Fibronectin binding to thrombin-stimulated platelets: evidence for fibrin(ogen) independent and dependent pathways

Plasma fibronectin binds in a specific and saturable manner to thrombin- stimulated platelets. gamma-Thrombin stimulated 80% as much fibronectin binding to platelets as alpha-thrombin with conversion of less than or equal to 1% of platelet fibrinogen to fibrin. Afibrinogenemic and normal platelets bound similar quantities of fibronectin in the presence of calcium or magnesium-ethylene glycol tetra-acetic acid (EGTA). These observations indicate that fibronectin can interact with platelets without involvement of fibrin or fibrinogen. Nevertheless, two different effects of fibrin(ogen) on fibronectin binding were observed. First, exogenous fibrinogen inhibited fibronectin binding to thrombin-stimulated platelets. This inhibition was unidirectional, as fibronectin did not inhibit fibrinogen binding to ADP or thrombin- stimulated cells. Second, formaldehyde-fixed cells with surface- associated fibrin bound significant quantities of fibronectin. This interaction required calcium and did not occur on fixed cells with or without surface-bound fibrinogen. A portion of the ligand bound to fixed cells with surface-associated fibrin was modified to form a derivative with a molecular weight identical to that of the fibronectin subunit cross-linked to the alpha-chain of fibrin. This high mol wt derivative was also observed to a variable extent with living cells in the presence of magnesium or calcium but not in the presence of magnesium-EGTA. Thus, fibronectin binds to platelets by at least two mechanisms: (1) a fibrin(ogen)-independent pathway that requires divalent ions and is inhibited by exogenous fibrinogen; and (2) a fibrin-dependent pathway with an absolute calcium requirement. With nonaggregated, thrombin-stimulated platelets, the former pathway appears to predominate.     

Pulmonary blastoma after liver transplant: a case report

There is an increased risk of cancer after organ transplantation mainly due to the immunosuppressive therapy required in these patients. We report a case of biphasic pulmonary blastoma in an adult male who underwent liver transplant for hepatocellular carcinoma in March 1999, followed by immunosuppressive treatment and adjuvant chemotherapy with epirubicin. Disease-free survival lasted 18 months, then a diagnosis of biphasic pulmonary blastoma was made and the patient underwent a lung lobectomy. Five months after surgical resection a recurrence of this rare tumor was recorded and two cycles of cisplatin + etoposide and ifosfamide + etoposide and one cycle of second-line chemotherapy with vinorelbine were administered. The tolerability and the efficacy of this treatment were poor. The patient died less than one year after diagnosis. To our knowledge this is the first reported case of pulmonary blastoma in a transplant patient. Our findings confirm that organ transplant recipients deserve long-term medical surveillance also in the absence of graft complications, and that pulmonary blastoma is an aggressive tumor with a poor prognosis.     

Blunted hormone responses to Ipsapirone are associated with trait impulsivity in personality disorder patients.

Impulsive aggression is associated with central serotonergic dysfunction. Animal models particularly implicate the 5-HT(1A) receptor in this behavior. We tested the hypothesis that central 5-HT(1A) receptor function is impaired in impulsive aggressive personality disorder patients. A total of 52 individuals with DSM-III-R personality disorders, all medically healthy adult outpatients without concurrent psychiatric medication treatment, underwent serial plasma cortisol, prolactin, and temperature measurements before and after ipsapirone 20 mg oral administration. Subjects completed self-report measures of impulsivity, hostility, depression and anxiety, and childhood maltreatment. Stepwise regression analysis revealed impulsivity alone among symptom measures to be associated with significantly decreased peak cortisol and prolactin responses. Diagnoses of borderline personality disorder (BPD) and intermittent explosive disorder-revised (IED-R) were associated with significantly increased and decreased cortisol responses, respectively. However, post hoc analyses indicated that impulsivity was significantly negatively correlated with cortisol responses in the BPD group, and may mediate the association of both BPD and IED-R with altered cortisol responses. Temperature response was associated with neither diagnostic nor symptom measures. Neither diagnostic nor dimensional measures of depression or anxiety, nor severity of childhood maltreatment, were significantly associated with cortisol, prolactin, or temperature responses. Impulsivity is related to impaired function at (or downstream to) postsynaptic 5-HT(1A) receptors, and this relationship may be partly responsible for the association of impaired serotonergic function with diagnoses such as BPD and IED-R. In addition, D(2) receptor dysfunction may play a role in impulsivity, whereas 5-HT(1A) cell-body autoreceptor function may be spared in these disorders.     

Blood pressure levels of preterm infants in the first year of life

Systolic blood pressure was measured in 36 infants with median gestational age of 29 weeks (range 24–35 weeks) and birth weight of 1160 g (range 642–1500 g). Measurements were made at 1, 6 and 12 weeks, and subsequently at 12-weekly intervals during the first year of life. No infant developed chronic lung disease. Systolic blood pressure increased over the first 24 weeks ( p < 0.001) to a mean value of 95 mmHg, but did not change significantly over the next 24 weeks. These data provide a reference range of blood pressure levels during the first year of life for infants born at an early gestational age.     

Serotonin-stimulated calcium release is decreased in platelets from high impulsivity patients

Impulsivity is a significant factor in many behavioural disorders. Previous studies have shown that dysfunction of serotonin (5-HT) pathways are correlated with impulsivity, but an underlying causative mechanism has not as yet been identified. The present study examined 5-HT-stimulated Ca2+ release from platelets from 33 patients exhibiting high impulsivity according to the Barratt Impulsivity Scale and from 26 healthy volunteers. 5-HT-stimulated Ca2+ release was significantly decreased in patients as compared to controls. These results indicate that impulsivity is linked to alterations in the 5-HT second-messenger cascade and suggest that further efforts should be made to understand the specific abnormalities in this complex pathway. This understanding may lead to the development of therapeutic strategies specific for regulation of 5-HT-stimulated Ca2+ release, providing more effective treatment for impulsive behavioural disorders.     

Developmental psychopathology and neurobiology of aggression

The aim of this paper is to clarify how neural mechanisms at the molecular level, specifically the serotonergic (5-HT) system and the hypothalamic-pituitary-adrenal axis system (HPA) in conjunction with early life stress may contribute to the emergence of aggression, self-directed and otherwise, in borderline personality disorder (BPD). Chronic dysregulation of these biological systems, which function to regulate stress and emotion, may potentiate the development of impulsive aggression in borderline personality conditions. Our central premise in this paper is that brain development, stress regulation, and early pathonomic experience are interactive and cumulative in their mutual influence on the development of impulsive aggression in BPD. We review the parameters of impulsive aggression in BPD, followed by a discussion of the neurobiological and neuroendocrine correlates of impulsive aggression with and without BPD. We then focus on the developmental continuities in BPD with attention to brain maturation of 5-HT and HPA axis function during the life span and the influence of early adverse experiences on these systems. Finally, we comment on the data of the relative stability of aggression in BPD, adolescence as a developmental stage of potential vulnerability, and the course of aggressive behavior during the life span.     

Neuroimaging and personality disorders

Within the past several years, neuroimaging research on personality disorders has begun to develop. Personality disorders can be thought of as trait-like dysfunctional patterns in cognitive, affective, impulse control, and interpersonal domains. These domains of dysfunction have been linked to specific neural circuits. Developments in brain imaging techniques have allowed researchers to examine the neural integrity of these circuits in personality-disordered individuals. This article reviews the neuroimaging literature on borderline personality disorder, antisocial personality disorder (including psychopathy) and schizotypal personality disorder. Functional and structural studies provide support for dysfunction in fronto-limbic circuits in borderline and antisocial personality disorder, whereas temporal lobe and basal striatal-thalamic compromise is evident in schizotypal personality disorder.     

Assessment of behavioral and cognitive impulsivity: development and validation of the Lifetime History of Impulsive Behaviors Interview

The construction and initial psychometric evaluation of an interview assessment of clinically significant impulsivity (Lifetime History of Impulsive Behaviors; LHIB) is presented. Personality-disordered and control subjects participated by completing self-report measures of depression, anxiety and social desirability, along with self-report and laboratory analogue measures of impulsivity, and finally the LHIB. The LHIB demonstrated good to excellent internal consistency and test-retest reliability. Supporting concurrent construct validity, scores on the LHIB correlated with other self-report measures of impulsivity. Diagnostic group differences were obtained and the LHIB evidenced concurrent validity in its ability to classify subjects by scores. No relationship was obtained between the LHIB and laboratory analogue measures. While evidence of discriminant validity was mixed, these data suggest that the LHIB may be a useful instrument for the assessment of impulsive behavior.