Removal of prion challenge from an immune globulin preparation by use of a size-exclusion filter

BACKGROUND: A size-exclusion filter (Viresolve 180, Millipore Corp.) was tested for its ability to remove transmissible spongiform encephalopathies prion protein from an immune globulin preparation during ultrafiltration. STUDY DESIGN AND METHODS: Hamster-adapted 263K scrapie brain homogenate (SBH) was spiked into Rh0(D) immune globulin (human) at 1 in 300 and 1 in 1000 dilutions. Before spiking, the SBH was treated with detergent, sonicated, and filtered through serial 0.45-, 0.22-, and 0.1-microm filters to present a rigorous filter challenge. Process variables were monitored throughout the ultrafiltration to ensure that the spiked material did not compromise the membrane flux. Removal of scrapie prion protein (PrP(Sc)) material was determined by use of a sensitive Western blot assay. RESULTS: The turbid SBH became completely translucent after sonication and passage through the 0.45-, 0.22-, and 0.1-microm filters. The filtration of the immune globulin containing PrP(Sc) material was more difficult to perform than was filtration of immune globulin spiked with the normal cellular isoform. Even during tangential flow filtration, the fibril material prevented the PrP(Sc)-spiked immune globulin from passing as readily through the filter. Western blot results indicated a removal of greater than or equal to 2.5 log PrP(Sc), while remaining within the normal filtration limits. CONCLUSIONS: The composition, physical condition, and the amount of SBH introduced have significant effects on the filtration of the immune globulin and the log removal values obtained. By use of a detergent-treated, sonicated, and filtered preparation of SBH, it was demonstrated that the Viresolve 180 effectively removes PrP(Sc) from the immune globulin.     

Familial Liability to Psychosis Is Associated With Attenuated Dopamine Stress Signaling in Ventromedial Prefrontal Cortex

Objective: Patients diagnosed with a psychotic disorder and their first-degree relatives display increased reactivity to stress. Theory predicts that experience of psychosocial stress is associated both with ventromedial prefrontal and mesolimbic dopamine neurotransmission. However, while there is evidence of aberrant striatal dopamine processing in psychotic disorder, the role of the prefrontal cortex remains under-researched. This study aimed at investigating stress-induced in vivo dopamine release in ventromedial prefrontal cortex (vmPFC) of individuals at familial risk for psychosis. Method: Fourteen healthy first-degree relatives of patients with a diagnosis of psychotic disorder and 10 control subjects underwent a single dynamic positron emission tomography (PET) scanning session after intravenous administration of 183.2 (SD = 7.6) MBq [¹⁸F]fallypride. Psychosocial stress was initiated at 100min postinjection using a computerized mental arithmetic task with social evaluative threat components. PET data were analyzed using the linearized simplified reference region model. Regression analyses were performed to compare the spatial extent of task-related ligand displacement between control subjects and relatives and to find how it related to self-rated experiences of psychosocial stress and psychosis. Results: First-degree relatives displayed hyporeactive dopamine signaling in the vmPFC in response to stress. Increased levels of subjectively rated stress were associated with increased intensity of psychotic experiences. This effect was particularly pronounced in first-degree relatives. Conclusion: Although previous studies have hypothesized a role for prefrontal dopamine dysfunction in psychosis, this study, to our knowledge, is the first in vivo human imaging study showing attenuated (ie, hyporeactive) dopamine stress neuromodulation in vmPFC of individuals at familial risk for psychosis.Key words: schizophrenia, positron emission tomography, neuromodulation, relatives, mesolimbic, salience     

William Thomas Shanahan

Psychiatric Quarterly -     

Selective peripheral denervation: comparison with pallidal stimulation and literature review

Patients with cervical dystonia who are non-responders to Botulinum toxin qualify for surgery. Selective peripheral denervation (Bertrand’s procedure, SPD) and deep brain stimulation of the globus pallidus (GPi-DBS) are available surgical options. Although peripheral denervation has potential advantages over DBS, the latter is nowadays more commonly performed. We describe the long-term outcome of selective peripheral denervation as compared with GPi-DBS, along with the findings of literature review. Twenty patients with selective peripheral denervation and 15 with GPi-DBS were included. Tsui scale, a visual analogue scale, and the global outcome score of the Toronto Western Spasmodic Torticollis Rating Scale were used to define a “combined global surgical outcome”. The “combined global surgical outcome” for patients with selective peripheral denervation or pallidal stimulation was respectively “bad” for 65 and 13.3 %, “fair-to-good” for 30 and 26.7 %, and “marked” improvement for 5 and 60 % (p < 0.001). Improvement on visual analogue scale (p < 0.002), global outcome score (p < 0.002), and Tsui score (p < 0.000) was larger for the pallidal stimulation group. Seventy-five percent of patients with selective peripheral denervation and 60 % of patients with pallidal stimulation reported side effects. Seven patients with selective peripheral denervation successively underwent GPi-DBS, with a further significant improvement in the Tsui score (?48.6 ± 17.4 %). GPi-DBS is to be preferred to selective peripheral denervation for the treatment of cervical dystonia because it produces larger benefit, even if it can have more potentially severe complications. GPi-DBS is also a valid alternative in case of failure of SPD.     

Emotional variability during mother–adolescent conflict interactions: Longitudinal links to adolescent disclosure and maternal control

The aim of this study was to examine relations of emotional variability during mother–adolescent conflict interactions in early adolescence with adolescent disclosure and maternal control in early and late adolescence. Data were used from 92 mother–adolescent dyads (M age T1 = 13.05; 65.20% boys) that were videotaped at T1 while discussing a conflict. Emotional variability was derived from these conflict interactions. Mothers also completed questionnaires at the start of the study (T1) and five years later (T6) on adolescent disclosure and maternal control. Path analysis showed that more emotional variability during conflict interactions in early adolescence was associated with higher levels of adolescent disclosure in early adolescence and with relative decreases in maternal control from early to late adolescence. More emotional variability of mother–adolescent dyads serves an important function in adaptively dealing with relational challenges that arise during adolescence.     

Active PAI-1 as marker for venous thromboembolism: Case–control study using a comprehensive panel of PAI-1 and TAFI assays

Background

Both activated Thrombin Activatable Fibrinolysis Inhibitor (TAFI) and active Plasminogen Activator Inhibitor-1 (PAI-1) attenuate fibrinolysis and may therefore contribute to the pathophysiology of Venous ThromboEmbolism (VTE). Whether increased TAFI and/or PAI-1 concentrations are associated with VTE is unclear.

Objective

To study an association of impaired fibrinolysis and VTE using a comprehensive panel of in-house developed assays measuring intact TAFI, activation peptide of TAFI (AP-TAFI), PAI-1 antigen, endogenous PAI-1:t-PA complex (PAI-1:t-PA) and active PAI-1 levels in 102 VTE patients and in 113 healthy controls (HC).

Results

Active PAI-1 was significantly higher in VTE patients compared to HC (20.9 [9.6-37.8] ng/ml vs. 6.2 [3.5-9.7] ng/ml, respectively). Active PAI-1 was the best discriminator with an area under the ROC curve and 95% confidence interval (AUROC [95%CI]) of 0.84 [0.79-0.90] compared to 0.75 [0.68-0.72] for PAI-1:t-PA, 0.65 [0.58-0.73] for PAI-1 antigen, 0.62 [0.54-0.69] for AP-TAFI and 0.51 [0.44-0.59] for intact TAFI. Using ROC analysis, we defined an optimal cut-off of 12.8 ng/ml for active PAI-1, with corresponding sensitivity of 71 [61–79] % and specificity of 89 [82–94] %. A lack of association with the time between VTE event and sample collection or with the intake of anticoagulant treatment suggests that active PAI-1 levels are sustainable high in VTE patients.

Conclusions

This case–control study emphasizes the clinical importance of measuring active PAI-1 instead of PAI-1 antigen and identifies active PAI-1 as a potential marker of VTE. Prognostic studies will need to address the clinical significance of active PAI-1 as biomarker.