Psychopharmacological treatment in borderline personality disorder: A pilot observational study in a real-world setting.

Psychotherapy is the cornerstone of treatment for borderline personality disorder (BPD) while pharmacotherapy should be considered only as an adjunctive intervention. In clinical practice, however, most of BPD patients only receive medication. The aim of the study is to first describe pharmacological treatment in BPD patients in Italy and secondly to evaluate if comorbidity or illness severity are associated with the prescription of different class compounds. Data on pharmacological treatment and clinical evaluation of 75 BPD patients were collected in 5 clinical settings. The association between comorbidity and medication was assessed. Moreover, we evaluated the association between pharmacotherapy and severity, defined by a cluster analysis aimed at detecting different groups of patients. Most of the participants (82.7%) were characterized by polypharmacy, with a mean of 2.4 medications per person. Interestingly, the prescription didn't seem to depend on/be based on the severity of the disorder and was only partially determined by the presence of comorbidity. In conclusion, our findings are similar to what described in other clinical studies, supporting the idea that medication management for BPD is only partially coherent with international guidelines. This pilot study confirms the need for more rigorous studies to gain greater understanding of this topic and diminish the gap between guidelines and the real clinical world.

Autistic traits in a sample of adult patients with schizophrenia: prevalence and correlates.

BACKGROUND: Schizophrenia and autism spectrum disorder (ASD) are currently conceptualized as distinct disorders. However, the relationship between these two disorders has been revisited in recent years due to evidence that they share phenotypic and genotypic expressions. This study aimed to identify ASD traits in patients with schizophrenia, and to define their demographic, psychopathological, cognitive and functional correlates. METHOD: Seventy-five schizophrenia patients (20 females, mean age 42 ± 12) were evaluated with the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview-Revised (ADI-R). Participants were also assessed with clinical, neuropsychological, and psychosocial functioning measures. RESULTS: Of the 75 patients, 47 were negative to all the autism scales administered (ADOS-TOT-NEG), 21 patients were positive to the ADOS Language sub-domain (ADOS-L-POS), 21 patients were positive to the ADOS Reciprocal Social Interaction (RSI) sub-domain (ADOS-RSI-POS), 14 patients were positive to the ADOS Total scale (ADOS-TOT-POS), and nine patients were positive to the ADI-R scale (ADI-R-POS). Demographic (duration of illness), psychopathological (negative symptoms and general psychopathology), and cognitive (working memory and processing speed) differences emerged between schizophrenic patients with and without ASD traits, while no differences in psychosocial functioning were detected. Results of this study indicate the existence, in a sample of patients with a diagnosis of schizophrenia, of a distinct group of subjects with ASD features, characterized by specific symptomatological and cognitive profile. CONCLUSIONS: These findings may contribute to better characterize patients with schizophrenia in order to develop new procedures and therapeutic tools in a more personalized perspective.

Adult Autism Subthreshold Spectrum (AdAS Spectrum): Validation of a questionnaire investigating subthreshold autism spectrum.

AIM: Increasing literature has shown the usefulness of a dimensional approach to autism. The present study aimed to determine the psychometric properties of the Adult Autism Subthreshold Spectrum (AdAS Spectrum), a new questionnaire specifically tailored to assess subthreshold forms of autism spectrum disorder (ASD) in adulthood. METHODS: 102 adults endorsing at least one DSM-5 symptom criterion for ASD (ASDc), 143 adults diagnosed with a feeding and eating disorder (FED), and 160 subjects with no mental disorders (CTL), were recruited from 7 Italian University Departments of Psychiatry and administered the following: SCID-5, Autism-Spectrum Quotient (AQ), Ritvo Autism and Asperger Diagnostic Scale 14-item version (RAADS-14), and AdAS Spectrum. RESULTS: The AdAS Spectrum demonstrated excellent internal consistency for the total score (Kuder-Richardson's coefficient=.964) as well as for five out of seven domains (all coefficients>.80) and sound test-retest reliability (ICC=.976). The total and domain AdAS Spectrum scores showed a moderate to strong (>.50) positive correlation with one another and with the AQ and RAADS-14 total scores. ASDc subjects reported significantly higher AdAS Spectrum total scores than both FED (p<.001) and CTL (p<.001), and significantly higher scores on the Childhood/adolescence, Verbal communication, Empathy, Inflexibility and adherence to routine, and Restricted interests and rumination domains (all p<.001) than FED, while on all domains compared to CTL. CTL displayed significantly lower total and domain scores than FED (all p<.001). A significant effect of gender emerged for the Hyper- and hyporeactivity to sensory input domain, with women showing higher scores than men (p=.003). A Diagnosis* Gender interaction was also found for the Verbal communication (p=.019) and Empathy (p=.023) domains. When splitting the ASDc in subjects with one symptom criterion (ASD1) and those with a ASD, and the FED in subjects with no ASD symptom criteria (FED0) and those with one ASD symptom criterion (FED1), a gradient of severity in AdAS Spectrum scores from CTL subjects to ASD patients, across FED0, ASD1, FED1 was shown. CONCLUSIONS: The AdAS Spectrum showed excellent internal consistency and test-retest reliability and strong convergent validity with alternative dimensional measures of ASD. The questionnaire performed differently among the three diagnostic groups and enlightened some significant effects of gender in the expression of autistic traits.

Cognitive remediation in schizophrenia: background, techniques, evidence of efficacy and perspectives.

Impairment of cognitive functions is a core feature of schizophrenia with relevant consequences on patients' psychosocial functioning. Cognitive remediation techniques have been recently developed with the aim to restore or compensate for such impairments and improve the functional outcome of the disease. There is now convincing evidence of the efficacy of many of these techniques, especially when delivered in the context of a comprehensive treatment programme. Whether the application of these techniques in the early phases of the disease could modify the disease course and outcome and how they could affect brain plasticity and the trajectory of brain disease of schizophrenia is still under scrutiny.

Sequential analysis of multistage hepatocarcinogenesis reveals that miR-100 and PLK1 dysregulation is an early event maintained along tumor progression.

MicroRNAs (miRNAs) have an important role in a wide range of physiological and pathological processes, and their dysregulation has been reported to affect the development and progression of cancers, including hepatocellular carcinoma (HCC). However, in the plethora of dysregulated miRNAs, it is largely unknown which of them have a causative role in the hepatocarcinogenic process. In the present study, we first aimed to determine changes in the expression profile of miRNAs in human HCCs and to compare them with liver tumors generated in a rat model of chemically induced HCC. We found that members of the miR-100 family (miR-100, miR-99a) were downregulated in human HCCs; a similar downregulation was also observed in rat HCCs. Their reduction was paralleled by an increased expression of polo like kinase 1 (PLK1), a target of these miRNAs. The introduction of miR-100 in HCC cells impaired their growth ability and their capability to form colonies in soft agar. Next, we aimed at investigating, in the same animal model, if dysregulation of miR-100 and PLK1 is an early or late event along the multistep process of hepatocarcinogenesis. The obtained results showed that miR-100 downregulation (i) is already evident in very early preneoplastic lesions generated 9 weeks after carcinogenic treatment; (ii) is also observed in adenomas and early HCCs; and (iii) is not simply a marker of proliferating hepatocytes. To our knowledge, this is the first work unveiling the role of a miRNA family along HCC progression.

Glutamate receptor RNA editing in health and disease.

RNA editing is a post-transcriptional process with an important role in gene modification. This editing process involves site-selective deamination of adenosine into inosine in the pre-mRNA, leading to the alteration of translation codons and splicing sites in nuclear transcripts, thereby enabling functionally distinct proteins to arise from a single gene. One important instance is the neuron editing of the ionotropic glutamate receptors (iGluRs). GluRs play a key role in excitatory synaptic transmission and plasticity in the central nervous system (CNS); their channel properties are largely dictated by the subunit composition of the tetrameric receptors. AMPA/kainate channels are assembled from GluA1-4 AMPA or GluK1-5 kainate receptor subunits. In particular, three of the four AMPA and two of the five kainate receptor subunits are subject to RNA editing. The editing positions have been named on the basis of the amino acid substitutions, such as the Q/R site in AMPA GluA2; the Q/R site in GluK1 and GluK2; the R/G site in GluA2, GluA3, and GluA4; and the I/V and Y/C sites in GluK2. These amino acid changes lead to profound alterations of the channel properties. This paper reviews the most relevant data showing the importance of glutamate receptor RNA editing in finely tuning glutamatergic neurotransmission in the normal CNS and following alterations of the editing process in association with disease phenotypes. Overall, these data indicate that a highly regulated process of glutamate receptor editing is of key importance in the proper function of neuronal cells and in their ability to adapt and modulate synaptic function.

Psychopathologic, neuropsychological and functional outcome measures during cognitive rehabilitation in schizophrenia: a prospective controlled study in a real-world setting.

BACKGROUND: Cognitive dysfunction has been demonstrated in patients with schizophrenia, and this may affect patients' functional outcome. The improvement of such dysfunction by means of cognitive remediation interventions has become a relevant target in the care of schizophrenia. OBJECTIVE: To assess the effectiveness of the cognitive subprograms of Integrated Psychological Therapy (IPT) on symptomatological, neuropsychological and functional outcome variables and to analyze the relationships between cognitive and functional outcome changes in schizophrenia. METHODS: Thirty-two patients with schizophrenia were assigned to cognitive remediation (IPT-cog) or usual rehabilitative interventions in a naturalistic setting of care. Clinical, neuropsychological and functional outcome variables were assessed at baseline and after 24 weeks of treatment. RESULTS: The IPT-cog group improved significantly more than the comparison group with respect to psychopathological and functional outcome variables. Moreover, only the IPT-cog group improved significantly in the neuropsychological domains of verbal and working memory, with specific significant correlations between neurocognitive performance and functional outcome changes. CONCLUSIONS: The results of the study confirm the effectiveness of the cognitive remediation component of IPT in schizophrenia, and indicate that some of the changes in functional outcome may be mediated by improvement in specific cognitive domains.

Chromosome abnormalities and Yq microdeletions in infertile italian couples referred for assisted reproductive technique.

This study analyses the prevalence of karyotype aberrations and Yq microdeletions in infertile couples undergoing intracytoplasmic sperm injection (ICSI). Before undergoing ICSI, each partner of 470 infertile couples was screened for karyotype aberrations by QFQ-banding technique on peripheral blood lymphocytes; male partners were also screened for Yq microdeletions. In 2.55% of the couples karyotype aberrations were found including numerical and structural alterations of autosomes and sex chromosomes. The female group had a high prevalence of low-level sex chromosome mosaicism (1.28%) and 5 cases of structural autosomal abnormalities (1.06%). The male group had 7 structural abnormalities of the autosomes (1.49%), 2 supernumerary marker chromosomes (0.42%), one case of low level gonosomal mosaicism (0.21%), and 2 cases of Y chromosome inversion (0.42%). Eight cases of Yq microdeletions (1.70%) were also found. Screening for genetic factors, chromosomal abnormalities and Yq microdeletions is indicated for couples undergoing assisted reproductive techniques due to the higher prevalence of these factors in infertile couples compared to the population as a whole although different chromosome aberrations have been reported elsewhere.

RNA interference against urokinase in hepatocellular carcinoma xenografts in nude mice.

The serine protease urokinase-type plasminogen activator (u-PA) is overexpressed in hepatocellular carcinoma (HCC) and its expression level is inversely correlated with the patients' survival. The purpose of this study was to examine the effects of vector-based RNA interference (RNAi) of u-PA on the growth of human HCC xenografts in nude mice in order to investigate the role of u-PA in human HCC. Our results showed that the subcutaneous injection of small interfering RNAs (siRNA) u-PA SKHep1C3 stable transfected cells (pS siRNA u-PA) led to a growth delay in xenograft development, compared to those generated from empty vector; the molecular characterization of nodules (carried out by PCR, RT-PCR and immunohistochemical analysis) revealed the presence of plasmid DNA, the u-PA gene expression knockdown, at both mRNA and protein levels, giving evidence of a long-term and target-specific inhibition by vector-based RNAi 11 weeks after cell inoculation. We further studied the effects of u-PA down modulation on extracellular matrix (ECM) proteins evaluating the expression and organization of fibronectin (FN; one of the main ECM proteins). Immunohistochemical and immunofluorescence analysis of FN revealed FN fibrils in pS siRNA u-PA xenografts and in pS siRNA u-PA cells, thus identifying the FN fibril organization as a downstream effect of u-PA knockdown in this system.

Dystrophic epidermolysis bullosa pruriginosa in Italy: clinical and molecular characterization.

Dystrophic epidermolysis bullosa (DEB) pruriginosa (DEB-Pr) is a rare variant of DEB due to COL7A1 dominant and recessive mutations, which is characterized by severe itching and lichenoid or nodular prurigo-like lesions, mainly involving the extremities. Less than 30 patients have been described showing variable disease expression, and frequently, delayed age of onset. We report the clinical and molecular characterization of seven Italian DEB patients, three affected with recessive DEB-Pr and four with dominant DEB-Pr. In all the patients, the signs were typical of a mild DEB phenotype, until the onset of pruritus, which was followed by worsening of the clinical picture, with appearance of the distinctive lichenified lesions of DEB-Pr. Nine mutations were found in the COL7A1 gene, three of which were novel and one was de novo. DEB-Pr patients with either dominant or recessive mutations were shown to synthesize a normal or variably reduced amount of type VII collagen, which was correctly deposited at the dermal-epidermal junction. Since six of these mutations have been reported in DEB patients in the absence of intense pruritus, these data implicate a role of yet unidentified phenotype-modifying factors in the pathogenesis of DEB-Pr.

RNA editing: a molecular mechanism for the fine modulation of neuronal transmission.

The term "RNA editing" is used to identify any mechanism responsible for producing mRNA molecules with sequence information not specifically encoded in the DNA. RNA editing is therefore an important event in gene modification, which takes place at a post-transcriptional level. The molecular mechanism of RNA editing involves site-selective deamination of adenosine to inosine in pre-mRNA, which leads to altering translation codons and splicing in nuclear transcripts, whereby functionally distinct proteins can be produced from a single gene. The mammalian editing enzymes ADARs (adenosine deaminases acting on RNA) are widely expressed in brain and other tissues: however, up until now their substrates have mainly been found in the Central Nervous System (CNS). Of particular relevance in the CNS is the editing occurring at the ionotropic glutamate receptors (GluRs) level. Three AMPA and two Kainate receptors are subject to RNA editing. The consequence of this process is the substitution of specific amino acids in functionally critical positions of the receptors. Depending on the GluR involved, the consequences of editing will involve: activation and/or inhibition of splicing sites; modulation of the trafficking of the receptor to the plasma membrane; the process of tetramerization of the receptor subunits; modification of the ions passage through the receptor channel; modulation of the desensitization and action potential recovery times. All these events are specific to the different GluRs and are genetically and developmentally controlled. RNA editing is therefore a crucial event involved in controlling transmission of the action potential at the postsynaptic level. This modulation involves the transmission of all sensory stimuli to the CNS and gives rise to the "Sensotype". The Sensotype therefore defines the "way" in which the information acquired from the environment by the sensory systems is transmitted to the brain. The signals and inputs deriving from the Sensotype are transmitted to the brain, which processes and stores these signals thus generating the "Brainotype". Brainotype and Sensotype are genetically and environmentally determined; they are individually unique and specific to every living organism with a nervous system. Their characteristics are, at least in part, dependent on the modulation of the "RNA editing" process since glutamate receptors represent the main neurotransmitter system in the CNS.

Association of partial AZFc region deletions with spermatogenic impairment and male infertility.

BACKGROUND: Complete deletions of the AZFc region in distal Yq are the most frequent molecular genetic cause of severe male infertility. They are caused by intrachromosomal homologous recombination between amplicons--large, nearly identical repeats--and are found in 5-10% of cases of azoospermia and severe oligozoospermia. Homologous recombination may also generate different partial deletions of AZFc, but their contribution to spermatogenic impairment has not been confirmed. METHODS: In this study we analysed the prevalence and characteristics of different partial AZFc deletions and their association with spermatogenic failure. We studied 337 infertile men with different spermatogenic impairment and 263 normozoospermic fertile men using AZFc specific sequence tagged site markers and DAZ specific single nucleotide variants. RESULTS: We identified 18 cases of partial AZFc deletions in the infertile group (5.3%) and one case in the control group (0.4%). Seventeen deletions had the "gr/gr" pattern, one the "b2/b3" pattern, and one represented a novel deletion with breakpoints in b3 and b4 amplicons. Partial AZFc deletions were associated with different spermatogenic phenotypes ranging from complete azoospermia to only moderate oligozoospermia. CONCLUSIONS: Together with published data, our analysis of DAZ gene copy suggested that the contribution of the different deletions to male infertility varies: only partial AZFc deletions removing DAZ1/DAZ2 seem to be associated with spermatogenic impairment, whereas those removing DAZ3/DAZ4 may have no or little effect on fertility. These data show that, beside complete AZFc deletions, specific partial deletions represent a risk factor for male infertility, even if with different effect on spermatogenesis.

Overexpression of wild-type and mutant mucolipin proteins in mammalian cells: effects on the late endocytic compartment organization.

Mucolipin-1 is a 65-kDa membrane protein encoded by the MCOLN1 gene, which is mutated in patients with mucolipidosis type IV (MLIV), a rare neurodegenerative lysosomal storage disorder. We studied the subcellular localization of wild-type and three different mutant forms (T232P, F408del and F465L) of mucolipin by expressing Myc-tagged proteins in HeLa cells. The overexpressed wild-type mucolipin colocalizes to late endocytic structures and induces an aberrant distribution of these compartments. F408del and F465L MLIV mutant proteins show a distribution similar to the wild-type protein, whereas T232P is retained in the endoplasmic reticulum. Among the mutants, only F408del induces a redistribution of the late endocytic compartment. These findings suggest that the overexpression of the mucolipin cation channel influences the dynamic equilibrium of late endocytic compartments.

Molecular and cytogenetic characterization of extra-structurally abnormal chromosomes (ESACs) found prenatally: outcome and follow-up.

A 40-year-old woman underwent amniocentesis at 15.3 weeks of gestation. Chromosome analysis performed using QFQ, DA-DAPI and CBG banding revealed two de novo extra-chromosomal markers (ESACs) in 11 of the 16 colonies analysed. Fluorescence in situ hybridization (FISH) showed that both chromosomes came from the Yq11.22.1 region of the Y chromosome. PCR analysis of genes and STS localized on the Y chromosome excluded the Yp presence specifically of the SRY gene, and most of the euchromatic region of Yq. After extensive genetic counselling and considering both laboratory and second-level ultrasound data, the couple decided to continue the pregnancy. At 37.4 weeks of gestational age, a girl weighing 2750 g was born with an Apgar score of 9/10. A blood sample taken from the umbilical cord showed three cellular lines: mos47,XX, +mar1 ish.der (Y)(wcpY+) [21%]/48,XX, +mar1 ish.der (Y)(wcpY+), +mar2 ish.der (Y)(wcpY+) [41%]/46,XX [38%]. One year after birth, the baby was developing normally and had normal psychomotorial activity.

Homozygosity mapping of a gene for arterial tortuosity syndrome to chromosome 20q13.

BACKGROUND: Arterial tortuosity syndrome (ATS) is an uncommon connective tissue disorder of unknown aetiology. The most prominent feature is tortuosity of the large arteries, but lengthening, stenosis, and aneurysm formation are also frequent. METHODS: We performed a genomewide screen by homozygosity mapping of three consanguineous multiplex families, two from Morocco, and one from Italy, which included 11 ATS patients. The two families from Morocco may possibly have a common ancestor. RESULTS: We mapped the ATS gene to chromosome 20q13. Recombinations within an extended haplotype of 11 microsatellite markers localised the ATS gene between markers D20S836 and D20S109, an interval of 9.5 cM. CONCLUSIONS: Cloning and completing functional and structural analysis of the ATS gene may provide new insights into the molecular mechanisms of elastogenesis.