On the origin of schizophrenia: Testing evolutionary theories in the post‐genomic era

Considering the relatively high heritability of schizophrenia and the fact that it significantly reduces the reproductive fitness of affected individuals, it is not clear how the disorder is still maintained in human populations at a disproportionally high prevalence. Many theories propose that the disorder is a result of a trade‐off between costs and benefits of the evolution of exclusively human adaptations. There have also been suggestions that schizophrenia risk alleles are accompanied with increase in fitness of affected persons or their relatives in both past and current social contexts. The discoveries of novel schizophrenia‐related genes and the advancements in comparative genomics (especially comparisons of the human genome and the genomes of related species, such as chimpanzees and extinct hominids) have finally made certain evolutionary theories testable. In this paper, we review the current understanding of the genetics of schizophrenia, the basic principles of evolution that complement our understanding of the subject, and the latest genetic studies that examine long‐standing evolutionary theories of schizophrenia using novel methodologies and data. We find that the origin of schizophrenia is complex and likely governed by different evolutionary mechanisms that are not mutually exclusive. Furthermore, the most recent evidence implies that schizophrenia cannot be comprehended as a trait that has elevated fitness in human evolutionary lineage, but has been a mildly deleterious by‐product of specific patterns of the evolution of the human brain. In other words, novel findings do not support previous hypotheses stating that schizophrenia risk genes have an evolutionary advantage.     

Prevention of antigen-induced microtubule organizing center reorientation in cytotoxic T cells by modulation of protein kinase C activity

Lysis of target cells (TC) by cytotoxic T lymphocytes (CTL) is achieved by directional exocytosis of cytolytic molecules-perforin and granzymes. They are stored within lytic granules which can be readily released following antigenic stimulation. Secretion of lytic molecules appears to be controlled by protein kinase C (PKC) activity, since specific modulators of PKC activity abolish the lysis of TC. We have examined the effect of PKC modulation on some of the earliest events in the perforin/granzyme-mediated cytotoxicity. De novo synthesis of perforin mRNA, required for the refilling of granules and sustained cytotoxicity, seems to be unaltered in the presence of PKC modulators. Immunofluorescent studies of CTL-TC conjugates revealed that PKC modulation impairs reorientation of the microtubule organizing center toward the contact point with the TC, which accounts for the specific direction of lytic granules exocytosis. Thus, it appears that PKC regulates exocytosis of lytic granules by governing microtubule reorganization, one of the initial steps in perforin/granzyme-mediated cytotoxicity.      

Alcohol and the appetizer effect

In order to evaluate the effects of alcohol on appetite, 12 unrestrained and 10 restrained men ate lunch 20 min after consuming preloads consisting of water, an alcoholic fruit juice (alcohol) and a non-alcoholic fruit juice (juice). The unrestrained men ate significantly less after the juice preload, and ate most after alcohol. Intake was not altered significantly in the restrained men. However, both the alcohol and juice preloads reduced rated hunger and increased fullness, relative to the water control, in both restrained and unrestrained men. When the relationship between rated appetite and intake within the test meal was modelled mathematically, it was found that hunger increased more during the initial stages of the test meal in the unrestrained men who had consumed alcohol than in any other condition. No such effects were seen in the restrained subjects. Overall, these results suggest that alcohol has a complex action on appetite, which includes some form of appetite stimulation, and this may explain the excess energy intake reported previously in moderate alcohol consumers.     

Oral teicoplanin versus oral vancomycin for the treatment of severe <Emphasis Type="Italic">Clostridium difficile</Emphasis> infection: a prospective observational study

The aim of this study was to compare clinical cure rate, recurrence rate and time to resolution of diarrhea in patients with severe and severe-complicated Clostridium difficile infection (CDI) treated with teicoplanin or vancomycin. This two-year prospective observational study included patients with first episode or first recurrence of CDI who had severe or severe-complicated CDI and were treated with teicoplanin or vancomycin. Primary outcomes of interest were clinical cure rate at discharge and recurrence rate after eight weeks follow up, and secondary outcomes were all-cause mortality and time to resolution of diarrhea. Among 287 study patients, 107 were treated with teicoplanin and 180 with vancomycin. The mean age of patients was 73.5?±?10.6 years. One hundred eighty six patients (64.8%) had prior CDI episode. Severe complicated disease was detected in 23/107 (21.5%) and 42/180 (23.3%) patients treated with teicoplanin and vancomycin, respectively. There was no statistically significant difference in time to resolution of diarrhea between two treatment arms (6.0?±?3.4 vs 6.2?±?3.1 days, p?=?0.672). Treatment with teicoplanin resulted in significantly higher clinical cure rate compared to vancomycin [90.7% vs 79.4%, p?=?0.013, odds ratio (OR) (95% confidence interval (CI)) 2.51 (1.19–5.28)]. Recurrence rates were significantly lower in patients treated with teicoplanin [9/97 (9.3%) vs 49/143 (34.3%), p?<?0.001, OR (95%CI) 0.20 (0.09–0.42)]. There was no statistically significant difference in overall mortality rate. Teicoplanin might be a good treatment option for patients with severe CDI. Patients treated with teicoplanin experienced remarkably lower recurrence rates compared to vancomycin-treated patients.     

Comparison of cartilage histopathology assessment systems on human knee joints at all stages of osteoarthritis development

ObjectiveTo compare the MANKIN and OARSI cartilage histopathology assessment systems using human articular cartilage from a large number of donors across the adult age spectrum representing all levels of cartilage degradation.DesignHuman knees (n = 125 from 65 donors; age range 23–92) were obtained from tissue banks. All cartilage surfaces were macroscopically graded. Osteochondral slabs representing the entire central regions of both femoral condyles, tibial plateaus, and the patella were processed for histology and Safranin O – Fast Green staining. Slides representing normal, aged, and osteoarthritis (OA) tissue were scanned and electronic images were scored online by five observers. Statistical analysis was performed for inter- and intra-observer variability, reproducibility and reliability.ResultsThe inter-observer variability among five observers for the MANKIN system showed a similar good Intra-class correlation coefficient (ICC > 0.81) as for the OARSI system (ICC > 0.78). Repeat scoring by three of the five readers showed very good agreement (ICC > 0.94). Both systems showed a high reproducibility among four of the five readers as indicated by the Spearman’s rho value. For the MANKIN system, the surface represented by lesion depth was the parameter where all readers showed an excellent agreement. Other parameters such as cellularity, Safranin O staining intensity and tidemark had greater inter-reader disagreement.ConclusionBoth scoring systems were reliable but appeared too complex and time consuming for assessment of lesion severity, the major parameter determined in standardized scoring systems. To rapidly and reproducibly assess severity of cartilage degradation, we propose to develop a simplified system for lesion volume.     

High risk of hypopituitarism in patients who recovered from hemorrhagic fever with renal syndrome

CONTEXT: Hemorrhagic fever with renal syndrome (HFRS) caused by hantaviruses, is a severe systemic infection, with acute shock, vascular leakage, hypotension, and acute renal failure. Pituitary ischemia/infarction and necrosis are known causes of hypopituitarism, often remaining unrecognized due to subtle clinical manifestations. Cases of hypopituitarism after HFRS were previously only sporadically reported. OBJECTIVE: The aim of this study was to determine, for the first time, the prevalence of hypopituitarism among HFRS survivors. SUBJECTS AND METHODS: In 60 adults (aged 35.8+/-1.3 yr) who recovered from HFRS 3.7 +/- 0.5 yr ago (median 2 yr), assessment of serum T(4), free T(4), TSH, IGF-I, prolactin, cortisol, and testosterone (in males) was followed by insulin tolerance test and/or GHRH+GH-releasing peptide-6 stimulation tests. RESULTS: Severe GH deficiency was confirmed in eight of 60 patients (13.3%): in five with multiple pituitary hormone deficiencies (MPHDs) and isolated in three. Thyroid axis deficiency was confirmed in five of 60 patients (8.3%), all with MPHD. Hypothalamus-pituitary-adrenal axis deficiency was observed in six of 60 (10.0%); in five with MPHD and isolated in one. Gonadal axis deficiency was confirmed in seven of 56 male subjects (12.5%): five with MPHD and isolated in two. Overall six patients (10.0%) had a single pituitary deficit (three GH, two gonadal, and one adrenal), and five (8.3%) had MPHD. The prevalence of patients having any endocrine deficiency was 18% (11 of 60). CONCLUSION: A high prevalence of hypopituitarism after recovery from HFRS is identified, with magnetic resonance imaging revealing atrophic pituitary and empty sella. Awareness is raised to neuroendocrine consequences of HFRS because unrecognized hypopituitarism significantly affects the physical and psychological well-being.     

Predictive factors of recurrence after pediatric acute pericarditis

ObjectiveThe predisposing factors for pericarditis recurrence in the pediatric population have not yet been established. This study aimed to define the risk factors for the unfavorable prognosis of pediatric acute pericarditis.MethodsThis was a retrospective study that included all patients with acute pericarditis treated from 2011 to 2019 at a tertiary referent pediatric center.ResultsThe study included 72 children. Recurrence was observed in 22.2% patients. Independent risk factors for recurrence were: erythrocyte sedimentation rate ≥ 50 mm/h (p = 0.003, OR 186.3), absence of myocarditis (p = 0.05, OR 15.2), C-reactive protein ≥ 125 mg/L (p = 0.04, OR 1.5), and non-idiopathic etiology pericarditis (p = 0.003, OR 1.3). Corticosteroid treatment in acute pericarditis was associated with a higher recurrence rate than treatment with non-steroid anti-inflammatory therapy (p = 0.04). Furthermore, patients treated with colchicine in the primary recurrence had lower recurrence rate and median number of repeated infections than those treated without colchicine (p = 0.04; p = 0.007, respectively).ConclusionIndependent risk factors for recurrence are absence of myocarditis, non-idiopathic etiology pericarditis, C-reactive protein ≥ 125 mg/L, and erythrocyte sedimentation rate ≥ 50 mm/h. Acute pericarditis should be treated with non-steroid anti-inflammatory therapy. A combination of colchicine and non-steroid anti-inflammatory drugs could be recommended as the treatment of choice in recurrent pericarditis.     

Gender specific effects of a mild stressor on alcohol cue reactivity in heavy social drinkers

RATIONALE: Stress plays an important role in the development and maintenance of alcohol-abuse. Some of the effects of stress on alcohol-related behaviours, however, appear to be gender-dependent. AIM: The present study set out to examine the effects of stress on feelings of desire for alcohol, skin conductance response and alcohol consumption in the presence of alcohol-related cues in relation to gender. Participants were heavy non-dependent alcohol drinkers. METHODS: Thirty-two (16 males) participants drinking more than 21 units of alcohol per week were randomly allocated to undergo the experimental stress (based on the 'Trier Social Stress' Test) or the non-stress procedure before the alcohol cue exposure procedure, during which participants handled and smelled their preferred drink. Mood and saliva cortisol level changes were used as indices of the stress effects, while alcohol craving, skin conductance and alcohol consumption were the cue reactivity measures. RESULTS: Self ratings of anxiety and tension increased and cortisol levels remained high in the stress compared to the non-stress condition; no gender differences were found. Stress induced gender-specific effects with regard to skin conductance response and alcohol consumption measurements. Stressed females did not show an increase from baseline in the skin conductance response during the alcohol cue-exposure session, which was observed in the non-stressed females; they also consumed less alcohol than males under stress. CONCLUSION: Female participants respond less to alcohol-related cues when in a negative mood state. Such a finding suggests that females when in a negative mood may be less sensitive to positive incentive processes mediating cue reactivity compared to males.