Applicability, potential and limitations of TSPO PET imaging as a clinical immunopsychiatry biomarker

PURPOSE: TSPO PET imaging may hold promise as a single-step diagnostic work-up for clinical immunopsychiatry. This review paper on the clinical applicability of TSPO PET for primary psychiatric disorders discusses if and why TSPO PET imaging might become the first clinical immunopsychiatry biomarker and the investment prerequisites and scientific advancements needed to accommodate this transition from bench to bedside. METHODS: We conducted a systematic search of the literature to identify clinical studies of TSPO PET imaging in patients with primary psychiatric disorders. We included both original case-control studies as well as longitudinal cohort studies of patients with a primary psychiatric diagnosis. RESULTS: Thirty-one original studies met our inclusion criteria. In the field of immunopsychiatry, TSPO PET has until now mostly been studied in schizophrenia and related psychotic disorders, and to a lesser extent in mood disorders and neurodevelopmental disorders. Quantitative TSPO PET appears most promising as a predictive biomarker for the transdiagnostic identification of subgroups or disease stages that could benefit from immunological treatments, or as a prognostic biomarker forecasting patients' illness course. Current scanning protocols are still too unreliable, impractical and invasive for clinical use in symptomatic psychiatric patients. CONCLUSION: TSPO PET imaging in its present form does not yet offer a sufficiently attractive cost-benefit ratio to become a clinical immunopsychiatry biomarker. Its translation to psychiatric clinical practice will depend on the prioritising of longitudinal research and the establishment of a uniform protocol rendering clinically meaningful TSPO uptake quantification at the shortest possible scan duration without arterial cannulation

Transcranial Magnetic Stimulation Provides Means to Assess Cortical Plasticity and Excitability in Humans with Fragile X Syndrome and Autism Spectrum Disorder

Fragile X Syndrome (FXS) is the most common heritable cause of intellectual disability. In vitro electrophysiologic data from mouse models of FXS suggest that loss of fragile X mental retardation protein affects intracortical excitability and synaptic plasticity. Specifically, the cortex appears hyperexcitable, and use-dependent long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength are abnormal. Though animal models provide important information, FXS and other neurodevelopmental disorders are human diseases and as such translational research to evaluate cortical excitability and plasticity must be applied in the human. Transcranial magnetic stimulation paradigms have recently been developed to non-invasively investigate cortical excitability using paired pulse stimulation, as well as LTP- and LTD-like synaptic plasticity in response to theta burst stimulation (TBS) in vivo in the human. TBS applied on consecutive days can be used to measure metaplasticity (the ability of the synapse to undergo a second plastic change following a recent induction of plasticity). The current study investigated intracortical inhibition, plasticity and metaplasticity in full mutation females with FXS, participants with autism spectrum disorders (ASD), and neurotypical controls. Results suggest that intracortical inhibition is normal in participants with FXS, while plasticity and metaplasticity appear abnormal. ASD participants showed abnormalities in plasticity and metaplasticity, as well as heterogeneity in intracortical inhibition. Our findings highlight the utility of non-invasive neurophysiological measures to translate insights from animal models to humans with neurodevelopmental disorders, and thus provide direct confirmation of cortical dysfunction in patients with FXS and ASD

Why are scientists not managers!?:the importance of interdisciplinary skills in business and science

Research is the translation from money to knowledge. Innovation is the metamorphosis of knowledge to money. Thus, business management and science are interdependent. That is no big news. But, in an ever faster changing economy, companies need a new type of scientist. Someone who knows not only science, but also business administration and management. Can the educational system satisfy those needs? In our opinion more work needs to be done – especially in the minds of scientists and managers alike

Compound heterozygosity of predicted loss-of-function DES variants in a family with recessive desminopathy

Background: Variants in the desmin gene (DES) are associated with desminopathy; a myofibrillar myopathy mainly characterized by muscle weakness, conduction block, and dilated cardiomyopathy. To date, only ~50 disease-associated variants have been described, and the majority of these lead to dominant-negative effects. However, the complete genotypic spectrum of desminopathy is not well established. Case presentation: Next-generation sequencing was performed on 51 cardiac disease genes in a proband with profound skeletal myopathy, dilated cardiomyopathy, and respiratory dysfunction. Our analyses revealed compound heterozygous DES variants, both of which are predicted to lead to a loss-of-function. Consistent with recessive inheritance, each variant was identified in an unaffected parent. Conclusions: This case report serves to broaden the variant spectrum of desminopathies and provides insight into the molecular mechanisms of desminopathy, supporting distinct dominant-negative and loss-of-function etiologies

Urban informality and confinement: toward a relational framework

In the 21st century, a growing number of people live ‘informal’ lives within fissures between legality and informality. Concomitantly, power relations are increasingly expressed through devices of confinement. While urban informality and confinement are on the rise often occurring simultaneously, scholars have so far studied them separately. By contrast, this article proposes a new framework for analysing urban informality and confinement relationally. It generates new insights into the role of informality in the (re)production of confinement and, vice versa, the role of confinement in shaping informal practices. While these insights are valuable for urban studies in general, the article charts new lines of research on urban marginality. It also discusses how the six articles included in this special issue signal the heuristic potential of this relational framework by empirically examining distinct urban configurations of ‘confined informalities’ and ‘informal confinements’ across the Global North and the Global South

Acute Infection and Subsequent Subclinical Reactivation of Herpes Simplex Virus 2 after Vaginal Inoculation of Rhesus Macaques.

Herpes simplex virus 2 (HSV-2) is a common sexually transmitted infection with a highly variable clinical course. Many infections quickly become subclinical, with episodes of spontaneous virus reactivation. To study host-HSV-2 interactions, an animal model of subclinical HSV-2 infection is needed. In an effort to develop a relevant model, rhesus macaques (RM) were inoculated intravaginally with two or three HSV-2 strains (186, 333, and/or G) at a total dose of 1 × 107 PFU of HSV-2 per animal. Infectious HSV-2 and HSV-2 DNA were consistently shed in vaginal swabs for the first 7 to 14 days after each inoculation. Proteins associated with wound healing, innate immunity, and inflammation were significantly increased in cervical secretions immediately after HSV-2 inoculation. There was histologic evidence of acute herpesvirus pathology, including acantholysis in the squamous epithelium and ballooning degeneration of and intranuclear inclusion bodies in epithelial cells, with HSV antigen in mucosal epithelial cells and keratinocytes. Further, an intense inflammatory infiltrate was found in the cervix and vulva. Evidence of latent infection and reactivation was demonstrated by the detection of spontaneous HSV-2 shedding post-acute inoculation (102 to 103 DNA copies/swab) in 80% of RM. Further, HSV-2 DNA was detected in ganglia in most necropsied animals. HSV-2-specifc T-cell responses were detected in all animals, although antibodies to HSV-2 were detected in only 30% of the animals. Thus, HSV-2 infection of RM recapitulates many of the key features of subclinical HSV-2 infection in women but seems to be more limited, as virus shedding was undetectable more than 40 days after the last virus inoculation.IMPORTANCE Herpes simplex virus 2 (HSV-2) infects nearly 500 million persons globally, with an estimated 21 million incident cases each year, making it one of the most common sexually transmitted infections (STIs). HSV-2 is associated with increased human immunodeficiency virus type 1 (HIV-1) acquisition, and this risk does not decline with the use of antiherpes drugs. As initial acquisition of both HIV and HSV-2 infections is subclinical, study of the initial molecular interactions of the two agents requires an animal model. We found that HSV-2 can infect RM after vaginal inoculation, establish latency in the nervous system, and spontaneously reactivate; these features mimic some of the key features of HSV-2 infection in women. RM may provide an animal model to develop strategies to prevent HSV-2 acquisition and reactivation

Choice between sequences of fixed-ratio schedules: effects of ratio values and probability of food delivery.

Pigeons were exposed to schedules of food delivery that consisted of two sequential fixed ratios. When alternative sequences provided two food deliveries per 50 responses, the schedule with the shorter initial fixed-ratio value was consistently preferred. Progressively reducing from 1.0 to .25 the probability of food delivery following completion of the second fixed ratio of the sequence with the shorter initial fixed ratio did not reduce preference for this sequence. Moreover, the sequence with the shorter initial fixed ratio also was preferred when the probability of food delivery following completion of the initial ratio in that sequence was progressively reduced from 1.0 to .5, although preference shifted to the alternative when the probability was reduced to 0. These findings suggest that the length of the initial fixed ratio was a primary determinant of choice. Subsequent manipulations demonstrated, however, that when the initial fixed ratios of the two alternatives were equal, changes in the ratio value and probability of food delivery following completion of the second fixed ratio lawfully affected choice

Precision measurement of the neutron β-decay asymmetry

A new measurement of the neutron β-decay asymmetry A_0 has been carried out by the UCNA Collaboration using polarized ultracold neutrons (UCNs) from the solid deuterium UCN source at the Los Alamos Neutron Science Center. Improvements in the experiment have led to reductions in both statistical and systematic uncertainties leading to A_0=−0.11954(55)_(stat)(98)_(syst), corresponding to the ratio of axial-vector to vector coupling λ ≡ g_A/g_V = −1.2756(30)