A prospective,iterative, adaptive trial of carfilzomib‐based desensitization

Proteasome inhibitor–based strategies hold promise in transplant but have yielded varying results. Carfilzomib, a second‐generation proteasome inhibitor, may possess advantages over bortezomib, the first‐generation proteasome inhibitors. The purpose of this study was to evaluate the safety, toxicity, and preliminary efficacy of carfilzomib in highly HLA‐sensitized kidney transplant candidates. Renal transplant candidates received escalating doses of carfilzomib followed by plasmapheresis (group A) or an identical regimen with additional plasmapheresis once weekly before carfilzomib dosing. Thirteen participants received carfilzomib, which was well tolerated with most adverse events classified as low grade. The safety profile was similar to bortezomib desensitization; however, neurotoxicity was not observed with carfilzomib. Toxicity resulted in permanent dose reduction in 1 participant but caused no withdrawals or deaths. HLA antibodies were substantially reduced with carfilzomib alone, and median maximal immunodominant antibody reduction was 72.8% (69.8% for group A, P = .031, 80.1% for group B, P = .938). After depletion, rebound occurred rapidly and antibody levels returned to baseline between days 81 and 141. Bone marrow studies revealed that approximately 69.2% of plasma cells were depleted after carfilzomib monotherapy. Carfilzomib monotherapy–based desensitization provides an acceptable safety and toxicity profile while leading to significant bone marrow plasma cell depletion and anti‐HLA antibody reduction.     

The release of excitatory amino acids,dopamine, and potassium following transplantation of embryonic mesencephalic dopaminergic grafts to the rat striatum,and their effects on dopaminergic neuronal survival in vitro

A major limitation to the effectiveness of grafts of fetal ventral mesencephalic tissue for parkinsonism is that about 90-95% of grafted dopaminergic neurones die. In rats, many of the cells are dead within 1 day and most cell death is complete within 1 week. Our previous results suggest that a major cause of this cell death is the release of toxins from the injured CNS tissue surrounding the graft, and that many of these toxins have dissipated within 1 h of inserting the grafting cannula. In the present experiments we measured the change over time in the concentration of several potential toxins around an acutely implanted grafting cannula. We also measured the additional effect of injecting suspensions of embryonic mesencephalon, latex microspheres, or vehicle on these concentrations. Measurements of glutamate, aspartate, and dopamine by microdialysis showed elevated levels during the first 20-60 min, which then declined to baseline. In the first 20 min glutamate levels were 10.7 times, aspartate levels 5 times, and dopamine levels 24.3 times baseline. Potassium levels increased to a peak of 33 +/- 10.6 mM 4-5 min after cannula insertion, returning to baseline of <5 mM by 30 min. Injection of cell suspension, latex microspheres, or vehicle had no significant effect on these levels. We then assayed the effect of high concentrations of glutamate, aspartate, dopamine, and potassium on dopaminergic neuronal survival in E14 ventral mesencephalic cultures. In monolayer cultures only dopamine at 200 microM showed toxicity. In three-dimensional cultures only the combination of raised potassium, dopamine, glutamate, and aspartate together decreased dopaminergic neuronal survival. We conclude that toxins other than the ones measured are the main cause of dopaminergic cell death after transplantation, or the effects of the toxins measured are enhanced by anoxia and metabolic challenges affecting newly inserted grafts.     

Post-learning intranasal oxytocin modulates human memory for facial identity

The nanopeptide oxytocin has physiological functions during labour and lactation. In addition, oxytocin is known to modulate aggression, anxiety, social behaviour and cognition. Little is known about its effects on memory for emotional stimuli. In the present single-blind, placebo-controlled, randomised study we have investigated the short- and long-term effects of a single post-learning dose (20 IU) of intranasal oxytocin on memory for facial identity and expression in 36 healthy young females and males using a face portrait recognition test. In the acquisition phase of the test, 60 different male faces with happy, angry or neutral expressions were presented to the volunteers. Thirty minutes and 24h after oxytocin administration, recognition memory tests were performed using portraits with neutral facial expressions, only. Oxytocin improved identity recognition memory independently of participant's gender, for neutral and angry faces, whereas this effect was not present for happy faces. Oxytocin-treated subjects had a lower bias to judge not previously seen faces as being previously seen. Oxytocin had no effect on facial expression memory. In conclusion, oxytocin has distinct effects on memory performance for facial identity and may contribute to the modulation of social behaviour.     

Verteporfin therapy for choroidal hemangioma: a long-term follow-up

BACKGROUND: To document the long-term follow-up of patients with circumscribed choroidal hemangioma who were treated with verteporfin photodynamic therapy (PDT). METHODS: Fifteen patients were included in a prospective interventional case series. Verteporfin PDT as a bolus infusion of 6 mg/m body surface area and a light dose of 100 J/cm at 689 nm applied over 166 seconds were administered. Standardized evaluation was performed every 3 months within the first year and at 12-month intervals during follow-up. RESULTS: At baseline, all patients presented with significant vision loss ranging from 20/26 to 20/500. During a mean follow-up of 36.6 months (range, 12-66 months), no patient had evidence of recurrence. Mean final visual acuity ranged from 20/20 to 20/400. In all patients, complete and permanent regression with no signs of tumor regrowth or recurring subretinal fluid was found. Of 15 patients, 13 had a substantial increase in visual acuity (range, 2-9 lines), and 2 patients' visual acuity remained stable. Chorioretinal atrophy at the previous tumor site did not enlarge over time. Retreatments after completion of the primary treatment were not necessary. CONCLUSION: Persistent and complete absence of choroidal hemangioma associated with persistent improvement in visual acuity and central visual fields can be obtained with verteporfin PDT.     

Substantia nigra echogenicity in Parkinson’s disease: relation to serum iron and C-reactive protein

In Parkinson’s disease (PD), substantia nigra hyperechogenicity (SN-h) has been related to both, local iron accumulation and microglia activation. We analysed its relationship in PD patients with serum iron (n = 31) and C-reactive protein (CRP; n = 193). SN-h correlated with lower CRP and iron levels. Also, patients with a first-degree relative with PD had lower iron levels. Microglia activation, if reflected by SN-h, may be therefore unrelated to serum CRP. Findings support the idea that SN-h indicates inherited alteration of iron metabolism.     

The survival of neural precursor cell grafts is influenced by in vitro expansion

Embryonic neural precursor cells (ENPs) provide a potential alternative for transplantation in neurodegenerative diseases, as they can be expanded in culture, avoiding many of the practical obstacles that limit the application of transplanting primary neurones. However, grafts of ENPs into animal models show variable survival and limited differentiation into neurones. The effect of expansion time on their ability to survive and differentiate may be an important factor in this and has not been examined directly. In these experiments, murine and human ENPs were expanded for short (4 weeks) and long (20 weeks) periods before transplantation into the adult rat striatum. Whereas grafts of both short- and long-term expanded human ENPs survived for 4 weeks following transplantation, by 20 weeks all long-term expanded grafts had disappeared. Murine ENPs behaved similarly: only grafts of short-term expanded ENPs survived at 12 weeks following transplantation. RT-PCR analysis of ENP cultures after 4 and 20 weeks of expansion demonstrated changes in expression of a number of different groups of genes. We conclude that long-term expansion of ENPs profoundly impairs their ability to survive long-term after transplantation into the adult brain. This has implications for the potential use of these cells for neural transplantation strategies.     

Can I trust in what I see? EEG evidence for a cognitive evaluation of perceptual constructs

Environmental information available to our senses is incomplete and to varying degrees ambiguous. It has to be disambiguated in order to construct stable and reliable percepts. Ambiguous figures are artificial examples where perception is maximally unstable and alternates between possible interpretations. Tiny low‐level changes can disambiguate an ambiguous figure and thus stabilize percepts. The present study compares ERPs evoked by ambiguous stimuli and disambiguated stimulus variants across three visual categories: geometry (Necker cube), motion (stroboscopic alternative motion stimulus, SAM) and semantics (Boring's old/young woman). We found that (a) disambiguated stimulus variants cause stable percepts and evoke two huge positive ERP excursions (Cohen's effect sizes 1–2), (b) the amplitudes of these ERP effects are inversely related to the degree of stimulus ambiguity, and (c) this pattern of results is consistent across all three tested visual categories. This generality across visual categories points to mechanisms at a very abstract (cognitive) level of processing. We discuss our results in the context of a high‐level Bayesian inference unit that evaluates the reliability of perceptual processing results, given a priori incomplete, ambiguous sensory information. The ERP components may reflect the outcome of this reliability estimation.     

Use of HCV Ab+/NAT− donors in HCV naïve renal transplant recipients to expand the kidney donor pool

Hepatitis C (HCV) disease transmission from the use of HCV antibody‐positive and HCV nucleic acid test‐negative (HCV Ab+/NAT?) kidneys have been anecdotally reported to be absent. We prospectively analyzed kidney transplant (KT) outcomes from HCV Ab+/NAT? donors to HCV naïve recipients under T‐cell depleting early steroid withdrawal immunosuppression. Allografts from 40 HCV Ab+/NAT? donors were transplanted to 52 HCV Ab? recipients between July 2016 and February 2018. Thirty‐three (82.5%) of donors met Public Health Service (PHS) increased risk criteria. De novo HCV infection was detected at 3 months post‐KT in one recipient (1.9%). This was a case of transmission from a HCV Ab+ NAT+ donor with an initial false‐negative NAT completed using sample collected on donor hospital admission (day 2). At the time of HCV diagnosis, a stored donor sample collected during procurement (day 4) was tested and resulted NAT‐positive. Subsequently, sustained virologic response (SVR) was achieved with 12 weeks of glecaprevir/pibrentasvir. One death with functioning graft at 261 days post‐KT was determined not related to HCV or donor factors. This experience provides evidence of a low transmission rate of HCV from HCV Ab+/ NAT? kidney donors, thereby arguing for increasing utilization.     

Altered psychobiological reactivity but no impairment of emotion recognition following stress in adolescents with non-suicidal self-injury

Impairments in both stress regulation and emotion recognition have been associated with borderline personality disorder (BPD) and non-suicidal self-injury (NSSI). Although it has been proposed that emotion recognition deficits particularly emerge during stress, this hypothesis has not been fully investigated. Adolescents with and without NSSI performed emotion recognition tasks before and after the employment of the Trier Social Stress Test (TSST). The psychobiological stress response was captured with psychological self-reports (affect, stress and dissociation), physiological recordings (heart rate, HR, and heart rate variability, HRV) and endocrinological sampling of saliva (cortisol and alpha-amylase). Mixed-linear models were applied to analyze stress-induced changes in emotion recognition performance and respective stress response measures. The TSST elicited altered psychobiological stress responses in adolescents with NSSI: A more pronounced decrease in positive affect, a more pronounced increase in negative affect, a less pronounced increase in HR, a less pronounced decrease in HRV and a more pronounced increase in alpha-amylase throughout the stress induction than adolescents without NSSI. Stress responses (dissociation, negative affect, cortisol and HR) differed as a function of BPD severity on a continuum, illustrating greater reactivity on self-reports but decreased biological responsiveness in those with greater BPD severity. Stress induction had similar effects on emotion recognition in adolescents with and without NSSI. Recognition sensitivity and recognition speed equally increased, in the absence of any differences in recognition accuracy. In contrast to prominent propositions, psychosocial stress does not appear to account for impaired emotion recognition across the BPD spectrum.