PreImplantation Factor in endometriosis: A potential role in inducing immune privilege for ectopic endometrium.

Endometriosis is a chronic inflammatory condition characterised by the growth of endometrial epithelial and stromal cells outside the uterine cavity. In addition to Sampson's theory of retrograde menstruation, endometriosis pathogenesis is facilitated by a privileged inflammatory microenvironment, with T regulatory FoxP3+ expressing T cells (Tregs) being a significant factor. PreImplantation Factor (PIF) is a peptide essential for pregnancy recognition and development. An immune modulatory function of the synthetic PIF analog (sPIF) has been successfully confirmed in multiple animal models. We report that PIF is expressed in the epithelial ectopic cells in close proximity to FoxP3+ stromal cells. We provide evidence that PIF interacts with FoxP3+ cells and modulates cell viability, dependent on cell source and presence of inflammatory mediators. Our finding represent a novel PIF-based mechanism in endometriosis that has potential for novel therapeutics.

Genetic characterization of p27(kip1) and stathmin in controlling cell proliferation in vivo.

The CDK inhibitor p27(kip1) is a critical regulator of cell cycle progression, but the mechanisms by which p27(kip1) controls cell proliferation in vivo are still not fully elucidated. We recently demonstrated that the microtubule destabilizing protein stathmin is a relevant p27(kip1) binding partner. To get more insights into the in vivo significance of this interaction, we generated p27(kip1) and stathmin double knock-out (DKO) mice. Interestingly, thorough characterization of DKO mice demonstrated that most of the phenotypes of p27(kip1) null mice linked to the hyper-proliferative behavior, such as the increased body and organ weight, the outgrowth of the retina basal layer and the development of pituitary adenomas, were reverted by co-ablation of stathmin. In vivo analyses showed a reduced proliferation rate in DKO compared to p27(kip1) null mice, linked, at molecular level, to decreased kinase activity of CDK4/6, rather than of CDK1 and CDK2. Gene expression profiling of mouse thymuses confirmed the phenotypes observed in vivo, showing that DKO clustered with WT more than with p27 knock-out tissue. Taken together, our results demonstrate that stathmin cooperates with p27(kip1) to control the early phase of G1 to S phase transition and that this function may be of particular relevance in the context of tumor progression.

Premorbid circadian profile of patients with major depression and panic disorder.

AIMS: This study aims to compare some behavioural characteristics related to circadian functions in healthy subjects, in patients with major depressive disorder (MDD) and panic disorder (PD) during adulthood (disease period) and during the premorbid age (between 12 and 20 years old). METHODS: 132 adult patients with MDD, 144 with PD and 151 adult healthy controls were enrolled in the study. All subjects completed a retrospective questionnaire. RESULTS: Several behaviours (such as falling asleep, awakening, having, appetite, perceiving energy and cognitive functioning) showed a phase delay or a phase advance in MDD and PD patients compared to healthy controls. Behavioural differences where found in patients even before the clinical onset of the disease. CONCLUSIONS: Circadian profiles of MDD and PD patients diverge from those of healthy controls not only during the disorder but also in the ages preceding its clinical onset. The analysis of these circadian patterns may aid physicians to early identify subjects with specific psychiatric vulnerabilities.

Cluster analysis of immunophenotypic data: the example of chronic lymphocytic leukemia.

Studies of gene expression profiling have been successfully used for the identification of molecules to be employed as potential prognosticators. In analogy with gene expression profiling, we have previously proposed an original method to identify the immunophenotypic signature of chronic lymphocytic leukemia (CLL) subsets with different prognosis, named surface-antigen expression profiling. According to this method, expression data for surface markers can be successfully analyzed by data mining tools identical to those employed in gene expression profiling studies, including unsupervised and supervised algorithms, with the aim to identify the immunophenotypic signature of CLL subsets with different prognosis. By employing an identical approach for investigating the reactivity of a wide panel of monoclonal antibodies provided by the "Ninth International Workshop on Leukocyte Differentiation Antigens", we were able to identify some of them (i.e. TCL1, CCR7, FCRL2, FCRL3, and CD150) as additional potential markers with prognostic relevance in CLL. These suggestions need to be confirmed: (i) in a new set of clinically characterized CLL cases; (ii) in combination with other prognostic markers in the context of comprehensive scoring systems for clinical outcome prediction.

Immediate serum growth hormone decrease as a potential index of dopamine-related response to electroconvulsive therapy in schizophrenic patients.

OBJECTIVES: : The objective of this study was to investigate the immediate response of the dopamine-regulated growth hormone (GH) to electroconvulsive therapy (ECT) in schizophrenic patients and the changes in the serum GH levels throughout the consecutive sessions of the therapeutic ECT course. METHODS: : Serum GH levels were measured in a sample of 11 men with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, who were administered a course of 8 bilateral ECT treatments. Measurements were performed 5 minutes before ECT, during ECT, 15 minutes after an ECT session, and 30 minutes after an ECT session during the first, fourth, and eighth ECT sessions. RESULTS: : At both the fourth and the eighth ECT sessions, a significant decrease in GH levels 15 and 30 minutes after ECT was observed compared with the baseline values. No change in baseline serum GH levels was observed either during or at the end of the treatment. Clinical improvement was indicated by a significant reduction in the total score, negative subscale score, and positive subscale score of the Positive and Negative Syndrome Scale. CONCLUSIONS: : The results are consistent with the potential role of immediate serum GH changes as an index of potential dopamine-mediated response to ECT. It can be assumed that GH reduction may be partially related to an antidopaminergic action of ECT, but further research is still needed to better evaluate the correlation of the dopamine system instability during the course of the illness with the previously mentioned immediate treatment response. Also, the role of other neurotransmitters in the regulation of GH production and ECT response must be taken into account for the purpose of an overall evaluation of the results and of their potential clinical implications.

Expression of mutated IGHV3-23 genes in chronic lymphocytic leukemia identifies a disease subset with peculiar clinical and biological features.

PURPOSE: B-cell chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease whose outcome can be foreseen by investigating the mutational status of immunoglobulin heavy chain variable (IGHV) genes. Moreover, a different prognosis was reported for CLL expressing specific IGHV genes in the context or not of stereotyped B-cell receptors. Here we investigated novel associations between usage of specific IGHV genes and clinical features in CLL. EXPERIMENTAL DESIGN: Among 1,426 CLL-specific IG-rearrangements, stereotyped B-cell receptor clusters never utilized the IGHV3-23 gene. Given this notion, this study was aimed at characterizing the IGHV3-23 gene in CLL, and identifying the properties of IGHV3-23-expressing CLL. RESULTS: IGHV3-23 was the second most frequently used (134 of 1,426) and usually mutated (M; 109 of 134) IGHV gene in our CLL series. In the vast majority of M IGHV3-23 sequences, the configuration of the 13 amino acids involved in superantigen recognition was consistent with superantigen binding. Clinically, M IGHV3-23 CLL had shorter time-to-treatment than other M non-IGHV3-23 CLL, and multivariate analyses selected IGHV3-23 gene usage, Rai staging, and chromosomal abnormalities as independent prognosticators for M CLL. Compared with M non-IGHV3-23 CLL, the gene expression profile of M IGHV3-23 CLL was deprived in genes, including the growth/tumor suppressor genes PDCD4, TIA1, and RASSF5, whose downregulation is under control of miR-15a and miR-16-1. Accordingly, relatively higher levels of miR-15a and miR-16-1 were found in M IGHV3-23 compared with M non-IGHV3-23 CLL. CONCLUSIONS: Altogether, expression of the IGHV3-23 gene characterizes a CLL subset with distinct clinical and biological features.

New tool (Laparotenser) for gasless laparoscopic myomectomy: a multicenter-controlled study.

OBJECTIVE: To assess feasibility and safety of a new surgical instrument-Laparotenser-in the procedure of gasless laparoscopic myomectomy. DESIGN: Multicenter controlled study. SETTING: Academic departments of obstetrics and gynecology, Italy. PATIENT(S): Thirty patients scheduled for gasless laparoscopic myomectomy (experimental group) and another group of 30 patients from our historical records that have undergone traditional laparoscopic myomectomy, matched with the cases for number of fibroids and for size of the main fibroid (control group). INTERVENTION(S): Gasless laparoscopic myomectomy using Laparotenser. MAIN OUTCOME MEASURE(S): Surgical data. RESULT(S): No significant differences in total operative time, postoperative ileus, hospitalization, time to return to full activity/work, and complication rates were observed between groups. Intraoperative blood loss, hemoglobin level, and surgical difficulty were significantly higher in the experimental than in the control group. Postoperative pain and number of analgesic vials used were significantly lower in the experimental group than in the control group. CONCLUSION(S): Although performed during the learning curve period, the use of the Laparotenser instrument in gasless laparoscopic myomectomy is a safe procedure.

CD38/CD31, the CCL3 and CCL4 chemokines, and CD49d/vascular cell adhesion molecule-1 are interchained by sequential events sustaining chronic lymphocytic leukemia cell survival.

CD38 and CD49d are associated negative prognosticators in chronic lymphocytic leukemia (CLL). Despite evidence that both molecules are involved in interactions occurring between CLL and normal cells in the context of CLL-involved tissues, a functional link is still missing. Using gene expression profiles comparing CD38(+)CD49d(+) versus CD38(-)CD49d(-) CLL cells, we showed overexpression of the CCL3 and CCL4 chemokines in cells from the former group. These chemokines were also up-regulated by CD38 signals in CLL; moreover, CCL3 was expressed by CLL cells from bone marrow biopsies (BMB) of CD38(+)CD49d(+) but not CD38(-)CD49d(-) cases. High levels of CCR1 and, to a lesser extent, CCR5, the receptors for CCL3 and CCL4, were found in CLL-derived monocyte-macrophages. Consistently, CCL3 increased monocyte migration, and CD68(+) macrophage infiltration was particularly high in BMB from CD38(+)CD49d(+) CLL. Conditioned media from CCL3-stimulated macrophages induced endothelial cells to express vascular cell adhesion molecule-1 (VCAM-1), the CD49d ligand, likely through tumor necrosis factor alpha overproduction. These effects were apparent in BMB from CD38(+)CD49d(+) CLL, where lymphoid infiltrates were characterized by a prominent meshwork of VCAM-1(+) stromal/endothelial cells. Lastly, CD49d engagement by VCAM-1 transfectants increased viability of CD38(+)CD49d(+) CLL cells. Altogether, CD38 and CD49d can be thought of as parts of a consecutive chain of events ultimately leading to improved survival of CLL cells.

[PANDAS: a possible model for adult OCD pathogenesis]. / Il PANDAS come possibile modello interpretativo del meccanismo patogenetico del DOC nell'adulto.

Obsessive-compulsive disorder is a disabling disorder. Genetic predisposing factors may have an important role in the onset of the symptoms, but is not been individualized any specific gene yet. In the last years it has been demonstrated that obsessive-compulsive disease and/or tic syndromes may be triggered by an antecedent infection especially with group A beta-hemolytic streptococci. On the basis of recent studies has been postulated that in genetically predisposed individuals, certain streptococcal antigens trigger antibodies which, through a process of molecular mimicry, cross-react with epitopes on the basal ganglia. According to such hypothesis, the acronym PANDAS has been used to describe a subset of children with abrupt onset or exacerbations of OCD or tics, or both, following streptococcal infections. Neuroimaging studies reveal increased basal ganglia volumes, and the proposed cause involves the cross-reaction of streptococcal antibodies with basal ganglia tissue. The hypothesis of a possible involvement of the immunitary system seems justified from quantitative alterations of TNF-alpha, IL-6 and IL-1 in the patients' serum with such syndrome. Echotomographic studies on cardiac valves have not yet demonstrated the parallels between PANDAS and Sydenham's chorea. The use of treatment strategies, such as therapeutic plasmapheresis or intravenous immunoglobulin, has been proposed to explain the autoimmune process responsible for the pathogenesis of PANDAS. Further research is still necessary in order to understand the role of streptococcal infection in the pathogenesis of PANDAS.

Genome-wide DNA analysis identifies recurrent imbalances predicting outcome in chronic lymphocytic leukaemia with 17p deletion.

Deletion of 17p (TP53) identifies a rare subset of chronic lymphocytic leukaemia (17p- CLL) with aggressive behaviour. Genome-wide DNA-profiling was performed to investigate 18 patients with 17p- CLL. All cases had multiple copy-number (CN) changes. Among the several recurrent CN changes identified, 8q24.13-q24.1-gain (MYC), 8p-loss (TNFRSF10A/B, also known as TRAIL1/2) and 2p16.1-p14-gain (REL/BCL11A) appeared frequently represented. 8p-loss and 2p16.1-p14-gain also appeared clinically relevant and predicted significant shorter time from diagnosis to treatment (8p-loss) and overall survival (8p-loss and 2p16.1-p14-gain, P < 0.05). These observations document a highly unstable genome in 17p- CLL and suggest that additional genes outside the TP53 locus may be important for tumour behaviour.

Pilot study of light therapy and neurocognitive performance of attention and memory in healthy subjects.

The aim of this pilot study was to investigate whether light therapy improves healthy subjects' neurocognitive performance of attention, memory, and language. Ten subjects were treated with white bright light for 5 days and a control group of 10 with no treatment were assessed with a battery of neurocognitive tests which included the Stroop Colour Word Interference Test, the Verbal Fluency Test, the Story Recall Test, and the Word Pairs Recall Test. Analysis showed improvements in cognitive scores in both groups, although on all the cognitive tests the mean difference scores between baseline and endpoint were significantly larger in the light-treated group. These preliminary results suggest that short-term bright light may exert beneficial effects on cognitive functions.

Laparoscopic-assisted vaginal hysterectomy versus minilaparotomy hysterectomy: a prospective, randomized, multicenter study.

STUDY OBJECTIVE: The aim of this study was to compare operative and early postoperative outcomes of laparoscopic-assisted vaginal hysterectomy (LAVH) and minilaparotomy in a randomized clinical trial including patients undergoing total hysterectomy for benign gynecologic disease and having 1 or more of the generally considered contraindications to vaginal route. DESIGN: Prospective, randomized, multicenter trial (Canadian Task Force classification I). SETTING: Departments of Gynecology from 3 major university hospitals in Rome. PATIENTS: Eighty-one patients who were candidates for abdominal hysterectomy. INTERVENTIONS: Laparoscopic-assisted vaginal hysterectomy and minilaparotomy hysterectomy. MEASUREMENTS AND MAIN RESULTS: Forty patients were randomized to LAVH and 41 to minilaparotomy. Characteristics of patients and indications for surgery in the 2 arms were comparable. In the minilaparotomy group, complications were as follows: 1 case (2.4%) of delayed laparotomy with 2 units of red blood cell transfusion, 2 cases (4.8%) of wound infection, and 3 cases (7.3%) of fever of unknown origin. No minor or major complications were observed in the LAVH group. Postoperative visual analog scale pain scores at days 1 and 2 were significantly lower in the LAVH group (p <.05). The complication rate between the 2 groups was significantly lower for LAVH (p = .026). CONCLUSION: Because LAVH was associated with significantly lower early postoperative pain scores and complication rates, in general LAVH should be preferred to minilaparotomy hysterectomy when the vaginal approach cannot be used.

A multicenter randomized, controlled study comparing laparoscopic versus minilaparotomic myomectomy: reproductive outcomes.

OBJECTIVE: To assess the reproductive outcomes after minilaparotomic and laparoscopic myomectomy in patients wishing to conceive. DESIGN: Randomized controlled trial. SETTING: Departments of obstetrics and gynecology of the universities of Catanzaro, Rome, and Florence, Italy. PATIENT(S): One hundred thirty-six women with symptomatic uterine leiomyomas or unexplained infertility. INTERVENTION(S): Laparoscopic and minilaparotomic myomectomy. MAIN OUTCOME MEASURE(S): Pregnancy, abortion, and live-birth rates. RESULT(S): Between the laparoscopic and minilaparotomic groups no difference was observed in cumulative pregnancy, live-birth, and abortion rates, whereas pregnancy and live-birth rates per cycle, and time to first pregnancy and live-birth were significantly higher in the laparoscopic than in the minilaparotomic group. Categorizing the patients according to surgical indication for myomectomy, cumulative pregnancy rate, pregnancy, and live-birth rates per cycle, and time to first pregnancy and live-birth were significantly better after laparoscopic myomectomy in symptomatic patients, whereas all reproductive outcomes were similar between the two groups in patients with unexplained infertility. CONCLUSION(S): Minilaparotomic and laparoscopic myomectomy improves in a similar manner the reproductive outcomes in patients with unexplained infertility, whereas the laparoscopic approach provides the best benefits in fertile patients with symptomatic leiomyomas.

A multicenter randomized, controlled study comparing laparoscopic versus minilaparotomic myomectomy: short-term outcomes.

OBJECTIVE: To compare the laparoscopic and minilaparotomic approaches for symptomatic uterine leiomyomas treatment in terms of safety and feasibility. DESIGN: Randomized controlled trial. SETTING: Three university departments of obstetrics and gynecology of Catanzaro, Rome, and Florence, Italy. PATIENT(S): One hundred thirty-six women wishing to conceive and candidate for myomectomy due to symptomatic uterine leiomyomas or unexplained infertility. INTERVENTION(S): Myomectomy through laparoscopic or minilaparotomic access. MAIN OUTCOME MEASURE(S): Surgical outcomes. RESULT(S): Leiomyoma enucleation and hysterotomy suturing times were significantly shorter after minilaparotomic myomectomy, whereas the degree of surgical difficulty was significantly higher for the laparoscopic myomectomy. Intraoperative blood loss, variation in hemoglobin levels, quantity of pain control drugs used postoperatively, and hospitalization were significantly lower in the laparoscopic group than in the minilaparotomic one. Our surgical outcomes were significantly influenced by specific investigational centers involved, and by leiomyoma dimensions and localizations. This last variable is the strongest predictor of surgical outcome. CONCLUSION(S): Laparoscopic and minilaparotomic approaches to myomectomy are two safe and minimally invasive surgical procedures. A careful evaluation of the dimensions and localizations of fibroids are needed to address to the right choice to the best approach.

Mood disorder in a patient with Smith-Magenis syndrome: a case report.

Smith-Magenis syndrome (SMS) is a microdeletion syndrome characterized by physical and neurobehavioural features. This report describes the case of a 27 year old female affected by SMS associated with a diagnosis, according to DSMIV criteria, of Mood Disorder N.O.S. and Intermittent Explosive Disorder. To our knowledge, the association of SMS with mood shifts has never been reported. Considering the genetic alterations that characterizes the SMS, further investigations on the region of the chromosome 17p11.2 could help produce more information on the role of melatonin in the genesis of mood disorder.

Comprehensive characterization of IGHV3-21-expressing B-cell chronic lymphocytic leukemia: an Italian multicenter study.

IGHV3-21-using chronic lymphocytic leukemia (CLL) is a distinct entity with restricted immunoglobulin gene features and poor prognosis and is more frequently encountered in Northern than Southern Europe. To further investigate this subset and its geographic distribution in the context of a country (Italy) with both continental and Mediterranean areas, 37 IGHV3-21 CLLs were collected out of 1076 cases enrolled by different institutions from Northern or Central Southern Italy. Of the 37 cases, 18 were identified as homologous (hom)HCDR3-IGHV3-21 CLLs and were found almost exclusively (16 of 18) in Northern Italy; in contrast, 19 nonhomHCDR3-IGHV3-21 cases were evenly distributed throughout Italy. Clinically, poor survivals were documented for IGHV3-21 CLLs as well as for subgroups of mutated and homHCDR3-IGHV3-21 CLLs. Negative prognosticators CD38, ZAP-70, CD49d, and CD79b were expressed at higher levels in homHCDR3 than nonhomHCDR3-IGHV3-21 cases. Differential gene expression profiling (GEP) of 13 IGHV3-21 versus 52 non-IGHV3-21 CLLs identified, among 122 best-correlated genes, TGFB2 and VIPR1 as down- and up-regulated in IGHV3-21 CLL cases, respectively. Moreover, GEP of 7 homHCDR3 versus 6 nonhomHCDR3-IGHV3-21 CLLs yielded 20 differentially expressed genes, with WNT-16 being that expressed at the highest levels in homHCDR3-IGHV3-21 CLLs. Altogether, IGHV3-21 CLLs, including those with homHCDR3, had a peculiar global phenotype in part explaining their worse clinical outcome.

Myolysis of uterine fibroids: is there a role?

Myolysis is among the new procedures under development for the treatment of symptoms related to uterine leiomyoma. The procedure targets the destruction of fibroids using one of a number of focused energy delivery systems including those based upon radiofrequency electricity, supercooled cryoprobes, and, most recently, focused ultrasound monitored by real time magnetic resonance imaging. For thermomyolysis and cryomyolysis, delivery of the energy requires access to the tissue by laparoscopy, and, in some instances, hysteroscopy. For focused ultrasound, the patient is detached from the energy source, which is delivered by an array of external beams. Clinical evaluation has been confined to case series, but it is evident that the approach results in a variable degree of reduction of the total uterine mass, and, usually, a reduction in uterine bleeding. Clearly, longer term appropriately designed comparative trials are required that evaluate and compare myolysis with myomectomy, uterine artery embolization, and hysterectomy, to name a few.

Presacral neurectomy for surgical management of pelvic pain associated with endometriosis: a descriptive review.

Pelvic pain associated with endometriosis is a common clinical problem. In approximately 20% of cases endometriosis-related pelvic pain is either minimally or not responsive to medical treatment; thus surgical treatment seems to be a valid option. The aim of this review is to describe presacral neurectomy surgical techniques, data regarding safety and efficacy of this procedure, its indications, and future research on its applications in clinical practice.