2-Deoxy-D-glucose administration after seizures has disease-modifying effects on kindling progression.

2-deoxy-D-glucose (2DG) is a glucose analog and reversible inhibitor of glycolysis with anticonvulsant and antiepileptic effects in multiple seizure models. 2DG at a dose of 250 mg/kg intraperitoneally (IP) delays progression of repeated seizures evoked by kindling in rats when administered 30 min prior to twice daily kindling stimulation. As toxicological studies have demonstrated that repeated daily oral administration of 2DG at doses of 60-375 mg/kg/day in rats induces dose-dependent, reversible cardiac myocyte vacuolation, it was of interest to determine if 2DG also slowed kindling progression when administered at or below doses causing cardiac toxicity and at various time points after evoked seizures. We found that: (1) 2DG slowed kindling progression nearly 2-fold when administered at a dose of 37.5 mg/kg given IP 30 min prior to kindling stimulation, and (2) 2DG 37.5 mg/kg IP also slowed kindling progression when given immediately after, and for as long as 10 min after evoked (kindled) seizures. These observations suggest potential clinical usefulness of post-seizure administration of 2DG to reduce seizure clusters and long-term consequences of repeated seizures at human equivalent doses that are likely to be safe and well tolerated in patients.

Safety and Efficacy of a Novel, Self-Adhering Dural Substitute in a Canine Supratentorial Durotomy Model.

BACKGROUND: Cerebrospinal fluid (CSF) leaks increase postoperative risk for complication, likelihood of reoperation, and costs. OBJECTIVE: To investigate a novel, self-adhering polyethylene glycol-coated collagen pad (PCC) as a dural substitute relative to Duragen XS (DGX; Integra LifeSciences Corporation, Plainsboro, New Jersey) and as a dural sealant relative to Tachosil (Takeda Austria GmbH, Linz, Austria), a fibrinogen and thrombin-coated collagen pad (FTC). METHODS: A canine supratentorial durotomy surgical model was used to investigate the safety and efficacy of PCC. For safety, 4 animals were bilaterally treated with DGX or PCC and recovered for 1, 8, or 16 wk; total 24 animals. Each animal underwent physical and neurological examinations weekly and 16-wk animals underwent a magnetic resonance imaging (MRI) examination at each time point. For efficacy, 9 animals were unilaterally treated with FTC or PCC and underwent a burst pressure test intraoperatively or 14 d postoperatively; total 36 animals. RESULTS: In the safety study, no abnormal clinical signs or changes were noted on physical and neurological examinations, or in clinical pathology, CSF analysis or histopathology of DGX or PCC-treated animals. No consistent signs of cerebral compression, CSF leak, hemorrhage, or hydrocephalus were noted on MRI. In the efficacy study, no significant difference was found between FTC and PCC at each time point or overall (13.9 vs 12.3 mm Hg, n = 18 per group, P = .46). CONCLUSION: PCC is safe for use as a dural substitute and effective as a dural sealant. The novel, self-adhering combination of a polyethylene glycol-based sealant and a collagen pad may offer unique benefits to the advancement of duraplasty.

Heart rate variability and suicidal behavior.

Identification of biological indicators of suicide risk is important given advantages of biomarker-based models. Decreased high frequency heart rate variability (HF HRV) may be a biomarker of suicide risk. The aim of this research was to determine whether HF HRV differs between suicide attempters and non-attempters. Using the Trier Social Stress Test (TSST), we compared HF HRV between females with and without a history of suicide attempt, all with a lifetime diagnosis of a mood disorder. To investigate a potential mechanism explaining association between HF HRV and suicide, we examined the association between self-reported anger and HF HRV. Results of an Area under the Curve (AUC) analysis showed attempters had a lower cumulative HF HRV during the TSST than non-attempters. In addition, while there was no difference in self-reported anger at baseline, the increase in anger was greater in attempters, and negatively associated with HF HRV. Results suggest that suicide attempters have a reduced capacity to regulate their response to stress, and that reduced capacity to regulate anger may be a mechanism through which decreased HF HRV can lead to an increase in suicide risk. Our results have implications for the prevention of suicidal behavior in at-risk populations.

Computed Tomographic Characterization of Traumastem-A New Oxidized Cellulose Hemostatic Agent.

Oxidized regenerated cellulose (ORC) is a commonly used surgical hemostatic agent. When retained at the surgical site, it is frequently misdiagnosed on postoperative computed tomography (CT) images as an abscess or a recurrent tumor. Oxidized nonregenerated cellulose (ONC) is a new, more effective version of ORC. It is more effective because of its unorganized fiber structure and greater material density, which may also alter its appearance on CT images relative to ORC. This image report compares the CT characteristics of ONC and ORC. A rabbit's bilateral femoral arteries were punctured to model peripheral vascular surgery. ORC was used to treat 1 of the femoral artery punctures and ONC to treat the contralateral puncture. Noncontrast CT imaging was performed immediately following surgery (day 0) and on postoperative day 14. On day 0, both ORC and ONC were isoattenuating relative to muscle and hyperattenuating to fat, although ONC appears more homogenous. On day 14, neither ORC nor ONC was clearly identifiable. Thus, postoperative retention of ONC can obscure immediate postoperative CT interpretation and, similar to ORC, lead to an erroneous diagnosis of an abscess. By day 14, ONC retention may not obscure CT interpretation. In noncontrast CT imaging, ONC appears more homogeneous than ORC, but is otherwise indistinguishable. The greater homogeneity of ONC may be caused by the unorganized fiber structure or greater material density. Intraoperative use of ONC should be clinically investigated before radiographically diagnosing a postoperative abscess or recurrent tumor.

Higher executive control and visual memory performance predict treatment completion in borderline personality disorder.

BACKGROUND: Non-completion of a prescribed course of treatment occurs in 20-60% of individuals diagnosed with borderline personality disorder (BPD). While symptom severity, personality traits and environmental factors have been implicated as predictors of treatment non-completion (TNC), there have been no studies of neuropsychological predictors in this population. METHODS: From a randomized controlled trial, a subsample of 31, unmedicated outpatients diagnosed with BPD with recent self-injurious behavior was assessed on 5 neuropsychological domains. Patients were also assessed for general IQ, demographic and other salient clinical variables. Patients were randomized to one of four treatment conditions, which lasted up to 1 year. Number of weeks in treatment (WIT) up to 1 year was utilized as the index of TNC. RESULTS: Thirty-three percent of the subsample (n = 12) did not complete 1 year of treatment. However, more WIT were predicted by better baseline executive control (Trails B; p < 0.01) and visual memory performance (Benton visual retention; p < 0.001); other neuropsychological domains did not predict WIT. CONCLUSION: In the treatment of outpatients with BPD, better executive control and visual memory performance predict more WIT. Assessing and addressing these neurocognitive factors in treatment may reduce TNC in this high-risk population.

Interaction between tryptophan hydroxylase I polymorphisms and childhood abuse is associated with increased risk for borderline personality disorder in adulthood.

INTRODUCTION: Borderline personality disorder (BPD) is a severe disorder with high morbidity and mortality, but unknown etiology. Childhood abuse has been proposed as an etiological factor, but the mechanism by which an abuse history could influence the risk for BPD has not been determined. The aim of this study was to determine whether the tryptophan hydroxylase 1 (TPH1) gene is related to BPD in a clinical sample, and whether TPH1 genotypes or haplotypes moderate the relationship between abuse history and BPD. METHODS: Three hundred and ninety-eight patients diagnosed with mood disorders were genotyped for TPH1 G-6526A promoter polymorphism (rs4537731) and the A218C intron 7 polymorphism (rs1800532) and a set of ancestry informative markers, assessed for Diagnostic and Statistical Manual of Mental Disorders, 4th edition diagnoses, and assessed for a history of physical and sexual abuse. RESULTS: Patients with a diagnosis of BPD were more likely to be risk allele carriers (A alleles at both loci) than the non-BPD group. Logistic regression analysis predicting BPD diagnosis with both single-nucleotide polymorphisms and haplotypes showed significant interaction effects between genotype and abuse history. Poisson regression predicting the number of BPD diagnostic criteria met with the same predictor set also included a significant interaction term. Risk allele carriers with a history of abuse had an increased likelihood of a BPD diagnosis. CONCLUSION: Variation in TPH1 may increase risk for developing BPD as a result of childhood abuse. Elements of BPD pathology may be due in part to a genetically influenced serotonergic dysfunction, which in turn may lead to a differential response to environmental stressors.

The tryptophan hydroxylase-1 A218C polymorphism is associated with diagnosis, but not suicidal behavior, in borderline personality disorder.

While there is some preliminary evidence that the tryptophan hydroxylase I (TPH1) polymorphisms are related to Borderline Personality Disorder (BPD), it is not clear if this association is due to the high rates of suicidal behavior in this patient group. Because of the reported association between TPH1 polymorphisms and suicidal behavior, determining whether TPH1 is related to BPD independent of suicidal behavior is of particular importance. One hundred patients diagnosed with BPD and 101 healthy controls were genotyped for TPH1 intron 7 A218C polymorphism and assessed for impulsiveness and hostility. The BPD patient group had a higher frequency of A allele carriers (AA/AC genotypes) than the control group (chi(2) = 6.12, df = 1, P = 0.01), and differed by genotype frequencies (P = 0.03). Suicide attempter status in the patient group was not related to genotype. Logistic regression analysis controlling for age and gender predicted BPD diagnosis from TPH1 allele group (AA/AC vs. CC, P = 0.03), and TPH1 heterozygotes (AC) appeared to have the highest risk for BPD (P = 0.03). In the full sample, participants with the AC genotype had higher impulsiveness and hostility scores. However, TPH1 did not predict these traits in either of the groups independently, suggesting the association may be an artifact of the association between TPH1 and BPD. Results suggest that the A allele of the tryptophan hydroxylase-1 A218 polymorphism may be associated with BPD, and that it does not appear to be related to suicidal behavior in this population. An aspect of BPD pathology may be due to serotonergic dysfunction.

Comparing impulsiveness, hostility, and depression in borderline personality disorder and bipolar II disorder.

OBJECTIVE: To determine whether borderline personality disorder (BPD) and bipolar II disorder can be differentiated from each other and from major depressive disorder (MDD) by comparing depression severity, impulsiveness, and hostility in mood disorder patients with and without BPD. METHOD: One hundred seventy-three patients with either MDD or bipolar II disorder were enrolled from a larger sample admitted to a multisite project on mood disorders and suicidal behavior conducted from June 1996 through June 2006. Patients were divided into 4 groups: MDD with BPD, MDD without an Axis II diagnosis, bipolar II disorder with BPD, and bipolar II disorder without an Axis II diagnosis. All diagnoses were based on DSM-IV criteria. Depression was assessed using the 17-item Hamilton Rating Scale for Depression (HAM-D) and the self-rated Beck Depression Inventory (BDI). Impulsiveness was assessed using the Barratt Impulsiveness Scale, and hostility was assessed using the Buss-Durkee Hostility Inventory. RESULTS: Patients with BPD reported higher levels of impulsiveness (p = .004) and hostility (p = .001), independent of Axis I diagnosis. Bipolar II patients reported greater attentional impulsiveness (p = .008) than MDD patients, independent of BPD status, while BPD patients reported greater nonplanning impulsiveness than patients without BPD, independent of Axis I diagnosis (p = .02). For motor impulsiveness, there was a main effect for Axis I diagnosis (p = .05) and Axis II diagnosis (p = .002). The bipolar II + BPD group scored the highest, suggesting a compound effect of comorbidity. There were no differences in depression severity when measured with the HAM-D, although the BPD groups reported more severe depression on the BDI, independent of their Axis I diagnosis (p = .05). The BPD groups scored higher on the cognitive factor (p = .01) and anxiety factor (p = .03) of the HAM-D. CONCLUSION: Results suggest that there is a unique symptom and trait profile associated with BPD that distinguishes the diagnosis from bipolar II disorder. Results also suggest that impulsiveness is an important aspect of both disorders and that there is a compounding effect associated with a diagnosis of bipolar II disorder with comorbid BPD.

Suicide risk in schizophrenia: learning from the past to change the future.

Suicide is a major cause of death among patients with schizophrenia. Research indicates that at least 5-13% of schizophrenic patients die by suicide, and it is likely that the higher end of range is the most accurate estimate. There is almost total agreement that the schizophrenic patient who is more likely to commit suicide is young, male, white and never married, with good premorbid function, post-psychotic depression and a history of substance abuse and suicide attempts. Hopelessness, social isolation, hospitalization, deteriorating health after a high level of premorbid functioning, recent loss or rejection, limited external support, and family stress or instability are risk factors for suicide in patients with schizophrenia. Suicidal schizophrenics usually fear further mental deterioration, and they experience either excessive treatment dependence or loss of faith in treatment. Awareness of illness has been reported as a major issue among suicidal schizophrenic patients, yet some researchers argue that insight into the illness does not increase suicide risk. Protective factors play also an important role in assessing suicide risk and should also be carefully evaluated. The neurobiological perspective offers a new approach for understanding self-destructive behavior among patients with schizophrenia and may improve the accuracy of screening schizophrenics for suicide. Although, there is general consensus on the risk factors, accurate knowledge as well as early recognition of patients at risk is still lacking in everyday clinical practice. Better knowledge may help clinicians and caretakers to implement preventive measures. This review paper is the result of a joint effort between researchers in the field of suicide in schizophrenia. Each expert provided a brief essay on one specific aspect of the problem. This is the first attempt to present a consensus report as well as the development of a set of guidelines for reducing suicide risk among schizophrenia patients.

Heightened subjective experience of depression in borderline personality disorder.

Despite the frequent comorbidity of major depression and borderline personality disorder (BPD), limited research has examined what effect this comorbidity has on the severity, course, and presentation of depression. The purpose of this study was to examine whether the severity of major depressive disorder (MDD) in the context of comorbid borderline personality disorder (BPD) differs from MDD when comorbid BPD is not present and to determine whether different measures of depression yield convergent findings. Sixty patients diagnosed with DSM-IV MDD participated in this study. Twenty-nine were diagnosed with DSM-IV BPD, while the remaining 31 had no Axis II diagnosis. Depression was evaluated with both clinician (Hamilton Rating Scale for Depression) and self-report (Beck Depression Inventory) ratings. While the two groups were rated as similarly depressed by clinicians on the overall rating and the factor scores, the MDD/BPD group reported more severe depressive symptoms on the self-report measure. This difference was significant even after controlling for clinician-rated severity. Gender interacted with diagnosis, males in the BPD group showed the largest discrepancies between clinician ratings and self-reports. Posthoc analyses of HDRS factors with the BDI showed that the clinicianrated cognitive disturbance and retardation factors were correlated with self-rated severity overall. Within subgroups, only the retardation factor was correlated with the BDI. Our results suggest that while depressed individuals with and without BPD may be rated as similarly depressed when assessed with objective rating methods, the subjective experience of the depression may be rated as more intense or severe by patients with comorbid BPD. The mechanism underlying this effect remains unknown, and requires further research.

Impulsivity, suicidality and alcohol use disorders in adolescents and young adults with borderline personality disorder.

Borderline Personality Disorder (BPD) is a severe and disabling psychiatric condition that typically emerges in late adolescence or early adulthood. Nearly 50% of individuals with BPD have a co-occurring Alcohol Use Disorder (AUD) at some point in the course of their illness. This study explores clinical characteristics of adolescents and young adults (age 30 years and younger) with BPD and AUD (N=21) compared to BPD without any history of substance use disorders (N=17). Based on theoretical considerations and previous findings, we hypothesized that adolescents and young adults with BPD and AUDs would be more impulsive and exhibit higher rates of suicidal behavior than individuals with BPD and no substance use disorders. Consistent with our first hypothesis, the BPD/AUD group was more impulsive than the BPD only group. However, the two groups did not differ on measures of suicidal behavior. Overall, impulsivity was correlated with total number of suicide attempts in the adolescent/young adult group. When older BPD participants were included in the comparison (up to age 55), the BPD/AUD group exhibited more lifetime suicide attempts that were higher in medical lethality than the BPD only group, suggesting an overall increased lifetime suicide risk in the BPD/AUD group. The relationship between impulsivity, AUD, and suicidal behavior and lifetime suicide risk in adolescent and young adults with BPD is discussed.