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Background Borderline Personality Disorder (BPD) is a complex and debilitating disorder, characterized by deficits in metacognition and emotion dysregulation. The “gold standard” treatment for this disorder is psychotherapy with pharmacotherapy as an adjunctive treatment to target state symptoms. The present randomized clinical trial aims to assess the clinical and neurobiological changes following Metacognitive Interpersonal Therapy (MIT) compared with Structured Clinical Management (SCM) derived from specific recommendations in APA (American Psychiatric Association) guidelines for BPD. Methods The study design is a randomized parallel controlled clinical trial and will include 80 BPD outpatients, aged 18–45 enrolled at 2 recruitment centers. Primary outcome will be the clinical change in emotion regulation capacities assessed with the Difficulties in Emotion Regulation Scale (DERS). We will also investigated the effect of psychotherapy on metacognitive abilities and several clinical features such as BPD symptomatology, general psychopathology, depression, personal functioning, and trait dimensions (anger, impulsivity, alexithymia). We will evaluate changes in brain connectivity patterns and during the view of emotional pictures. A multidimensional assessment will be performed at the baseline, at 6, 12, 18 months. We will obtain structural and functional Magnetic Resonance Images (MRIs) in MIT-Treated BPD (N = 30) and SCM-treated BPD (N = 30) at baseline and after treatment, as well as in a group of 30 healthy and unrelated volunteers that will be scanned once for comparison. Discussion The present study could contribute to elucidate the neurobiological mechanisms underlying psychotherapy efficacy. The inclusion of a multidisciplinary study protocol will allow to study BPD considering different features that can affect the treatment response and their reciprocal relationships. Trial registration NCT02370316. Registered 02/24/2015. Electronic supplementary material The online version of this article (10.1186/s12888-019-2127-2) contains supplementary material, which is available to authorized users.

Rationale Variables influencing real-life functioning have repeatedly been modeled in schizophrenia subjects but not systematically investigated in their unaffected first-degree relatives (SRs), in whom milder forms of deficits reported in schizophrenia have been observed, but confounders of clinical cohorts are not in play. Demonstrating that pathways to functional outcome are similar between patients and SRs would validate structural models developed in schizophrenia subjects. The present multicenter study aimed to explore whether variables associated with real-life functioning are similar in schizophrenia patients and their unaffected relatives. Methods The study sample included 921 schizophrenia patients, 379 SRs and 780 healthy controls. Structural Equation Models (SEMs) were used in patients and SRs to test associations of psychopathological dimensions, neurocognition, social cognition, resilience, perceived stigma and functional capacity with real-life functioning domains, impaired in both patients and SRs. Results Interpersonal Relationships and Work Skills were the only functional domains impaired in both patients and SRs. For both domains, functional impairment in patients was found to predict impairment in unaffected relatives, suggesting the involvement of similar illness-related vulnerability factors. In both groups variables significantly associated with Interpersonal Relationships included Social Cognition, Neurocognition, Avolition, Resilience, Disorganization, Perceived Stigma and Gender, and those significantly associated with Work Skills included Social Cognition, Neurocognition and Disorganization. Conclusions Pathways to functional outcome for Interpersonal relationships and Work skills are similar between schizophrenia patients and their unaffected first-degree relatives. These findings validate, in the absence of confounders of clinical cohorts, structural models of determinants of functional outcome in people with schizophrenia.

The serine protease urokinase-type plasminogen activator (u-PA) is involved in a variety of physiologic and pathological processes; in particular, u-PA mRNA is up-regulated in human hepatocellular carcinoma (HCC) biopsies and its level of expression is inversely correlated with patients' survival. To determine the role of u-PA in the invasiveness properties of HCC, we successfully down-regulated u-PA by RNA interference (RNAi) technology, in an HCC-derived cell line at high level of u-PA expression. RNAi is a multistep process involving generation of small interfering RNAs (siRNA) that cause specific inhibition of the target gene. SKHep1C3 cells were transfected with a U6 promoter plasmid coding for an RNA composed of two identical 19-nucleotide sequence motifs in an inverted orientation, separated by a 9-bp spacer to form a hairpin dsRNA capable of mediating target u-PA inhibition. Stable transfectant cells showed a consistently decreased level of u-PA protein. In biological assays, siRNA u-PA–transfected cells showed a reduction of migration, invasion, and proliferation. In conclusion, u-PA down-regulation by RNAi technology decreases the invasive capability of HCC cells, demonstrating that stable expression of siRNA u-PA could potentially be an experimental approach for HCC gene therapy.

Many studies suggest that hepatocellular carcinoma (HCC) is an androgen-dependent tumor with an incidence five times higher in males, but few data are available on the androgen receptor (AR) mRNA levels in different physiological classes of human liver specimens. In this study 108 human hepatic samples have been analyzed for AR mRNA expression by a comparative RT-PCR assay. These consisted of 35 non-tumoral hepatic samples (3 normal parenchymas, 4 steatosis, 10 hepatitis, 18 cirrhosis), 38 tumoral specimens derived from uninodular and multinodular HCCs and 35 peritumoral hepatic tissues. Normalized AR mRNA levels in tumoral and peritumoral liver tissues spanned from 0 to 146% and from 7 to 125% respectively. Only in a relatively small percentage of HCCs, the levels of expression of AR mRNA were higher than in the corresponding peritumoral tissues (16% of total HCCs). Although extremely variable, the AR mRNA levels were related to histological tumoral differentiation and proved to be lower in the highly dedifferentiated HCCs as compared to the well differentiated ones. Therefore, the evaluation of AR expression in HCC patients might be relevant for the planning of clinical studies on anti-androgen therapies, which might be useful only in the cases in which a high level of AR mRNA is detected, considering the high heterogeneity of AR mRNA levels which characterizes HCC samples. It is likely that the HCCs, expressing low or undetectable levels of AR mRNA, would not benefit by the antiandrogen therapy.

Dystrophic epidermolysis bullosa (DEB) is a rare genetic skin disorder. In this report we have investigated an Italian child affected with recessive DEB (RDEB) and demonstrated that he was homozygous for the mutation R226X in the type VII collagen gene (COL7A1), leading to absence of type VII collagen at the dermal-epidermal junction. There was no family history of inherited skin blistering but the child's father was affected by Marfan syndrome, an autosomal dominant connective tissue disorder that results from mutations in the fibrillin-1 gene (FBN1). Analysis of this gene showed that the RDEB patient and his father were both heterozygous for a novel FBN1 mutation, C1971Y. This mutation affects one of the six obligate cysteine residues within one of the calcium-binding epidermal growth factor-like regions of the protein. At the age of 2-years the RDEB patient showed signs of early aortic dilatation, suggesting that he is likely to develop a Marfan syndrome phenotype in the future. This is a unique case of these two coexisting inherited disorders.

We describe an image analysis (IA) system that has been applied for the quantitative evaluation of mRNAs evidenced by in situ hybridization (ISH) with radiolabelled probes in cultured cells and in tissue sections. The ISH-IA method was used for the evaluation of cultured cell morphological parameters such as cell and nucleous area (CA and NA, respectively) in parallel with the levels of mRNAs detected as hybridization grains areas (GA). The evaluation of these parameters, together with the analysis of the levels of mRNAs (c-jun, cyclin A) specific for given cell cycle phases (i.e. G1 and S/G2), allowed the identification, in asynchronous cultures of human skin fibroblasts, of cells in G1 and SlG2 phases. The mRNA levels measured by ISH-AI were comparable with those detected by RT-PCR. This method was also applied for the analysis of fibronectin (FN) gene expression in control skin fibroblasts in relationship with the different phases of the cell cycle and in comparison with a tumor cell line (Sk-Hepl), heterogeneous either for morphometric parameters or for the levels of this transcript. Finally, the ISH-AI was applied for the semiquantitative evaluation of the expression, localization and alternative splicing pattern of FN mRNA in normal liver and in hepatocellular carcinoma (HCC) tissue sections.

The viral typization in Human Papillomavirus (HPV) infections of the lower female genital tract is relevant both from the epidemiological and the clinical point of view. We have tested DNA from specimens obtained by guided biopsies on neoplastic and benign lesions, using single probes of the different virus types (6, 11, 16 and 18) by Dot-blot and Southern blot analysis. According to previous studies HPV 16 and 18 have been detected in neoplastic lesions, while 6 and 11 were more frequently found associated to condylomata. Negative specimens and intermediate were 36% of the total. In our experience both methods have shown same sensibility.

Plasminogen activators (PAs) present in the plasma of BALB/c mice and produced in vitro by murine tumor cell cultures (B77-3T3, SR-BALB, AA6) have been characterized using electrophoretic-zymographic techniques. BALB/c mouse plasma contains a main PA activity with an approximate molecular weight of 88,000 and pI 6.3, inhibited by anti-human tissue-type plasminogen activator (t-PA) serum, here defined as murine t-PA. On the contrary, all tumor cells tested release a PA activity with a molecular weight of 44,500 and pI 9.2 characteristic of urokinase-type activator (murine u-PA). The injection s.c. of the different tumorigenic cells into BALB/c mice leads to tumor development and to a rapid increase of t-PA from the first day following the injection. This early enhancement of t-PA activity is not detectable in mice given injections of lethally irradiated B77-3T3 cells. Moreover the development of the tumor in the animals is related to the appearance of increasing levels of u-PA in the blood. This activity is detectable in the plasma of treated mice almost 2 wk before detection of a tumor 1 mm in diameter. During tumor development, the molecular weight of the u-PA and t-PA forms present in the plasma does not change, while there is a decrease of the isoelectric point of the u-PA leading to the appearance of distinct PA activities with pI 7.6 and 8.9. Syngenic and allogenic lymphocytes, injected in BALB/c mice, do not induce any modification in the pattern of the plasma PA. The injection of highly metastatic cells, as opposed to nonmetastatic or low-metastatic cells, does not give rise to detectable levels of u-PA in the plasma of treated mice. These data suggest that the lack of plasma u-PA activity facilitates the formation of metastates, while the increase of this activity is important in tumor development and is independent of the metastatic potential of the injected cells.

Background/Aims: Compelling evidence would suggest the involvement of the serotonin 2C receptor in the pathophysiology of affective disorders and in the action of antidepressants. We analyzed the time course of 5-HT2C receptor (5-HTR2C) mRNA expression during antidepressant treatment in the prefrontal/frontal cortex (P/FC) and in the hippocampus (HC) of rats chronically treated with fluoxetine (a selective serotonin reuptake inhibitor) and reboxetine (a selective noradrenaline reuptake inhibitor). We also analyzed the 5-HTR2C RNA-editing levels at the sites called A, B, C, C’ and D, which are known to modulate 5-HTR2C receptor function. Results: The expression profile of 5-HTR2C mRNA was modified during treatment with both antidepressants. In particular, we found a general down-regulation of 5-HTR2C mRNA expression in P/FC, which became significant after 3 weeks of treatment with both antidepressants and persisted after a fourth week of drug withdrawal (–46% with fluoxetine, –41% with reboxetine, p < 0.05). In HC, however, reboxetine induced significant down-regulation (–56%, p < 0.05) of 5-HTR2C mRNA after 3 weeks, while fluoxetine induced threefold up-regulation (p < 0.01) by the 2nd and 3rd week, returning to the base level after drug withdrawal of both antidepressants. Moreover, the frequency of 5-HTR2C-edited isoforms showed no significant alterations, although analysis of the RNA-editing level at the single editing sites showed small decreases in the C’ and D sites induced by reboxetine in P/FC. Conclusion: Our results suggest that chronic administration of antidepressants in rats slightly modifies the editing levels of 5-HT2C receptor but has considerable influence on its mRNA expression patterns in a way that is area- and time-specific.

OBJECTIVE: We surveyed the datasheets of 29 laboratories concerning prenatal diagnosis of de novo apparently balanced chromosome rearrangements to assess the involvement of specific chromosomes, the breakpoints distribution and the impact on the pregnancy outcome. METHOD: By means of a questionnaire, data on 269.371 analyses performed from 1983 to 2006 on amniotic fluid, chorionic villus and fetal blood samples were collected. RESULTS: A total of 246 balanced anomalies were detected at frequencies of 72% for reciprocal translocations, 18% for Robertsonian translocations, 7% for inversions and 3% for complex chromosome rearrangements. The total frequencies of balanced rearrangements were 0.09%, 0.08% and 0.05% on amniotic fluid, chorionic villus and fetal blood samples. CONCLUSION: A preferential involvement of chromosomes 22, 7, 21, 3, 9 and 11 and a less involvement of chromosomes X, 19, 12, 6 and 1 was observed. A nonrandom distribution of the breakpoints across chromosomes was noticed. Association in the location of recurrent breakpoints and fragile sites was observed for chromosomes 11, 7, 10 and 22, while it was not recorded for chromosome 3. The rate of pregnancy termination was about 20%, with frequencies decreasing from complex chromosomal rearrangements (33%), reciprocal translocations (24%) to inversions (11%) and Robertsonian translocations (3%).

CaM kinase II, a regulator of synaptic plasticity, is implicated in pathophysiology and pharmacology of psychiatric disorders. Chronic treatment with antidepressants desipramine and reboxetine up-regulated CaM kinase II in neuronal cell bodies of hippocampus. mRNA/protein expression for αCaM kinase II was unchanged, whereas Thr 286 phosphorylation was increased in pyramidal/granular cell bodies, suggesting that increased phosphorylation is responsible for kinase activation. Short-term treatment of neuronal cultures with reboxetine reduced kinase activation in a concentration-dependent manner. The short-term inhibitory effect of reboxetine suggests that kinase up-regulation during antidepressant drug treatment is an adaptive response compensating for initial functional down-regulation.