupted connectivity of prefrontal areas may underpin socio-communicative impairments observed in SHANK3 mutation carriers., (Copyright © 2019 the authors.)

Functional connectivity aberrancies, as measured with resting-state functional magnetic resonance imaging (rsfMRI), have been consistently observed in the brain of autism spectrum disorders (ASD) patients. However, the genetic and neurobiological underpinnings of these findings remain unclear. Homozygous mutations in contactin associated protein-like 2 (CNTNAP2), a neurexin-related cell-adhesion protein, are strongly linked to autism and epilepsy. Here we used rsfMRI to show that homozygous mice lacking Cntnap2 exhibit reduced long-range and local functional connectivity in prefrontal and midline brain "connectivity hubs." Long-range rsfMRI connectivity impairments affected heteromodal cortical regions and were prominent between fronto-posterior components of the mouse default-mode network, an effect that was associated with reduced social investigation, a core "autism trait" in mice. Notably, viral tracing revealed reduced frequency of prefrontal-projecting neural clusters in the cingulate cortex of Cntnap2-/- mutants, suggesting a possible contribution of defective mesoscale axonal wiring to the observed functional impairments. Macroscale cortico-cortical white-matter organization appeared to be otherwise preserved in these animals. These findings reveal a key contribution of ASD-associated gene CNTNAP2 in modulating macroscale functional connectivity, and suggest that homozygous loss-of-function mutations in this gene may predispose to neurodevelopmental disorders and autism through a selective dysregulation of connectivity in integrative prefrontal areas.

Autism spectrum disorders (ASD) and epilepsy are neurodevelopmental conditions that appear with high rate of co-occurrence, suggesting the possibility of a common genetic basis. Mutations in Synapsin (SYN) genes, particularly SYN1 and SYN2, have been recently associated with ASD and epilepsy in humans. Accordingly, mice lacking Syn1 or Syn2, but not Syn3, experience epileptic seizures and display autistic-like traits that precede the onset of seizures. Here, we analyzed social behavior and ultrasonic vocalizations emitted in 2 social contexts by SynI, SynII, or SynIII mutants and show that SynII mutants display the most severe ASD-like phenotype. We also show that the behavioral SynII phenotype correlates with a significant decrease in auditory and hippocampal functional connectivity as measured with resting state functional magnetic resonance imaging (rsfMRI). Taken together, our results reveal a permissive contribution of Syn2 to the expression of normal socio-communicative behavior, and suggest that Syn2-mediated synaptic dysfunction can lead to ASD-like behavior through dysregulation of cortical connectivity., (© The Author 2017. Published by Oxford University Press.)

The mechanisms underlying the neurodevelopmental deficits associated with CHARGE syndrome, which include cerebellar hypoplasia, developmental delay, coordination problems, and autistic features, have not been identified. CHARGE syndrome has been associated with mutations in the gene encoding the ATP-dependent chromatin remodeler CHD7. CHD7 is expressed in neural stem and progenitor cells, but its role in neurogenesis during brain development remains unknown. Here we have shown that deletion of Chd7 from cerebellar granule cell progenitors (GCps) results in reduced GCp proliferation, cerebellar hypoplasia, developmental delay, and motor deficits in mice. Genome-wide expression profiling revealed downregulated expression of the gene encoding the glycoprotein reelin (Reln) in Chd7-deficient GCps. Recessive RELN mutations have been associated with severe cerebellar hypoplasia in humans. We found molecular and genetic evidence that reductions in Reln expression contribute to GCp proliferative defects and cerebellar hypoplasia in GCp-specific Chd7 mouse mutants. Finally, we showed that CHD7 is necessary for maintaining an open, accessible chromatin state at the Reln locus. Taken together, this study shows that Reln gene expression is regulated by chromatin remodeling, identifies CHD7 as a previously unrecognized upstream regulator of Reln, and provides direct in vivo evidence that a mammalian CHD protein can control brain development by modulating chromatin accessibility in neuronal progenitors.

Several pieces of evidence from animal and human studies indicate that the organophosphate insecticide chlorpyrifos (CPF) acts as a developmental neurotoxicant at environmentally relevant doses, and it is possibly endowed with endocrine-disrupting activity. Data collected in rodent models show that developmental exposure to CPF at sub-toxic doses induces long-lasting and sex-dimorphic changes in social and investigative responses in exposed offspring. The aim of this study was to evaluate the effects of gestational CPF treatment on social and olfactory discrimination in adult mice of both sexes. Pregnant CD1 out-bred mice were exposed to CPF per os on gestational days (GD) 14-17 at the sub-toxic dose of 6 mg/kg/bw. At adulthood, male and female offspring underwent the same experimental paradigms, namely i) a social discrimination test where mice were presented with a simultaneous binary choice between a novel conspecific and a familiar one, and ii) an olfactory habituation/dishabituation test to evaluate their capability to discriminate between odors with different eco-ethological salience (non-social vs. social odors). Results showed that in the social discrimination test prenatal CPF primarily affected the female sex by raising the investigation time in females to the same levels as found in vehicle- and CPF-exposed males. The ability to discriminate between a familiar and a novel social mate was not affected by CPF in either sex. In the olfactory habituation/dishabituation test, mice of both sexes successfully discriminated non-social from social odors regardless of the prenatal treatment received. These results confirm previous evidence indicating that developmental exposure to CPF causes long-lasting and sex-dimorphic changes in responsiveness to social cues, in the absence of significant impairment of social and olfactory discrimination capacity. These findings are discussed within the framework of recent data pointing to the limbic/hypothalamic circuitry and steroid hormonal regulations as possible targets for CPF neurotoxicity., (Copyright © 2014. Published by Elsevier Inc.)

Morbid obesity (body mass index > 40 kg/m2) is a risk factor for cardiovascular, pulmonary, metabolic, neoplastic, and psychologic sequelae. In the present prospective clinical study 65 patients (11 men, 54 women) underwent vertical banded gastroplasty (Mason procedure) from June 1994 to October 1997. The median age was 41 +/- 5.3 years (range 18-69; n = 65). Preoperative body weight was 135 +/- 23 kg (96-229; n = 65), excess body weight in kg was 75 +/- 6.9 (44-155; n = 65) or in % 126 +/- 10 (78-223; n = 65) and BMI was 49 +/- 7.4 kg/m2 (39-69; n = 65). Mean hospital stay was 9.7 +/- 2.4 days (6-18; n = 65). Hospital mortality was 0% (0/65). Early complications were vomiting (30%) and problems in wound healing (15%; n = 65). Late complications (> 30 days) were incisional hernias (13.8%) and staple-line disruptions (12.3%; n = 65) with a reoperation rate of 23% (15/65). Median follow-up was 15.0 +/- 5.2 months (2-42) with a follow up rate of 100%. Mean weight loss after 12 months was 38.5 +/- 17 kg (30-98; n = 34) (P < 0.0001) and loss of excessive body weight 65 +/- 10% (57-86; n = 34), respectively (P < 0.0001). Cardiovascular risk factors (hypertension, diabetes, hyperlipidemia) were significantly improved within 12 months (n = 34). Vertical banded gastroplasty (Mason procedure)--well established for 20 years--is a good, safe therapy for morbid obesity if strict indications for operation are observed and if there is multidisciplinary long-term follow-up. Comorbid risk factors are considerably reduced and a long-term weight loss of more than 50% can be achieved without the risk of pathological metabolic changes.

Objective: The association of known prognostic factors with immune cell counts and beta2-microglobulin and soluble IL-2 receptor (sIL-2r) serum levels as markers of activation of the immune system was investigated in breast cancer., Methods: Two hundred thirty five operated stage I and II breast cancer patients to receive adjuvant treatment in IBSCG trials were assessed in a cross-sectional study immediately before the first treatment. Leukocytes, lymphocytes and lymphocyte subset counts, beta2-microglobulin and sIL-2r serum levels were assessed as immunological parameters. Prognostic factors were tumor load, receptor status, patient characteristics, and contextual factors of the immune assessment (such as time of the day, time since surgery, type of surgery, concomitant medication, co-morbidity)., Results: In an operated early stage breast cancer patient population, tumor load was not associated with immune cell counts, beta2-microglobulin, or sIL-2r before adjuvant treatment. There was a pattern of association of prognostically favorable factors such as estrogen receptor (ER) positive tumor and older age with higher NK cell counts or with beta2-microglobulin or sIL-2r. In addition, immune cell counts and the markers of activation of the immune system were affected by several contextual factors, such as diurnal variability, time since surgery, type of surgery, and the intake of concomitant medication., Conclusions: The association of NK cell counts and beta2-microglobulin or sIL-2r serum levels with prognostically favorable factors such as ER positive tumor and older age supports the assumption that the immune system plays a role in the course of early breast cancer. The exact nature of this role requires further study.

Animal research has indicated that the activity of the hypothalamic-pituitary-adrenal axis can be influenced by classical (Pavlovian) conditioning procedures. To test the hypothesis that alterations in plasma cortisol levels can be conditioned in humans, the present study used a prospective, randomized, double-blind, placebo-controlled design in which a distinctively flavored beverage was paired with p.o. administration of dexamethasone. Twenty-five healthy men were randomly assigned to one of two groups. During the conditioning phase of the study, subjects in the experimental group received three conditioning trials (pairings of a distinctively flavored beverage with a capsule containing 5 mg dexamethasone) separated by 1 wk recovery periods. Subjects in the control group were treated identically, except that the capsule contained a placebo. During the test phase, all subjects underwent a test day (reexposure to the distinctively flavored beverage before receiving a placebo capsule) and a comparison day (no exposure to the beverage or the capsule). Plasma cortisol was assessed repetitively before and after administration of the beverage and capsule, as were possible confounding factors, including: behavioral variables, psychological distress, aversive reactions to the beverage, and expectations of treatment. After reexposure to the beverage and administration of a placebo capsule (conditioned stimuli), the experimental group had significantly higher levels of plasma cortisol than the control group, after controlling for variability in baseline levels of cortisol (F(5,60)=3.09; P=0.015) that could not be explained by differences in other study variables. No differences in cortisol levels were found on the comparison day. These results support the study hypothesis that changes in plasma cortisol levels can be classically conditioned in humans by pairing a distinctive beverage with p.o. administration of dexamethasone.

Relations among coping, physical symptoms, and affect were investigated in 43 women undergoing adjuvant chemotherapy for breast cancer. Patients were assessed at the same point in their treatment so that the time for which coping was reported would be equivalent across individuals. Patients were asked how they coped specifically with chemotherapy, rather than how they coped with cancer in general, to make the domain specific. Positive and negative affect were assessed separately, using a scale free of somatic content. Relations between coping and affect were consistent with prior studies that have employed a general approach to assessing coping. Coping correlates of positive and negative mood differed. When the relations between physical symptoms and affect were examined, physical symptoms were related to negative affect but not to positive affect. Findings are discussed in terms of their implications for coping with cancer as well as their implications for the general coping literature.

Patients receiving cycles of cytotoxic chemotherapy for cancer often experience noxious side effects following treatments and may develop classically conditioned side effects, such as anticipatory nausea and vomiting (ANV) during the course of repeated infusions. The present study explored the possibility that classical conditioning processes may also contribute to treatment related psychological distress. Sixty-six patients, scheduled for adjuvant chemotherapy for breast cancer (stages I, II, IIIa), agreed to participate. Patients were assessed in the clinic on the first day of every chemotherapy cycle and in their homes three to five days before their final cycle. Patients experienced considerable psychological distress during the course of chemotherapy, and particularly before the first infusion. Prior to the last cycle of chemotherapy, psychological distress was significantly higher in the clinic environment than in patients' homes. Consistent with classical conditioning, psychological distress did not escalate over the days before treatment, but rather increased abruptly when patients returned to the clinic. The results of the present study indicate that several factors are involved in patients' anticipatory psychological distress and highlight the potential contribution that conditioning processes may make to patients' emotional distress in the clinic environment.