Early social isolation differentially affects the glucocorticoid receptor system and alcohol-seeking behavior in male and female Marchigian Sardinian alcohol-preferring rats.

Adverse early life experiences during postnatal development can evoke long-lasting neurobiological changes in stress systems, thereby affecting subsequent behaviors including propensity to develop alcohol use disorder. Here, we exposed genetically selected male and female Marchigian Sardinian alcohol-preferring (msP) and Wistar rats to mild, repeated social deprivation from postnatal day 14 (PND14) to PND21 and investigated the effect of the early social isolation (ESI) on the glucocorticoid receptor (GR) system and on the propensity to drink and seek alcohol in adulthood. We found that ESI resulted in higher levels of GR gene and protein expression in the prefrontal cortex (PFC) in male but not female msP rats. In female Wistars, ESI resulted in significant downregulation of Nr3c1 mRNA levels and lower GR protein levels. In male and female msP rats, plasma corticosterone levels on PND35 were similar and unaffected by ESI. Wistar females exhibited higher levels of corticosterone compared with males, independently from ESI. In alcohol self-administration experiments we found that the pharmacological stressor yohimbine (0.0, 0.312, 0.625, and 1.25 mg/kg) increased alcohol self-administration in both rat lines, regardless of ESI. After extinction, 0.625 mg/kg yohimbine significantly reinstated alcohol seeking in female rats only. ESI enhanced reinstatement in female msP rats. Overall, the present results indicate that repeated social deprivation during the third week of postnatal life affects GR expression in a strain- and sex-dependent manner: such effect may contribute, at least partially, to the heightened sensitivity of female msP rats to the effects of yohimbine-induced alcohol seeking.

Psilocybin prevents reinstatement of alcohol seeking by disrupting the reconsolidation of alcohol-related memories.

BACKGROUND: For most psychiatric conditions, including alcohol use disorder (AUD), FDA-approved pharmacological treatments are limited and their efficacy is restricted to only certain subgroups of patients. Scientific interest in the potential of psychedelic drugs has dramatically increased because of clinical preliminary evidence of efficacy in treating various psychiatric disorders. One of the most promising compounds belonging to this class of molecules is psilocybin. Here, to elucidate the therapeutic potential and treatment modalities of this drug, we investigated the effect of psilocybin on alcohol drinking and seeking in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats, a well validated animal model of AUD characterized by excessive drinking and seeking. METHODS: Using male and female msP rats, we tested the effect of psilocybin on home cage voluntary alcohol consumption. We also tested the effect of the drug on the alcohol deprivation effect (ADE) model of relapse and on cue-induced reinstatement of alcohol seeking after a period of abstinence. Finally, we evaluated if psilocybin may disrupt the reconsolidation process of alcohol-related memory. RESULTS: Psilocybin did not reduce alcohol consumption, nor it prevented increased alcohol drinking after a period of forced abstinence and cue-induced reinstatement of alcohol-seeking. Noteworthy, in a memory retrieval-reconsolidation paradigm, psilocybin markedly attenuated resumption of alcohol seeking. CONCLUSIONS: Altogether these data suggest that, despite psilocybin does not affect alcohol drinking and relapse, it may be highly effective if used to block the reconsolidation process of alcohol-related memories. This opens to the possibility of using this psychedelic drug in clinical settings in which AUD patients undergo procedures to recall the memory of alcohol and are then treated with psilocybin during the memory reconsolidation phase.

The proximity between styloid process and internal carotid artery as a possible risk factor for dissection: a case-control study.

PURPOSE: The anatomical proximity of the styloid process (SP) to the ipsilateral internal carotid artery (ICA) has been recently recognized as a possible risk factor for carotid artery dissection (CAD). We aimed to verify this hypothesis by comparing the minimum distance between SP and ICA in young adult patients (< 55 years) with and without CAD. METHODS: Thirty-one CAD patients (cases) were compared with 41 sex-matched patients without dissection, group one of control (G1), and with 16 sex-matched patients with vertebral artery dissection (VAD), group two of control (G2). Two independent observers measured, on CT angiography images, the minimum distance on the axial plane between the SP and ICA in cases and controls. They evaluated both the intercentric and the marginal distance. Differences between groups were estimated by Student t-test. RESULTS: SP-ICA intercentric distance ipsilateral to dissection was significantly shorter compared to that of the contralateral side of cases (p < 0.001), to those of left and right side of G1 patients (p < 0.001 for both), and to those of left and right side of G2 patients (p < 0.001 for both). SP-ICA marginal distance of cases was significantly shorter compared to those of left and right side of G1 patients (p < 0.001 for both) and to those of left and right side of G2 patients (p < 0.001 for both). CONCLUSION: A short SP-ICA distance appears to be a risk factor for CAD as it likely induces a continuous microtraumatism of the vessel wall during normal head and neck movements.

Eating psychopathology in ballet dancers: a meta-analysis of observational studies.

OBJECTIVE: To assess whether ballet dancers have higher eating psychopathology mean scores than the general population. METHODS: Meta-analysis of cross-sectional observational studies comparing the scores of one or more of the validated eating psychopathological scales between ballet dancers and any control groups. RESULTS: Twelve studies were included in the metanalysis. Ballet dancers had a significantly higher EAT score (12 studies retrieved, SMD 0.82 [95% CI 0.44-1.19], p < 0.00001, I2 = 84)]; subgroup analysis suggested a possible role of control subjects' choice in explaining heterogeneity. Scores on the EDI subscales of Drive for Thinness, Bulimia, and Body dissatisfaction were available from four studies; Drive for Thinness was higher in ballet dancers (SMD 0.62 [0.01, 1.22]), as well as the Bulimia scale (SMD 0.38 [0.02, 0.73], p = 0.04) and the Body Dissatisfaction scale (SMD 0.34 [0.15, 0.53]). Data on Perfectionism, Interpersonal problems, Ineffectiveness, and Maturity fears, were available from three studies. Higher scores in Perfectionism (SMD 0.68 [0.24, 1.12] p = 0.02), Interpersonal problems (SMD 0.24 [0.02, 0.47], in Inefficacy, (SMD 2.18 [1.31, 3.06]) were found for ballet dancers; on the other hand, Maturity fears scores were not significantly different between ballet dancers and controls (IV-MD = 0.15 [- 0.07, 0.36]). Seven studies reported tests not performed elsewhere. DISCUSSION: Ballet dancers show a higher level of restriction and drive for thinness than controls, and they may be, therefore, at higher risk for the development of eating disorders. Available studies do not allow the discrimination of dysfunctional eating attitudes and behaviors from adaptive responses. LEVEL OF EVIDENCE: Level I (evidence obtained from systematic reviews and meta-analyses).

SARS-CoV-2 infection in patients with autoimmune rheumatic diseases in northeast Italy: A cross-sectional study on 916 patients.

BACKGROUND: Whether patients with autoimmune rheumatic diseases (ARD) have a higher risk for SARS-CoV-2 infection (COVID-19) and how SARS-CoV-2 pandemic impacts on adherence to therapy has not been fully elucidated. We assessed the rate and clinical presentation of COVID-19, and adherence to therapy in a large cohort of patients with ARD followed-up in a tertiary University-Hospital in Northeast Italy. METHODS: Between April 9th and April 25th, 2020, after SARS-CoV-2 infection peak, a telephone survey investigating the impact of COVID-19 on patients with systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA), ANCA-associated vasculitis (AAV), and idiopathic inflammatory myopathies (IIM) was administered. Demographics, disease activity status, therapy, occupational exposure, and adherence to social distancing advise were also collected. RESULTS: 916 patients (397 SLE, 182 AAV, 176 SSc, 111 RA, 50 IIM) completed the survey. 148 patients developed at least one symptom compatible with COVID-19 (cough 96, sore throat 64, fever 64, arthromyalgias 59, diarrhea 26, conjunctivitis 18, ageusia/hyposmia, 18). Among the 916 patients, 65 (7.1%) underwent SARS-CoV-2 nasopharyngeal swab (18 symptomatic and 47 asymptomatic), 2 (0.21%) tested positive, a proportion similar to that observed in the general population of the Veneto region. No deaths occurred. 31 patients (3.4%) withdrew ≥1 medication, mainly immunosuppressants or biologics. Adoption of social distancing was observed by 860 patients (93.9%), including 335 (36.6%) who adopted it before official lockdown. CONCLUSIONS: COVID-19 incidence seems to be similar in our cohort compared to the general population. Adherence to therapy and to social distancing advise was high.

Repeated AAV-mediated gene transfer by serotype switching enables long-lasting therapeutic levels of hUgt1a1 enzyme in a mouse model of Crigler-Najjar Syndrome Type I.

Adeno-associated virus (AAV) -mediated gene therapy is a promising strategy to treat liver-based monogenic diseases. However, two major obstacles limit its success: first, vector dilution in actively dividing cells, such as hepatocytes in neonates/children, due to the non-integrating nature of the vector; second, development of an immune response against the transgene and/or viral vector. Crigler-Najjar Syndrome Type I is a rare monogenic disease with neonatal onset, caused by mutations in the liver-specific UGT1 gene, with toxic accumulation of unconjugated bilirubin in plasma, tissues and brain. To establish an effective and long lasting cure, we applied AAV-mediated liver gene therapy to a relevant mouse model of the disease. Repeated gene transfer to adults by AAV-serotype switching, upon neonatal administration, resulted in lifelong correction of total bilirubin (TB) levels in both genders. In contrast, vector loss over time was observed after a single neonatal administration. Adult administration resulted in lifelong TB levels correction in male, but not female Ugt1-/- mice. Our findings demonstrate that neonatal AAV-mediated gene transfer to the liver supports a second transfer of the therapeutic vector, by preventing the induction of an immune response and supporting the possibility to improve AAV-therapeutic efficacy by repeated administration.

Dendritic cell functional improvement in a preclinical model of lentiviral-mediated gene therapy for Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency caused by the defective expression of the WAS protein (WASP) in hematopoietic cells. It has been shown that dendritic cells (DCs) are functionally impaired in WAS patients and was(-/-) mice. We have previously demonstrated the efficacy and safety of a murine model of WAS gene therapy (GT), using stem cells transduced with a lentiviral vector (LV). The aim of this study was to investigate whether GT can correct DC defects in was(-/-) mice. As DCs expressing WASP were detected in the secondary lymphoid organs of the treated mice, we tested the in vitro and in vivo function of bone marrow-derived DCs (BMDCs). The BMDCs showed efficient in vitro uptake of latex beads and Salmonella typhimurium. When BMDCs from the treated mice (GT BMDCs) and the was(-/-) mice were injected into wild-type hosts, we found a higher number of cells that had migrated to the draining lymph nodes compared with mice injected with was(-/-) BMDCs. Finally, we found that ovalbumin (OVA)-pulsed GT BMDCs or vaccination of GT mice with anti-DEC205 OVA fusion protein can efficiently induce antigen-specific T-cell activation in vivo. These findings show that WAS GT significantly improves DC function, thus adding new evidence of the preclinical efficacy of LV-mediated WAS GT.

Adaptive physical activity and back pain: a non-randomised community-based intervention trial.

BACKGROUND: Back pain is a significant problem due to the high healthcare utilization, rising costs of care and low effectiveness of many current treatments. AIM: Aim of this study was to determine the effects of a community-based Adapted Physical Activity (APA) program focused on chronic, non-specific back pain. DESIGN: Open-label intervention study. SETTING: Community. POPULATION: All patients admitted to Empoli Rehabilitation Department for non-specific back pain for at least three months, were considered for APA. Exclusion criteria were: "red flags", difficulty/disability in basic daily living activities, severe/acute medical conditions, acute pain, psychiatric disease or cognitive impairment, severe visuoauditory deficit. Overall, 650 persons were enrolled. METHODS: The APA program, including strength and flexibility training and exercises for improving posture was delivered for 12 months, with 1-hour group classes three times per week. RESULTS: Overall 261 (40.2%) subjects completed the 12-month APA program and were compared to the 310 (47.7%) who were screened but failed to initiate or complete the study. There were no significant differences in baseline demographic and clinical characteristics between groups. Patients who followed the APA program reported significantly improved health status and significant back pain improvement, compared with those who did not adhere to the program. In the logistic regression analysis adjusted for age and gender, a distance from home to gymnasium greater than the median for the study population (2.6 km) was the only baseline characteristic significantly associated with an increased risk of non-adherence (OR 1.44, 95%CI 1.01-2.13; P=0.04). CONCLUSION: This study suggests that a community-based APA program can improve back pain and health status in persons with chronic, non-specific low back pain. CLINICA REHABILITATION IMPACT: These findings highlight the potential for new approaches to manage chronic disease and disability by facilitating a healthy lifestyle and promoting physical activity through implementation of community-based exercise programs.

[Characteristics of patients with hand dermatitis referred to the contact dermatitis unit of a tertiary hospital and impact of patch testing on diagnosis]. / Perfil de los pacientes con dermatosis en las manos remitidos a la Unidad de Contacto de un hospital terciario e impacto de las pruebas epicutáneas en el diagnóstico.

UNLABELLED: OBJECTIVE. This study aimed to define the epidemiological and clinical characteristics of patients referred to a contact dermatitis unit for hand dermatitis. MATERIAL AND METHODS: We retrospectively analyzed patients referred for hand dermatitis to the contact dermatitis unit of the Hospital Germans Trias i Pujol, Barcelona, Spain, between 2004 and 2007. RESULTS: A total of 96 patients were included. The most common diagnosis was irritant contact dermatitis, followed by allergic contact dermatitis, psoriasis, dyshydrosis, and atopic dermatitis. Standard patch tests were done for all patients and complementary batteries were ordered in 42 (44%). Patch tests were positive in 59% of the patients. Positive results were considered of present relevance in 59%, of past relevance in 6%, and of unknown relevance in the remaining positive tests. When proposed as the initial diagnosis, allergic contact dermatitis was confirmed in 67% of the patients. The most frequent clinically relevant allergens were chrome, nickel, rosin, plant allergens, and p-phenylenediamine. CONCLUSIONS: Hand dermatitis is a frequent presenting complaint in our contact dermatitis unit, with allergic contact dermatitis being the most common. Good correlation was found between presumed diagnosis of allergic contact dermatitis and the finding of clinically relevant allergens.

Antioxidative effects of sulfurous mineral water: protection against lipid and protein oxidation.

OBJECTIVES: To investigate the antioxidative properties of sulfurous drinking water after a standard hydropinic treatment (500 ml day(-1) for 2 weeks). SUBJECTS/METHODS: Forty apparently healthy adults, 18 men and 22 women, age 41-55 years old. The antioxidant profile and the oxidative condition were evaluated in healthy subjects supplemented for 2 weeks with (study group) or without (controls) sulfurous mineral water both before (T0) and after (T1) treatment. RESULTS: At T1, a significant decrease (P<0.05) in both lipid and protein oxidation products, namely malondialdehyde, carbonyls and AOPP, was found in plasma samples from subjects drinking sulfurous water with respect to controls. Concomitantly, a significant increment (P<0.05) of the total antioxidant capacity of plasma as well as of total plasmatic thiol levels was evidenced. Tocopherols, carotenoids and retinol remained almost unchanged before and after treatment in both groups. CONCLUSIONS: The improved body redox status in healthy volunteers undergoing a cycle of hydropinic therapy suggests major benefits from sulfurous water consumption in reducing biomolecule oxidation, possibly furnishing valid protection against oxidative damage commonly associated with aging and age-related degenerative diseases.

Extraction of information on elder motor ability from clinical and biomechanical data through data mining.

This study aimed at evaluating the additional knowledge provided by a biomechanical test coupled with clinical tests for motor ability assessment. A database including clinical test scores and sit-to-stand test variables obtained from 110 medically stable elderly subjects was submitted to data mining by searching for association rules. The presence of rules revealed some redundancies due to sample homogeneity, as mainly observed in the joint analysis of a questionnaire for daily activities assessment (Nottingham test) and the sit-to-stand, and due to similar evaluated information, as resulted from the joint analysis of a balance and gait scale (Tinetti test) and the sit-to-stand. Conversely, when no association rules were found, the tests carried unrelated information. The associations mined while analysing these clinical tests encouraged the integration of biomechanical tests, increasing significantly its clinical applicability and reducing the information redundancy. The information extracted also allowed to highlight rules typical of elderly persons that may serve as a knowledge-based tool for the detection of possible deviation from normality.

Optimised procedure for the calibration of the force platform location.

An innovative optimised method, including an experiment and a mathematical model, for the calibration of the force platform location in the optoelectronic reference frame is proposed. The calibration experiment adopts a bearing-marker testing object contacting the platform and does not directly measure the platform location. The experiment is designed in order to avoid the main drawbacks possibly occurring in commonly adopted methods. The mathematical model of the experiment estimates the expected ground reaction. An optimisation algorithm identifies the optimal platform location as the one that best matches the measured outcome of the calibration experiment with the corresponding model estimate. The innovative calibration procedure has been assessed in terms of inter-tester reliability and compared with commonly used calibration procedures of platform location. These results evidenced how the introduction of such optimised procedure could improve the reliability of the calibrated platform location and, consequently, of the kinetic variables considered in posture and gait analysis.

Genetic vaccination for the immunotherapy of B-cell malignancies.

Vaccination protocols based on targeting of the idiotype expressed on malignant B cells have so far provided encouraging results in clinical trials. The essential requirement to induce an immune response is the inclusion of carriers to overcome T-cell tolerance. Chemical cross-linking of idiotypic protein is so far the method of choice to induce protective responses in human studies. Meanwhile, a flurry of alternative strategies to simplify vaccine production is being tested in murine model. Thanks to the advance in antibody engineering the two relevant antigenic domains of the lymphoma immunoglobulin can be assembled into an appropriate format, genetically linked to molecules that act as immunological adjuvants and directly delivered as plasmid DNA. Upon immunization, rejection of tumor cells may depend on cellular or humoral mechanisms, whose relative importance has not been entirely estimated. We have recently analyzed the specificity of anti-idiotypic antibodies induced by DNA vaccination and characterised the elements contributing to optimal anti-idiotypic responses.

Cortical silent period in two patients with meningioma and preoperative seizures: a pre- and postsurgical follow-up study.

OBJECTIVES: Prolongation of the cortical silent period (CSP) following transcranial magnetic stimulation has been reported in patients with partial epilepsy involving the primary motor cortex (M1). This study aimed to investigate the relationship between the expected intraindividual variations in risk factors for seizures and CSP duration. METHODS: We studied a 59-year-old woman with a rolandic meningioma and simple motor partial seizures and a 71-year-old woman with a parietal/occipital meningioma and complex partial seizures. Both patients had seizure as their initial symptom with complete postsurgical remission. Repeated pre- and postoperative CSP recordings were made from both first dorsal interosseous muscles. We compared the results to those obtained in 13 normals. RESULTS: In the patient with simple motor partial seizures, the CSP was significantly prolonged in preoperative recordings and 3 weeks after surgery. This CSP lengthening partly subsided 3 months after surgery. Finally, the CSP was normal 6, 8, and 18 months after surgery. In the patient with complex partial seizures, no CSP change was observed. CONCLUSIONS: In our patient with a rolandic meningioma, CSP prolongation was observed when the risk of seizure relapse was supposed to be higher (preoperative and early postoperative periods). This supports the view that CSP changes reflect compensatory mechanisms in M1 epilepsy.

Anti-idiotypic antibodies induced by genetic immunisation are directed exclusively against combined V(L)/V(H) determinants.

DNA vaccines encoding the idiotype of immunoglobulins of tumour B cells were shown to induce protection in several mouse lymphoma models. The mechanism of rejection of tumour cells has not been fully understood, but there is strong evidence suggesting that engagement of the idiotype by anti-idiotypic antibodies may directly result in inhibition of tumour growth. In this study, we have investigated the structural basis of the idiotypic/anti-idiotypic interaction following immunisation with DNA vaccines. scFvs containing only one of the two tumour-derived V regions recombined to an irrelevant V region partner were generated. These constructs encoding a secretory form of the scFv were used as immunogens to induce anti-Id antibodies. The same scFvs were expressed as membrane-bound molecules on the surface of mammalian cells. Analysis of immune sera on the membrane-displayed idiotypes revealed that DNA immunisation induced a polyclonal antibody response restricted to conformational combined epitopes formed by the parental V(L)/V(H) association. Immune sera raised by scFv DNA vaccination did not show any detectable reactivity towards chimeric scFvs containing only one of the two immunising V regions, indicating that the response against combined V(L)/V(H)determinants is highly dominant. Remarkably, the same immunogen, delivered as scFv protein, induced antibodies also directed against chain-specific determinants. These findings indicate that presentation of properly folded idiotypes results in a highly specific antibody response directed exclusively to private idiotypic determinants of the V(L)/V(H) combination of the immunogen.

Effects of low frequency electromagnetic fields on expression of lymphocyte subsets and production of cytokines of men and women employed in a museum.

The objective of this study was to analyse the immune response to electromagnetic fields (ELMFs) in seven men and eight women employed in a museum. The workers were exposed in a room to an ELMFs (range 0.2-3.6 microT and 40-120 V/m) induced by 50 Hz electricity for 20 h a week. Control groups consisted of 47 women and 39 men with a similar percentage of atopic subjects, age (range 30-51 years) and smoking habits of the workers included in the study. Levels of blood lead (Pb) and urinary trans-trans muconic acid, a metabolite of benzene (markers of exposure to traffic and smoking) of the control and exposed groups were similar. Lymphocyte subsets were determined in men and women using conjugated antibodies. Serum interleukin (IL) 4 and interferon gamma and their 'in vitro' production by peripheral mononuclear blood cells (PMBCs) stimulated by phytohemoglutinin (PHA), as well as blastogenesis of PMBCs induced by PHA, were determined in women only. ELMF-exposed women showed a significant reduction in the percentage of B and NK CD3(-)-CD25+ lymphocytes and a slight reduction of CD16(+)-56+ NK lymphocytes. They also showed significantly lower levels of interferon gamma in serum, or produced in the supernatants by PMBCs both spontaneously and stimulated by PHA, while they did not show significant changes in serum and 'in vitro' produced IL-4, or in blastogenesis of PMBCs. Men working in the museum showed, in relation to the controls, a statistically significant reduction in both number and percentage of CD16(+)- CD56+ and CD3(-)-CD25+ lymphocyte subsets. On the whole, this investigation demonstrates a reduction of blood NK lymphocytes and of the production of interferon gamma in workers exposed to low frequency ELMFs. Recent studies have shown that stress and poor lifestyle induce the reduction of blood cytotoxic activities possibly acting on nervous functions. This may suggest that ELMFs reduces blood NK lymphocytes by combined effects on the immune and nervous systems.