Association between serum BDNF levels and maternal perinatal depression: A review: Special Section on "Translational and Neuroscience Studies in Affective Disorders" Section Editor, Maria Nobile MD, PhD.

INTRODUCTION: A large amount of studies demonstrated reduced serum Brain-Derived Neurotrophic Factor (BDNF) levels in stress-related and depressive disorders. However, it is still unclear if a similar deficit in BDNF concentrations might also characterize maternal perinatal depression. METHODS: We performed a bibliographic search on PUBMED of all the studies investigating the association between maternal BDNF levels and perinatal depression. The inclusion criteria were met by thirteen studies. RESULTS: Overall, the majority of the studies reported a significant reduction in serum BDNF levels among depressed mothers compared to healthy mothers either during pregnancy or in the postpartum period. Moreover, some studies also demonstrated that the BDNF reduction could be more evident in those depressed mothers with perinatal stressful life events and suicide risk. LIMITATIONS: BDNF were collected at different time points across the studies. Potential confounding factors, including the clinical characteristics of the samples employed by the original studies, might have influenced the results. CONCLUSIONS: So far, the evidences suggested the presence of decreased BDNF concentrations in perinatal depressive disorders. However, further studies are needed in order to confirm the role of BDNF in this disorder.

The impact of BDNF Val66Met polymorphism on cognition in Bipolar Disorder: A review: Special Section on "Translational and Neuroscience Studies in Affective Disorders" Section Editor, Maria Nobile MD, PhD. This Section of JAD focuses on the relevance of translational and neuroscience studies in providing a better understanding of the neural basis of affective disorders. The main aim is to briefly summaries relevant research findings in clinical neuroscience with particular regards to specific innovative topics in mood and anxiety disorders.

BACKGROUND: Converging lines of evidence suggest that Brain-Derived Neurotrophic Factor (BDNF) may play a central role in the pathogenesis of Bipolar Disorder (BD), thus representing a valid biomarker of the disease. A common genetic variation in the BDNF gene, the Val66Met, is associated with reduced maturation and secretion of BDNF and therefore it has been related to specific mood, cognitive and neuroanatomical alterations in BD. However, so far, only a handful of studies have investigated the association between Val66Met polymorphism and cognitive functioning in BD. METHODS: We performed a bibliographic search on PUBMED of all genetic studies investigating Val66Met modulation on cognitive performances in BD subjects. The inclusion criteria were met by nine studies, including a total amount of 897 BD subjects and 803 healthy controls. RESULTS: From the analysis of the existing literature emerged that a) Val allele in BD adults, but not in BD adolescents, was associated with better performances in selective cognitive domains including executive functions, verbal learning and memory; b) Met allele may negatively modulate the association between childhood trauma and performances in memory, verbal ability and verbal fluency tasks; c) Met allele may also negatively regulate structural abnormalities in cognitive cerebral structures; d) Val/Met carriers showed greater improvements in cognitive functions compared to Val/Val and Met/Met carriers. LIMITATIONS: Few genetic studies exploring the impact of Val66Met on cognition in BD. CONCLUSIONS: Val66Met polymorphism likely modulates cognitive functions in BD patients with complex gene-environment interactions and through potential modulations of cerebral structures. Further and larger genetic studies are required in order to detect association between BDNF polymorphism, BDNF levels, brain abnormalities and cognition in BD.

The impact of COMT polymorphisms on cognition in Bipolar Disorder: A review: Special Section on "Translational and Neuroscience Studies in Affective Disorders" Section Editor, Maria Nobile MD, PhD. This Section of JAD focuses on the relevance of translational and neuroscience studies in providing a better understanding of the neural basis of affective disorders. The main aim is to briefly summaries relevant research findings in clinical neuroscience with particular regards to specific innovative topics in mood and anxiety disorders.

BACKGROUND: Cognitive deficits represent a core feature of Bipolar Disorder. The dopamine system is considered fundamental for cognitive functions relying on prefrontal cortex, such as attention and executive functions. A genetic regulation of prefrontal dopamine has been described and the catechol-O-methyltransferase (COMT) has been extensively studied in relation to numerous psychiatric phenotypes, especially because of the involvement of its polymorphisms in the regulation of cognitive functions. Specifically, the Val158Met polymorphism greatly alters COMT function and cognitive performance in both psychiatric disorders and healthy controls. However, only few studies assessed the association between COMT polymorphisms and cognitive functions in bipolar disorder (BD) subjects and this association might help in the comprehension of cognitive alterations in BD. METHODS: In this context, the present review summarizes results from genetic studies that investigated COMT genetic modulation on cognitive performance in patients affected by BD. RESULTS: Overall the results confirmed that (a) COMT Val158Met polymorphism is associated with altered cognitive functions in BD patients, especially in the domains of memory, executive functions and emotion detection; and (b) COMT genotype may interact with both mood episodes and pharmacologic treatments in determining the cognitive profile of these subjects. LIMITATIONS: Few genetic studies exploring COMT genetic effect on cognition in BD. CONCLUSIONS: These findings seem to indicate a role of COMT polymorphisms in regulating cognitive functioning in patients with BD. The genetically determined dopaminergic tone may be further affected by mood episodes and pharmacological treatments.

Pharmacological properties of cannabidiol in the treatment of psychiatric disorders: a critical overview.

Cannabidiol (CBD) represents a new promising drug due to a wide spectrum of pharmacological actions. In order to relate CBD clinical efficacy to its pharmacological mechanisms of action, we performed a bibliographic search on PUBMED about all clinical studies investigating the use of CBD as a treatment of psychiatric symptoms. Findings to date suggest that (a) CBD may exert antipsychotic effects in schizophrenia mainly through facilitation of endocannabinoid signalling and cannabinoid receptor type 1 antagonism; (b) CBD administration may exhibit acute anxiolytic effects in patients with generalised social anxiety disorder through modification of cerebral blood flow in specific brain sites and serotonin 1A receptor agonism; (c) CBD may reduce withdrawal symptoms and cannabis/tobacco dependence through modulation of endocannabinoid, serotoninergic and glutamatergic systems; (d) the preclinical pro-cognitive effects of CBD still lack significant results in psychiatric disorders. In conclusion, current evidences suggest that CBD has the ability to reduce psychotic, anxiety and withdrawal symptoms by means of several hypothesised pharmacological properties. However, further studies should include larger randomised controlled samples and investigate the impact of CBD on biological measures in order to correlate CBD's clinical effects to potential modifications of neurotransmitters signalling and structural and functional cerebral changes.

Intracranial hematopoiesis in a patient with AIDS-related central nervous system lymphoma and severe pancytopenia.

The case here reported reflects the difficulty in diagnosing meningeal extramedullary hematopoiesis (EMH), which clinically appeared concomitantly with primary cerebral lymphoma and occurred in a patient with HIV infection and severe pancytopenia. Pancytopenia secondary to HIV infection could be hypothesized as a predisposing factor for the ectopic development of hematopoietic tissue outside the bone marrow. Although rare, intracranial EMH should always be considered in the differential diagnosis of headache and other endocranial hypertension symptoms in patients with chronic bone marrow dysfunction.

Adult stem cells: perspectives for therapeutic applications.

The use of adult stem cells in tissue regeneration appears to be a powerful research tool, due to the intrinsic characteristics of these cells, i.e., self-renewal and unlimited capacity for proliferation. In particular, mesenchymal stem cells (MSCs) obtained from bone marrow or peripheral blood can be easily isolated, cultivated, propagated and can be differentiated into several specialized cell types thanks to their plasticity. Among these cells, MSCs can evolve into cardiac cell lineages. Since heart damage leads to the irreversible loss of cardiac function, cell transplantation could be a potential therapy for heart injury. Our laboratory has focused on the purification and expansion of rat and sheep MSCs, their differentiation into cardiomyocytes and their characterisation. Numerous results indicate that MSCs could be promising for therapy, however we need to better understand the biology of stem cells to improve methods for delivery and/or pharmacological activation. These techniques can indeed track engrafted cells and systems to guarantee their safe use.

Human myeloma cells express the bone regulating gene Runx2/Cbfa1 and produce osteopontin that is involved in angiogenesis in multiple myeloma patients.

Osteopontin (OPN) is a multifunctional bone matrix glycoprotein that is involved in angiogenesis, cell survival and tumor progression. In this study we show that human myeloma cells directly produce OPN and express its major regulating gene Runx2/Cbfa1. The activity of Runx2/Cbfa1 protein in human myeloma cells has also been demonstrated. Moreover, using small interfering RNA (siRNA) to silent Runx2 in myeloma cells, we suppressed OPN mRNA and protein expression. OPN production in myeloma cells was stimulated by growth factors as IL-6 and IFG-1 and in turn OPN stimulated myeloma cell proliferation. In an 'in vitro' angiogenesis system we showed that OPN production by myeloma cells is critical for the proangiogenic effect of myeloma cells. The expression of OPN by purified bone marrow (BM) CD138(+) cells has also been investigated in 60 newly diagnosed multiple myeloma (MM) patients, finding that 40% of MM patients tested expressed OPN. Higher OPN levels have been detected in the BM plasma of MM patients positive for OPN as compared to controls. Moreover, significantly higher BM angiogenesis has been observed in MM patients positive for OPN as compared to those negative. Our data highlight that human myeloma cells with active Runx2/Cbfa1 protein directly produce OPN that is involved in the pathophysiology of MM-induced angiogenesis.

Monitoring surgical treatment of screen-detected breast lesions in Italy.

The object of this study was to assess quality of care and adherence to treatment guidelines of screen-detected lesions in Italy using a new audit system. Data on screen-detected cases surgically treated in 1997 were collected using a system (QT 2.3) developed within the Italian Group for Planning and Evaluating Mammographic Screening Programmes (GISMa) and the European Breast Cancer Screening Network. Results of 18 performance parameters were considered compared with the reference standards. In 1997, 515 lesions (335 invasive, 60 in situ and 120 benign) in 496 patients were collected from 14 departments in the Central and Northern area of Italy. The 18 indicators were analysed and grouped according to six quality objectives. Some results were good and others were excellent, such as intraoperative identification, breast conservation surgery, adequate axillary procedures and completeness of pathology reports, but most of them failed: waiting times, preoperative diagnosis, employment of frozen section on small lesions and avoiding axillary procedures in ductal carcinoma-in-situ. This work is a first attempt in Italy to evaluate and uniform the criteria adopted for quality control of breast cancer treatment, using a standardised system. Some results are good or excellent, the overall level of compliance with quality indicators is not satisfactory and corrective actions should be undertaken for a number of issues. A continuous monitoring should be performed and appropriate action taken in order to verify the effectiveness of the corrective actions and to provide screen-detected patients with the best quality of care.

[A case of primary non-Hodgkin's lymphoma of the adrenal gland]. / Su di un caso di linfoma non-Hodgkin primitivo del surrene.

The paper reports a case of non-Hodgkin's primary lymphoma of the adrenal gland which is justified by the rarity of this pathology as can be seen from the literature. Following adrenalectomy and subsequent polychemotherapy, a complete remission of the disease was obtained. The Authors report that, in the absence of particular symptoms, diagnosis is generally based on X-ray examinations performed to clarify the causes of aspecific symptoms such as, for example, fever and asthenia. Lastly, it is underlined that the disease may be diagnosed during surgery when CT reveals the presence of an adrenal mass with a diameter of more than 3 centimetres.

On the myoepithelium of human salivary glands. An immunocytochemical study.

This study investigated the immunocytochemical characteristics of normal myoepithelial cells (MECs) of human major and minor salivary glands using the LSAB method. Other human exocrine glands were used as controls. Immunoreactivity of MECs was observed exclusively with fully differentiated smooth muscle antibodies (a-SMA; SMMS-1; CALP; hCD) and with epithelial markers (cytokeratins) Ck14 and Ck17. This epithelial-muscular immunophenotype was similarly expressed in the MECs of other human exocrine glands used as control. In the salivary MECs, we did not observe evidence for neuroectodermic phenotype (S-100 protein, GFAP, NSE). On the contrary, positivity was observed for S-100 protein in Mecs of control glands (mammary, bronchial and sweat glands). Immunoreaction for extracellular matrix markers (fibronectin, laminin and collagen IV) and vimentin always were negative. Our data show that in normal "non transformed" MECs of the salivary glands the smooth muscle phenotype is in a state of complete differentiation, while the epithelial phenotype expresses only Ck14 and Ck17. This double and simultaneous immunoreactivity represents a differential marker of MECs from the epithelial basal cell (EBCs).

[Effect of menstrual cycle on the immune response to surgical stress]. / Effetto del ciclo mestruale sulla risposta immunitaria all'aggressione chirurgica.

The Authors have studied the effects of different surgical interventions on some factors of humoral and cell-mediated immuno-competence: 112 premenopausal women, operated on mainly for benign conditions, have been considered in order to evaluate the influence of various phases of menstrual cycle on surgical immunosuppression. Two schemes were used to stratify the study sample: in the first analysis, we have subdivided the patients in 59 cases in perimenstrual phase (0 through 6 and 21 through 36 days from last menstrual period, LMP) and 53 in periovulatory (7-20 days from LMP). The second stratification relied on the hormone-dependent phases determined by the putative time of ovulation 14 days after LMP: 51 cases in follicular phase and 61 cases in luteal phase have been considered. Immune parameters have been evaluated before surgery and the day after intervention. The first comparison stresses the worst outcome of immune parameters in patients operated on in the perimenstrual period (CD4, activated lymphocytes and C3 have significantly reduced post-operatively). The second part of the study shows no significant difference in the two groups as to such parametres.

[Second look yes, second look no, in the surgical therapy of intestinal infarct]. / "Second look sì", "second look no" nella terapia chirurgica dell'infarto intestinale.

The thorny second-look problem is examined on the basis of personal experience of 65 cases of intestinal infarction over a period of 10 years. The medical literature is particularly lacking in indications on this point and only from careful assessment of reported experience and personal experience itself has it been possible to find indications and limitations. Data are reported which do not pretend to be absolute but do provide a useful aid for those faced with doubtful anatomopathological pictures during operation for acute intestinal ischaemia.

[Reimplantation of the inferior mesenteric artery during surgery of abdominal aortic aneurysm. Current trends]. / Il reimpianto dell'arteria mesenterica inferiore nella chirurgia dell'aneurisma aortico addominale. Moderni orientamenti.

After a review of world literature and on the basis of personal experience, the problem of ischaemic colitis following abdominal aortic aneurysmectomy is examined. After remarks on the aetiopathogenesis and clinical picture of the condition the paper stresses the need for early detection of patients at high risk, to prevent a clinical picture that is insidious but serious and tends to develop rapidly. The use of preoperative angiography to study the SMA and IMA as well as intraoperative stump-pressure measurement is considered essential. The paper concludes that ischaemic colitis following abdominal aortic reconstruction can be avoided in a large percentage of cases by IMA implantation on the Dacron prosthesis, a surgical technique that is easy and not time-consuming.

[A rare case of primary abdominal actinomycosis]. / Un raro caso di actinomicosi addominale primitiva.

The authors describe a case of primary abdominal actinomycosis operated on because of peritonitis sustained by a tubo-ovarian abscess. They discuss the pathogenesis of the case: the patient had been on intrauterine device contraception till two months earlier and had been operated on for breast cancer. Preoperative diagnosis is quite impossible and only the microscopic observation of the specimen can show the causative agent. Surgical options are reported, stressing the need for an adequate period of antimicrobial therapy.

PIP: In September 1993 a 43-year-old female patient with cancer underwent left mastectomy followed by immediate reconstruction. 6 days passed without problems, but then she presented at the emergency ward with abundant exudation of serous material from the cicatrices. Microbiological test showed evidence of Staphylococcus epidermitis. Drainage of the skin and smooth muscle was performed and the secretion was immediately reduced and seemed to disappear in a short time. In the next 3 days fever arose accompanied by abdominal pain. Blood test showed leucocytosis (24,500 GB), increase of the suppressor lymphocytes (CD8) and the reduction of CD4/CD8 ratio. Abdominal-pelvic echogram showed evidence of an enlarged right adnexum as well as that of the homolateral tube, but no discharge of fluid in the pelvic cavity. Gynecological examination in this patient, who had worn an IUD two months prior, excluded lesions in the portio or vagina and the vaginal flora did not show fungi or parasites. Diagnostic laparoscopy followed, which demonstrated in the pelvic cavity a large para-uterine tumefaction. The pelvic organs were adhering to the parietal layer of the peritoneum and in the whole peritoneal cavity, including the interhepatic-diaphragmatic space, fibrin plaque and pus was observed. Laparotomy was performed, which confirmed a parauterine mass and a tubo-ovarian complex with numerous recesses containing fetid, grayish pus. Complete right adnexectomy was carried out with abundant lavage and multiple drainage of the peritoneal cavity. Subsequently, the abdominal situation improved, but a new examination of drained liquid showed the presence of cutaneous bacterial flora but no fungi or parasites. Ovarian actinomycotic abscess with acute peritonitis and salpingitis was demonstrated. Subsequent antibiotic therapy consisted of piperacilline for 15 days, and 4 months after the episode the patient was well without return of the foci of infection.

[Prosthesis and emergency surgery of hernia]. / Prothèse et chirurgie herniaire en urgence.

Use of prostheses in emergency surgery is a controversial issue due to the risk of infection. We report our experience with a series of 31 strangled hernias treated in emergency situations with a polypropylene (n = 29) or a vinyl (n = 2) sheath placed in a pre-peritoneal or retro-muscular position. There were three small bowel resections and 13 resections of the omentum for necrosis. There were no cases of infectious complications during the post-operative period. There were no recurrent hernias during the follow-up. The absence of any supplementary morbidity after emergency prosthesis is in agreement with the data in the literature. These results suggest that a prosthesis can be proposed for strangled hernias when the weakness of the parietal wall would compromise a conventional procedure. Excluded are cases with severe infection, including peritonitis by gangrenous perforation of an incarcerated loop and associated colonic resections.

Hypoxia-inducible factor (HIF)-1α suppression in myeloma cells blocks tumoral growth in vivo inhibiting angiogenesis and bone destruction.

Hypoxia-inducible transcription factor-1 (HIF-1α) is overexpressed in multiple myeloma (MM) cells within the hypoxic microenvironment. Herein, we explored the effect of persistent HIF-1α inhibition by a lentivirus short hairpin RNA pool on MM cell growth either in vitro or in vivo and on the transcriptional and pro-angiogenic profiles of MM cells. HIF-1α suppression did not have a significant impact on MM cell proliferation and survival in vitro although, increased the antiproliferative effect of lenalidomide. On the other hand, we found that HIF-1α inhibition in MM cells downregulates the pro-angiogenic genes VEGF, IL8, IL10, CCL2, CCL5 and MMP9. Pro-osteoclastogenic cytokines were also inhibited, such as IL-7 and CCL3/MIP-1α. The effect of HIF-1α inhibition was assessed in vivo in nonobese diabetic/severe combined immunodeficiency mice both in a subcutaneous and an intratibial MM model. HIF-1α inhibition caused a dramatic reduction in the weight and volume of the tumor burden in both mouse models. Moreover, a significant reduction of the number of vessels and vascular endothelial growth factors (VEGFs) immunostaining was observed. Finally, in the intratibial experiments, HIF-1α inhibition significantly blocked bone destruction. Overall, our data indicate that HIF-1α suppression in MM cells significantly blocks MM-induced angiogenesis and reduces MM tumor burden and bone destruction in vivo, supporting HIF-1α as a potential therapeutic target in MM.

Myeloma cells inhibit non-canonical wnt co-receptor ror2 expression in human bone marrow osteoprogenitor cells: effect of wnt5a/ror2 pathway activation on the osteogenic differentiation impairment induced by myeloma cells.

Multiple myeloma (MM) is characterized by the impaired osteogenic differentiation of human mesenchymal stromal cells (hMSCs). Canonical Wnt signaling is critical for the regulation of bone formation, however, recent evidence suggests that the non-canonical Wnt agonist Wnt5a stimulates human osteoblastogenesis through its co-receptor Ror2. The effects of MM cells on non-canonical Wnt signaling and the effect of the activation of this pathway on MM-induced osteoblast exhaustion are not known and were investigated in this study. We found that the osteogenic differentiation of bone marrow hMSCs toward osteoprogenitor cells (PreOB) significantly increased Ror2 expression, and that MM cells inhibit Ror2 expression by PreOB in co-culture by inhibiting the non-canonical Wnt5a signaling. The activation of the non-canonical Wnt pathway in hMSCs by means of Wnt5a treatment and the overexpression of Wnt5 or Ror2 by lentiviral vectors increased the osteogenic differentiation of hMSCs and blunted the inhibitory effect of MM in co-culture. Consistently, Wnt5a inhibition by specific small interfering RNA reduced the hMSC expression of osteogenic markers. Our findings demonstrate that the Wnt5a/Ror2 pathway is involved in the pathophysiology of MM-induced bone disease and that the activation of the non-canonical Wnt5a/Ror2 pathway in hMSCs increases osteogenic differentiation and may counterbalance the inhibitory effect of MM cells.

Increased osteocyte death in multiple myeloma patients: role in myeloma-induced osteoclast formation.

The involvement of osteocytes in multiple myeloma (MM)-induced osteoclast (OCL) formation and bone lesions is still unknown. Osteocytes regulate bone remodelling at least partially, as a result of their cell death triggering OCL recruitment. In this study, we found that the number of viable osteocytes was significantly smaller in MM patients than in healthy controls, and negatively correlated with the number of OCLs. Moreover, the MM patients with bone lesions had a significantly smaller number of viable osteocytes than those without, partly because of increased apoptosis. These findings were further confirmed by ultrastructural in vitro analyses of human preosteocyte cells cocultured with MM cells, which showed that MM cells increased preosteocyte death and apoptosis. A micro-array analysis showed that MM cells affect the transcriptional profiles of preosteocytes by upregulating the production of osteoclastogenic cytokines such as interleukin (IL)-11, and increasing their pro-osteoclastogenic properties. Finally, the osteocyte expression of IL-11 was higher in the MM patients with than in those without bone lesions. Our data suggest that MM patients are characterized by a reduced number of viable osteocytes related to the presence of bone lesions, and that this is involved in MM-induced OCL formation.

Dorsolateral prefrontal cortex and hippocampus sustain impulsivity and aggressiveness in borderline personality disorder.

BACKGROUND: Borderline Personality Disorder (BPD) patients are characterized by increased levels of aggressivity and reduction of impulse control, which are behavioural dimensions mainly sustained by hippocampus and dorsolateral prefrontal cortex (DLPFC). In this study we aimed at investigating whether hippocampus and DLPFC anatomy may sustain impulsive and aggressive behaviours in BPD. METHODS: Fifteen DSM-IV BPD patients (11 females, 4 males) and fifteen 1:1 matched healthy controls (11 females, 4 males) were studied with a 1.5T magnetic resonance imaging (MRI) and underwent a psychopathological assessment in order to measure the severity of aggressive and impulsive traits. RESULTS: Right hippocampal volumes were significantly reduced in BPD patients compared to healthy subjects (p=0.027), particularly in those with a history of childhood abuse (p=0.01). Moreover, in patients but not in controls, right hippocampal volumes significantly inversely correlated with aggressiveness and DLPFC grey matter volumes significantly inversely associated with impulsiveness (p<0.05). CONCLUSIONS: Our results provide evidence that hippocampus and DLPFC play a separate and unique role in sustaining the control of impulse and aggressive behaviours in BPD patients.