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 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.

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.

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.

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.

HOXB7 expression by myeloma cells regulates their pro-angiogenic properties in multiple myeloma patients.

The deregulation of the homeobox genes as homeoboxB (HOXB)-7 has been previously associated to tumor progression and angiogenesis; here we investigated the potential role of HOXB7 in the pro-angiogenic properties of multiple myeloma (MM) cells. We found that HOXB7 was expressed in 10 out of 22 MM patients analyzed at the diagnosis related to high bone marrow angiogenesis and overexpressed in about 40% of myeloma cell lines compared with normal plasma cells. Enforced HOXB7 expression in MM cells by a lentiviral vector significantly modified their transcriptional and angiogenic profile, checked by combined microarray and angiogenesis PCR analyses, upregulating VEGFA, FGF2, MMP2, WNT5a and PDGFA and downregulating thrombospoindin-2. The pro- and anti-angiogenic HOXB7-related gene signature was also validated in a large independent dataset of MM patients. Accordingly, MM-induced vessel formation was significantly increased by HOXB7 overexpression both in vitro angiogenic and chorioallantoic membrane assays, as well as the HOXB7 silencing by small interfering RNA inhibited the production of angiogenic factors, and the pro-angiogenic properties of MM cells. Finally, in SCID-NOD mice we confirmed that HOXB7 overexpression by MM cells stimulated tumor growth, increased MM-associated angiogenesis and the expression of pro-angiogenic genes by microarray analysis supporting the critical role of HOXB7 in the angiogenic switch in MM.

Cognitive memory control in borderline personality disorder patients.

BACKGROUND: It has been demonstrated that the mechanism of cognitive memory control in humans is sustained by the hippocampus and prefrontal cortices, which have been found to be structurally and functionally abnormal in borderline personality disorder (BPD). We investigated whether the memory control mechanism is affected in BPD. METHOD: Nineteen Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV BPD patients and 19 matched healthy controls (HC) performed a specific think/no-think paradigm exploring the capacity of remembering and suppressing pair of words previously learned. After the think-no think phase, the second member of each word pair has to be remembered either when subjects are presented with the cue word showed at the beginning of the test (Same Probe Test; SPT) or when they are presented with an extra-list categorical word (Independent Probe Test; IPT). We evaluated the effect of suppression and of retrieval activity on later retention of words. RESULTS: Both on the SPT and on the IPT, HC showed the expected improvement of memory retrieval on to-be-remembered words, unlike BPD patients. On the SPT, HC, but not BPD patients, correctly recalled significantly more words among remembered words (RW) than among suppressed words (SW). Similarly to HC, subjects with BPD without a history of childhood abuse showed a significantly higher percentage of correctly recalled words among RW than among SW. CONCLUSIONS: The mechanism of active retrieval of memories and of improvement through repetition is impaired in BPD, particularly in those who experienced traumatic experiences. This impairment might play an important role, possibly resulting in the emergence of unwanted memories and dissociative symptoms.

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.

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.

Depression after lung transplantation: causes and treatment.

During the postoperative course of lung transplantation, patients may experience depressive symptoms that negatively influence their ability to cope with the new organ, their adherence to rehabilitation and pharmacologic therapy, and their overall quality of life (QoL). To date, no review has explored the causes of depression following transplantation or the efficacy and safety of therapeutic interventions in this patient group. We conducted a comprehensive 1966-2006 MEDLINE, EMBASE, and PsycINFO search for studies of the causes and treatments of depression in lung transplant recipients. We identified 25 studies of variable methodologic quality. Depression rates are high among candidates for lung transplantation. In the short term, after surgery depressive symptoms remain low with an improvement in QoL, whereas in the long term (>3 years), the decline of functional status is associated with a dramatic increase in such symptomatology. Personality disorders, coping strategies, stressful life events, physical complications, corticosteroid medications, age, gender, and psychosocial support all play a central role in causing depressive states in lung transplant recipients. Serotonin reuptake inhibitors (SSRIs) and new-generation antidepressants (mirtazapine) represent the best therapeutic choices for this group of patients. The risk of serious drug-drug interactions should be carefully monitored by experienced clinicians. Complementary therapies and psychoeducational intervention also help recipients to strengthen their coping strategies, offering further advantages after transplantation. Additional well-conducted randomized controlled trials are needed to clarify the epidemiologic course of depression following lung transplantation and to tailor effective pharmacologic or psychological interventions accordingly.

Long-term study of TNBS-induced colitis in rats: focus on mast cells.

OBJECTIVE AND DESIGN: To investigate the severity and duration of colitis induced by two different doses of 2,4,6-trinitrobenzenesulfonic acid (TNBS) and the changes in mast cell number in acute inflammation and in the recovery process of colitis. METHODS: Colitis was induced in rats by an enema of TNBS (10 or 30 mg) in 25% ethanol. Macroscopic and histologic changes of the colon, colon weight and mast cell counts were examined at various times (7, 30 and 60 days) after colitis induction. RESULTS: TNBS induced a colonic damage which was dose-related for both severity and time necessary to complete recovery. On day 7 after colitis induction 10 mg TNBS induced macroscopic and microscopic alterations of colonic architecture that completely resolved at day 60. By contrast, 30 mg TNBS induced massive necrosis, thickening of the colon, severe histologic changes that were only partially reversed after two months. Mast cell number in the submucosa and muscularis propria decreased significantly in the acute phase of inflammation (7 days) and slowly increased thereafter, reaching a maximum level (up to about 5-fold) at day 60 after both doses of TNBS. CONCLUSIONS: Present data confirm the ability of TNBS to induce in rats damage to the colon that was dose-dependent for severity and duration. Moreover, these data unravel a different role of mast cells in TNBS-induced colitis: an early degranulation in the acute phase of inflammation and a subsequent accumulation of mast cells in the late phase of the disease, associated with tissue repair.

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.

Myeloma cells induce imbalance in the osteoprotegerin/osteoprotegerin ligand system in the human bone marrow environment.

Although osteolysis is a common complication in patients with multiple myeloma (MM), the biologic mechanisms involved in the pathogenesis of MM-induced bone disease are poorly understood. Two factors produced by stromal-osteoblastic cells seem critical to the regulation of bone resorption: osteoprotegerin (OPG) and its ligand (OPGL). OPGL stimulates osteoclast differentiation and activity, whereas OPG inhibits these processes. The present study investigated whether myeloma cells affect physiologic OPG/OPGL balance in the bone marrow (BM) environment. Ten human myeloma cell lines and myeloma cells isolated from 26 consecutive patients with MM failed to express OPGL and only rarely produced a low amount of OPG. In a coculture system, human myeloma cells up-regulated OPGL expression but strongly down-regulated OPG production in preosteoblastic (preOB) or stromal cells (BMSCs) of primary human BM at the mRNA and protein levels. This effect, which was dependent on cell-to-cell contact between myeloma cells and BMSCs or preOB, partially involved the integrin VLA-4. In addition, overexpression of OPGL mRNA occurred in ex vivo BM cultures obtained from MM patients as compared with healthy donors, and immunohistochemical staining performed on BM biopsy specimens showed an increase of OPGL and a reduction of OPG expression in MM patients as compared with healthy subjects. In summary, these data indicate that myeloma cells affect the OPG/OPGL ratio in the BM environment and tend to confirm that the OPG/OPGL system is involved in the pathogenesis of MM-induced bone disease.