AKR1A1 Variant Associated With Schizophrenia Causes Exon Skipping, Leading to Loss of Enzymatic Activity

Schizophrenia is a heterogeneous psychiatric disorder characterized by positive symptoms such as hallucinations and delusions, negative symptoms such as anhedonia and flat affect, and cognitive impairment. Recently, glucuronate (GlucA) levels were reported to be significantly higher in serum of patients with schizophrenia than those in healthy controls. The accumulation of GlucA is known to be related to treatment-resistant schizophrenia, since GlucA is known to promote drug excretion by forming conjugates with drugs. However, the cause of GlucA accumulation remains unclear. Aldo-keto reductase family one member A1 (AKR1A1) is an oxidoreductase that catalyzes the reduction of GlucA. Genetic loss of AKR1A1 function is known to result in the accumulation of GlucA in rodents. Here, we aimed to explore genetic defects in AKR1A1 in patients with schizophrenia, which may result in the accumulation of GlucA. We identified 28 variants of AKR1A1 in patients with schizophrenia and control subjects. In particular, we identified a silent c.753G > A (rs745484618, p. Arg251Arg) variant located at the first position of exon 8 to be associated with schizophrenia. Using a minigene assay, we found that the c.753G > A variant induced exon 8 skipping in AKR1A1, resulting in a frameshift mutation, which in turn led to truncation of the AKR1A1 protein. Using the recombinant protein, we demonstrated that the truncated AKR1A1 completely lost its activity. Furthermore, we showed that AKR1A1 mRNA expression in the whole blood cells of individuals with the c.753G > A variant tended to be lower than that in those without the variants, leading to lower AKR activity. Our findings suggest that AKR1A1 carrying the c.753G > A variant induces exon skipping, leading to a loss of gene expression and enzymatic activity. Thus, GlucA patients with schizophrenia with the c.753G > A variant may show higher GlucA levels, leading to drug-resistant schizophrenia, since drug excretion by GlucA is enhanced.

Toxic YouTubers “hated” by Doctor Who? Animating multiphrenic incarnations of Not My Doctor anti-fandom

This article considers how popular/spreadable misogyny enters into Doctor Who fans’ discourse communities via fan-cultural appropriation, mixing external political and internal fan discourses. This can oppose fannish communal norms such as “convivial evaluation” and “ante-fandom”. The theoretical perspective taken in the article combines work on toxic fandom with anti-fandom to thus understand fan toxicity as “multiphrenic”, i.e. drawing on multiple discourses and self-investments, including responding to its own anti-fans. The article goes on to examine YouTube voiceover-commentary videos from one communally-prominent Whotuber representing Not My Doctor anti-fandom, showing how they use devices such as the acousmetre and “stripped down” subjectivity to open a projective space for toxic fandom and enact a flat affect characterising what is termed “performative rationality”. Crucially, leftwing narratives of toxicity and hate are completely inverted to the extent that Doctor Who and the BBC are presumed, without evidence, to “hate” straight white male conservative fandom.

Konseling untuk mengurangi inferioritas pada pasien skizofrenia

Schizophrenia is a thought disorder that is not interconnected, the presence of erroneous perceptions, flat affect, withdrawal from the social environment, and failed functioning of life. This study examines the effect of Adlerian counseling to reduce feelings of inferiority in Schizophrenic patients. The assessment method used in this study is interview, observation, psychological tests namely Graphics Test, SSCT, WWQ, TAT, and WAIS. The intervention was given using counseling with the Adler approach which consisted of nine sessions. The results of the intervention showed that the inferior subject could be reduced, which was indicated by no longer being ashamed to talk to women, being able to find an understanding that he had implemented the wrong lifestyle all this time. Subjects also become more active.

Autistic Adults May Be Erroneously Perceived as Deceptive and Lacking Credibility

We hypothesized that autistic adults may be erroneously judged as deceptive or lacking credibility due to demonstrating unexpected and atypical behaviors. Thirty autistic and 29 neurotypical individuals participated in video-recorded interviews, and we measured their demonstration of gaze aversion, repetitive body movements, literal interpretation of figurative language, poor reciprocity, and flat affect. Participants (N = 1410) viewed one of these videos and rated their perception of the individual’s truthfulness or credibility. The hypothesis was partially supported, with autistic individuals perceived as more deceptive and less credible than neurotypical individuals when telling the truth. However, this relationship was not influenced by the presence of any of the target behaviors, but instead, by the individual’s overall presentation.

The Deficit of Multimodal Perception of Congruent and Non-Congruent Fearful Expressions in Patients with Schizophrenia: The ERP Study

Emotional dysfunction, including flat affect and emotional perception deficits, is a specific symptom of schizophrenia disorder. We used a modified multimodal odd-ball paradigm with fearful facial expressions accompanied by congruent and non-congruent emotional vocalizations (sounds of women screaming and laughing) to investigate the impairment of emotional perception and reactions to other people’s emotions in schizophrenia. We compared subjective ratings of emotional state and event-related potentials (EPPs) in response to congruent and non-congruent stimuli in patients with schizophrenia and healthy controls. The results showed the altered multimodal perception of fearful stimuli in patients with schizophrenia. The amplitude of N50 was significantly higher for non-congruent stimuli than congruent ones in the control group and did not differ in patients. The P100 and N200 amplitudes were higher in response to non-congruent stimuli in patients than in controls, implying impaired sensory gating in schizophrenia. The observed decrease of P3a and P3b amplitudes in patients could be associated with less attention, less emotional arousal, or incorrect interpretation of emotional valence, as patients differed from healthy controls in the emotion scores of non-congruent stimuli. The difficulties in identifying the incoherence of facial and audial components of emotional expression could be significant in understanding the psychopathology of schizophrenia.

The utility of proton MR spectroscopy in diagnosing B cell lymphoma.

e13536 Background: Diffuse Large B Cell Lymphoma (DLBCL) is the most common and increasingly prevalent subtype of Non-Hodgkin lymphoma in both immunocompromised and immunocompetent patients. Its pathogenesis is thought to represent rearrangements, translocations, and transformations of both the immunoglobulin heavy and light chain genes along with somatic mutations of the variable regions of these same genes. A 66-year old Caucasian male with a past medical history of smoking presented to the hospital due to concerns of mental status change, flat affect, and fronto-orbital headache for one-week duration. The patient denied any drug or substance abuse. Physical exam was diffusely normal with the exception of flat affect. Methods: Magnetic resonance spectroscopy is a noninvasive, non-ionizing diagnostic analytical technique that has been used to measure metabolic changes in brain lesions. Results: Lhermitte’s sign was negative and NIH stroke scale was calculated to be 0. CT demonstrated a 17mm frontal lobe lesion. Follow up with MRI showed three bilateral enhancing brain lesions, but no metastasis or primary tumor was seen via CT of chest, abdomen, and pelvis. Initial differential diagnosis included: Tumefactive Multiple Sclerosis, Acute Demyelinating Encephalomyelitis or CNS lymphoma. EEG did not highlight any focal or epileptiform abnormalities and lumbar puncture was negative for Creutzfeld Jacob Disease and Multiple Sclerosis. The patient was discharged with a course of intravenous steroids only to present a few weeks later with no improvement of symptoms. The patient then had proton magnetic resonance spectroscopy (MRS). MRS pattern spikes and chemical profile suggested lymphoma, which was confirmed by a brain biopsy. The patient was subsequently transferred to the University of Pennsylvania for treatment and further management. Conclusions: This case illustrates the beneficial use of MRS, as data patterns it provides compliments the clinician’s knowledge to proceed with appropriate treatment.

Voice Patterns in Schizophrenia: A systematic Review and Bayesian Meta-Analysis

Voice atypicalities have been a characteristic feature of schizophrenia since its first definitions. They are often associated with core negative symptoms such as flat affect and alogia, and with the social impairments seen in the disorder. This suggests that voice atypicalities may represent a marker of clinical features and social functioning in schizophrenia. We systematically reviewed and meta-analyzed the evidence for distinctive acoustic patterns in schizophrenia, as well as their relation to clinical features. We identified 46 articles, including 55 studies with a total of 1254 patients with schizophrenia and 699 healthy controls. Summary effect sizes (Hedges’g and Pearson’s r) estimates were calculated using multilevel Bayesian modeling. We identified weak atypicalities in pitch variability (g = - 0.55) related to flat affect, and stronger atypicalities in proportion of spoken time, speech rate, and pauses (g’s between -0.75 and -1.89) related to alogia and flat affect. However, the effects were mostly modest (with the important exception of pause duration) compared to perceptual and clinical judgments, and characterized by large heterogeneity between studies. Moderator analyses revealed that tasks with a more demanding cognitive and social component showed larger effects both in contrasting patients and controls and in assessing symptomatology. In conclusion, studies of acoustic patterns are a promising but, yet unsystematic avenue for establishing markers of schizophrenia. We outline recommendations towards more cumulative, open, and theory-driven research.

Current Concepts and Treatments of Schizophrenia

Schizophrenia is a debilitating mental illness which involves three groups of symptoms, i.e., positive, negative and cognitive, and has major public health implications. According to various sources, it affects up to 1% of the population. The pathomechanism of schizophrenia is not fully understood and current antipsychotics are characterized by severe limitations. Firstly, these treatments are efficient for about half of patients only. Secondly, they ameliorate mainly positive symptoms (e.g., hallucinations and thought disorders which are the core of the disease) but negative (e.g., flat affect and social withdrawal) and cognitive (e.g., learning and attention disorders) symptoms remain untreated. Thirdly, they involve severe neurological and metabolic side effects and may lead to sexual dysfunction or agranulocytosis (clozapine). It is generally agreed that the interactions of antipsychotics with various neurotransmitter receptors are responsible for their effects to treat schizophrenia symptoms. In particular, several G protein-coupled receptors (GPCRs), mainly dopamine, serotonin and adrenaline receptors, are traditional molecular targets for antipsychotics. Comprehensive research on GPCRs resulted in the exploration of novel important signaling mechanisms of GPCRs which are crucial for drug discovery: intentionally non-selective multi-target compounds, allosteric modulators, functionally selective compounds and receptor oligomerization. In this review, we cover current hypotheses of schizophrenia, involving different neurotransmitter systems, discuss available treatments and present novel concepts in schizophrenia and its treatment, involving mainly novel mechanisms of GPCRs signaling.