Morpho-electric diversity of human hippocampal CA1 pyramidal neurons.

Hippocampal pyramidal neuron activity underlies episodic memory and spatial navigation. Although extensively studied in rodents, extremely little is known about human hippocampal pyramidal neurons, even though the human hippocampus underwent strong evolutionary reorganization and shows lower theta rhythm frequencies. To test whether biophysical properties of human Cornu Amonis subfield 1 (CA1) pyramidal neurons can explain observed rhythms, we map the morpho-electric properties of individual CA1 pyramidal neurons in human, non-pathological hippocampal slices from neurosurgery. Human CA1 pyramidal neurons have much larger dendritic trees than mouse CA1 pyramidal neurons, have a large number of oblique dendrites, and resonate at 2.9 Hz, optimally tuned to human theta frequencies. Morphological and biophysical properties suggest cellular diversity along a multidimensional gradient rather than discrete clustering. Across the population, dendritic architecture and a large number of oblique dendrites consistently boost memory capacity in human CA1 pyramidal neurons by an order of magnitude compared to mouse CA1 pyramidal neurons.

Opportunities and Challenges of Prognostic Models for Extremely Preterm Infants.

Predicting the short- and long-term outcomes of extremely preterm infants remains a challenge. Multivariable prognostic models might be valuable tools for clinicians, parents, and policymakers for providing accurate outcome estimates. In this perspective, we discuss the opportunities and challenges of using prognostic models in extremely preterm infants at population and individual levels. At a population level, these models could support the development of guidelines for decisions about treatment limits and may support policy processes such as benchmarking and resource allocation. At an individual level, these models may enhance prenatal counselling conversations by considering multiple variables and improving transparency about expected outcomes. Furthermore, they may improve consistency in projections shared with parents. For the development of prognostic models, we discuss important considerations such as predictor and outcome measure selection, clinical impact assessment, and generalizability. Lastly, future recommendations for developing and using prognostic models are suggested. Importantly, the purpose of a prognostic model should be clearly defined, and integrating these models into prenatal counselling requires thoughtful consideration.

Genes associated with cognitive ability and HAR show overlapping expression patterns in human cortical neuron types.

GWAS have identified numerous genes associated with human cognition but their cell type expression profiles in the human brain are unknown. These genes overlap with human accelerated regions (HARs) implicated in human brain evolution and might act on the same biological processes. Here, we investigated whether these gene sets are expressed in adult human cortical neurons, and how their expression relates to neuronal function and structure. We find that these gene sets are preferentially expressed in L3 pyramidal neurons in middle temporal gyrus (MTG). Furthermore, neurons with higher expression had larger total dendritic length (TDL) and faster action potential (AP) kinetics, properties previously linked to intelligence. We identify a subset of genes associated with TDL or AP kinetics with predominantly synaptic functions and high abundance of HARs.

A Tailored Approach for Justice Involved Youth With an Intellectual Disability: The Suitability of a Small-Scale Community-Integrated Approach.

Youngsters with intellectual disabilities are overinvolved within the youth justice system. The aim of this study was to explore the suitability of a small-scale community-integrated approach for justice involved youngsters with intellectual disabilities. This study compared the numbers of transfers, the number, type, and rate of change in incidents, and the possible mediating effect of resilience thereon, between 40 youngsters with and 19 youngsters without intellectual disabilities, placed in a small-scale facility. There were no differences in the number of transfers, the number, type, and rate of change in incidents, and no mediating effect of resilience was found. A small-scale community integrated approach for youth justice facilities can be suited to provide tailored placement for youngsters with intellectual disabilities, given the presence of protective factors and motivation. Both youngsters with and without intellectual disabilities showed a low number of incidents and were able to continue or initiate structural daytime activities.

Experiences with tailoring of primary diabetes care in well-organised general practices: a mixed-methods study.

BACKGROUND: Dutch standard diabetes care is generally protocol-driven. However, considering that general practices wish to tailor diabetes care to individual patients and encourage self-management, particularly in light of current COVID-19 related constraints, protocols and other barriers may hinder implementation. The impact of dispensing with protocol and implementation of self-management interventions on patient monitoring and experiences are not known. This study aims to evaluate tailoring of care by understanding experiences of well-organised practices 1) when dispensing with protocol; 2) determining the key conditions for successful implementation of self-management interventions; and furthermore exploring patients' experiences regarding dispensing with protocol and self-management interventions. METHODS: in this mixed-methods prospective study, practices (n = 49) were invited to participate if they met protocol-related quality targets, and their adult patients with well-controlled type 2 diabetes were invited if they had received protocol-based diabetes care for a minimum of 1 year. For practices, study participation consisted of the opportunity to deliver protocol-free diabetes care, with selection and implementation of self-management interventions. For patients, study participation provided exposure to protocol-free diabetes care and self-management interventions. Qualitative outcomes (practices: 5 focus groups, 2 individual interviews) included experiences of dispensing with protocol and the implementation process of self-management interventions, operationalised as implementation fidelity. Quantitative outcomes (patients: routine registry data, surveys) consisted of diabetes monitoring completeness, satisfaction, wellbeing and health status at baseline and follow-up (24 months). RESULTS: Qualitative: In participating practices (n = 4), dispensing with protocol encouraged reflection on tailored care and selection of various self-management interventions A focus on patient preferences, team collaboration and intervention feasibility was associated with high implementation fidelity Quantitative: In patients (n = 126), likelihood of complete monitoring decreased significantly after two years (OR 0.2 (95% CI 0.1-0.5), p < 0.001) Satisfaction decreased slightly (- 1.6 (95% CI -2.6;-0.6), p = 0.001) Non-significant declines were found in wellbeing (- 1.3 (95% CI -5.4; 2.9), p = 0.55) and health status (- 3.0 (95% CI -7.1; 1.2), p = 0.16). CONCLUSIONS: To tailor diabetes care to individual patients within well-organised practices, we recommend dispensing with protocol while maintaining one structural annual monitoring consultation, combined with the well-supported implementation of feasible self-management interventions. Interventions should be selected and delivered with the involvement of patients and should involve population preferences and solid team collaborations.

Associations between olfactory identification and (social) cognitive functioning: A cross-sectional study in schizophrenia patients and healthy controls.

Schizophrenia patients have difficulties identifying odors, possibly a marker of cognitive and social impairment. This study investigated olfactory identification (OI) differences between patients and controls, related to cognitive and social functioning in childhood and adolescence, to present state cognition and to present state social cognition. 132 schizophrenia patients and 128 healthy controls were assessed on OI performance with the Sniffin' Sticks task. Multiple regression analyses were conducted investigating OI in association with cognitive and social functioning measures in childhood/adolescence and in association with IQ, memory, processing speed, attention, executive functioning, face recognition, emotion recognition and theory of mind. Patients had reduced OI performance compared to controls. Also, patients scored worse on childhood/adolescence cognitive and social functioning, on present state cognitive functioning and present state social cognition compared to controls. OI in patients and controls was significantly related to cognitive and social functioning in childhood/adolescence, to present state cognition and to present state social cognition, with worse functioning being associated with worse OI. In this study, findings of worse OI in patients relative to controls were replicated. We also showed associations between OI and cognitive and social functioning which are not specific to schizophrenia.

Gender Dysphoria and Co-Existing Psychosis: Review and Four Case Examples of Successful Gender Affirmative Treatment.

PURPOSE: Controversy exists as to if, and when, gender affirmative (GA) treatment should be offered to individuals with gender dysphoria (GD) and co-existing psychosis. Concerns exist regarding a high risk of misdiagnosis, regret afterward due to impulsive decision making, and deterioration of psychotic symptoms. This case series aims at extending the sparse literature on GA treatment in this population by identifying challenges in diagnosis and treatment and offering recommendations to overcome them. CASE SERIES: The authors present case descriptions of two transgender men and two transgender women in the age range of 29-57 years with a diagnosis of GD and a schizophrenia-related diagnosis. All had undergone GA treatment with a minimum follow-up of 3 years. The gender diagnosis was complicated by the fact that feelings of GD were only shared after the onset of psychosis, and GA treatment was hampered by the persistence of mild psychotic symptoms despite antipsychotic treatment. Close communication with the psychosis treating clinicians proved useful to address these problems. GA treatment was paralleled by a stabilization of psychotic symptoms, and adherence to and satisfaction with the therapy was high. CONCLUSION: These case examples show that GA treatment is possible and safe in this vulnerable population.

Association between olfactory identification and parkinsonism in patients with non-affective psychosis.

AIM: Olfactory identification deficits (OIDs) are seen in schizophrenia patients and individuals at increased risk for psychosis but its pathophysiology remains unclear. Although dopaminergic imbalance is known to lie at the core of schizophrenia symptomatology, its role in the development of OIDs has not been elucidated yet. This study investigated the association between OIDs and symptoms of parkinsonism as a derivative of dopaminergic functioning. METHODS: In 320 patients diagnosed with non-affective psychosis, olfactory identification performance was assessed by means of the Sniffin' Sticks task. Level of parkinsonian symptoms was assessed by means of the Unified Parkinson's Disease Rating Scale (UPDRS-III). By means of multiple linear regression with bootstrapping, the association between UPDRS and Sniffin' Sticks score was investigated while correcting for potential confounders. A Bonferroni corrected P-value of 0.007 was used. RESULTS: Higher UPDRS scores significantly predicted worse olfactory identification in patients with non-affective psychosis with an unadjusted b = -0.07 (95% CI -0.10 to -0.04) and an adjusted b = -0.04 (95% CI -0.07 to -0.01). CONCLUSION: Results provide preliminary evidence that the same vulnerability may underlie the development of parkinsonism and OIDs in patients with non-affective psychosis. Further investigation should evaluate the clinical value of OIDs as a marker of dopaminergic vulnerability that may predict psychosis.

[Delusional infestation, a therapeutic challenge]. / Parasieten- of infestatiewaan: een therapeutische uitdaging.

Delusional infestation, formally known as delusional parasitosis, poses a therapeutic challenge. This article provides tools to engage these patients with psychiatric treatment. We present two men aged 49 and 48 who saw the dermatologist with skin symptoms due to primary and secondary delusional infestation, respectively. Despite their anosognosia, both patients were successfully treated with antipsychotics thanks to the collaboration between dermatology and psychiatry. To increase the acceptability of treatment with antipsychotics, emphasis should be placed on their antipruritic properties and the effect on degree of preoccupation with the infection rather than their antipsychotic properties. Follow-up is important, as patients mostly do not attribute their recovery to antipsychotics and the risk of recurrence is high after cessation of antipsychotic medication.

Premorbid adjustment profiles in psychosis and the role of familial factors.

Disease heterogeneity in patients with psychotic disorder may be explained by distinct profiles of premorbid adjustment. The current study explored premorbid adjustment profiles in patients with psychotic disorders, associations with cognitive and clinical characteristics after disease onset, and the role of familial factors. A total of 666 patients with psychosis (predominantly schizophrenia), 673 siblings, 575 parents, and 585 controls were included in this study. Cluster analyses were performed on the patients' scores of the Premorbid Adjustment Scale (PAS), using information on domains (social, academic) and age epochs (childhood, early adolescence, late adolescence). Resulting profiles were compared with characteristics in patients and their unaffected relatives. Six clusters, labeled normal, social intermediate, academic decline, overall decline, overall intermediate, and overall impaired adjustment, were identified in patients. Patients in different clusters differed from each other on cognitive, clinical, and functional characteristics after disease onset. Heterogeneity in the patient population may be explained in part by the adjustment profile prior to disease onset. This is in line with theories that propose different etiologies in the development of psychosis. Patient profiles were expressed in unaffected siblings, suggesting a role for familial factors.

Is a schizo-obsessive subtype associated with cognitive impairment? Results from a large cross-sectional study in patients with psychosis and their unaffected relatives.

The current study investigated whether candidate cognitive endophenotypes may be used to validate a schizo-obsessive subtype. Using within-subject random effect regression analyses and cross-trait cross-relative analyses, we evaluated the association between obsessive-compulsive symptoms (OCSs) and cognitive performance in 984 patients with nonaffective psychosis (22.5% with OCSs), 973 unaffected siblings (7.7% with OCSs), 851 parents (4.2% with OCSs), and 573 controls (4.5% with OCSs). No significant within-subject associations between OCSs and cognitive functioning were found for patients and siblings. Severity of OCSs was associated with worse set-shifting ability in parents and worse processing speed in controls, but effect sizes were small (0.10 and 0.05 respectively). Cross-trait cross-relative analyses yielded no significant results. Contrary to our expectations, neither within-subject analyses nor cross-relative analyses yielded a clear association between OCSs and cognitive performance. Results do not support a schizo-obsessive subtype associated with cognitive impairment.

Striatal dopamine D2/3 receptor binding following dopamine depletion in subjects at Ultra High Risk for psychosis.

Altered striatal dopaminergic neurotransmission is thought to be fundamental to schizophrenia. Increased presynaptic dopaminergic activity ([18F]-DOPA PET) may predate the onset of psychotic symptoms and correlates to clinical symptoms in subjects at Ultra High Risk (UHR) for developing psychosis. Postsynaptic dopaminergic neurotransmission has not been investigated yet in UHR patients. We hypothesized that synaptic dopamine concentration would be increased in UHR patients, and that synaptic dopamine concentration would be related to symptom severity. 14 UHR patients and 15 age and IQ matched controls completed an [123I]-IBZM SPECT scan at baseline and again after dopamine depletion with alpha-methyl-para-tyrosine (AMPT). We measured changes in radiotracer binding potential, compared these between UHR patients and controls, and correlated these to symptom severity. The UHR group as a whole did not differ significantly from controls. AMPT significantly reduced symptom severity in the UHR group (p=0.014). Higher synaptic dopamine concentration predicted larger reduction of positive symptoms following depletion in the UHR group (p=0.01). In UHR patients, positive symptoms responded to dopamine depletion, comparable to observations in schizophrenia, suggesting a similar mechanism. Higher synaptic dopamine concentration was associated with more severe positive symptoms and a greater reduction of these symptoms following depletion.

White matter abnormalities in adults with 22q11 deletion syndrome with and without schizophrenia.

Dysfunction of cerebral white matter (WM) is a potential factor underlying the neurobiology of schizophrenia. People with 22q11 deletion syndrome have altered brain morphology and increased risk for schizophrenia, therefore decreased WM integrity may be related to schizophrenia in 22q11DS. We measured fractional anisotropy (FA) and WM volume in 27 adults with 22q11DS with schizophrenia (n=12, 22q11DS SCZ+) and without schizophrenia (n=15, 22q11DS SCZ-), 12 individuals with idiopathic schizophrenia and 31 age-matched healthy controls. We found widespread decreased WM volume in posterior and temporal brain areas and decreased FA in areas of the frontal cortex in the whole 22q11DS group compared to healthy controls. In 22q11DS SCZ+ compromised WM integrity included inferior frontal areas of parietal and occipital lobe. Idiopathic schizophrenia patients showed decreased FA in inferior frontal and insular regions compared to healthy controls. We found no WM alterations in 22q11DS SCZ+ vs. 22q11DS SCZ-. However, there was a negative correlation between FA and PANSS scores (Positive and Negative Symptom Scale) in the whole 22q11DS group in the inferior frontal, cingulate, insular and temporal areas. This is the first study to investigate WM integrity in adults with 22q11DS. Our results suggest that pervasive WM dysfunction is intrinsic to 22q11DS and that psychotic development in adults with 22q11DS involves similar brain areas as seen in schizophrenia in the general population.

Semantic fluency deficits and reduced grey matter before transition to psychosis: a voxelwise correlational analysis.

Early identification of subjects with an increased risk of psychosis is necessary to develop interventions to delay or prevent disease onset. We recently reported that decreased semantic verbal fluency performance in ultra high risk (UHR) subjects predicts the development of psychosis (Becker et al., 2010). The present study investigated whether semantic and verbal fluency scores correlate with grey matter density in UHR subjects. Thirty-seven UHR subjects underwent structural MRI scanning and verbal fluency assessment after which they were followed up for 2 years. Using voxel-based morphometry, we investigated whether grey matter density correlated with verbal fluency scores in 10 UHR subjects who developed psychosis during follow-up and 27 UHR subjects who did not develop psychosis. In UHR subjects developing psychosis, lower semantic fluency scores correlated significantly with reduced grey matter density in the right superior and middle temporal gyrus, the right insula, and the left anterior cingulate cortex. This study shows that a correlation between semantic fluency performance and grey matter density in task-related areas can differentiate between UHR subjects who subsequently will develop psychosis and those who will not. Combining these two measures could improve psychosis prediction in UHR subjects.

Dopamine metabolism in adults with 22q11 deletion syndrome, with and without schizophrenia--relationship with COMT Val¹°8/¹58Met polymorphism, gender and symptomatology.

22q11 Deletion syndrome (22q11DS) is a major risk factor for schizophrenia. In addition, both conditions are associated with alterations of the dopaminergic system. The catechol-O-methyltransferase (COMT) gene, located within the deleted region, encodes for the enzyme COMT that is important for degradation of catecholamines, including dopamine (DA). COMT activity is sexually dimorphic and its gene contains a functional polymorphism, Val¹°8/¹58 Met; the Met allele is associated with lower enzyme activity. We report the first controlled catecholamine study in 22q11DS-related schizophrenia. Twelve adults with 22q11DS with schizophrenia (SCZ+) and 22 adults with 22q11DS without schizophrenia (SCZ-) were genotyped for the COMT Val¹°8/¹58 Met genotype. We assessed dopaminergic markers in urine and plasma. We also correlated these markers with scores on the Positive and Negative Symptom Scale (PANSS). Contrary to our expectations, we found SCZ+ subjects to be more often Val hemizygous and SCZ- subjects more often Met hemizygous. Significant COMT cross gender interactions were found on dopaminergic markers. In SCZ+ subjects there was a negative correlation between prolactin levels and scores on the general psychopathology subscale of the PANSS scores. These findings suggest intriguing, but complex, interactions of the COMT Val¹°8/¹58 Met polymorphism, gender and additional factors on DA metabolism, and its relationship with schizophrenia.

In practice, the theory is different: a processual analysis of breastfeeding in northeast Brazil.

'Na prática, a teoria è outra' (in practice, the theory is different) is an old Brazilian saying. This phrase summarizes well the general practice of breastfeeding in Brazil: 'Breast is best' is central in the pregnant women's future oriented 'theory' of how their infant should be fed. In the subsequent weeks after delivery, however, in the daily practicalities of feeding their infant, this theory is, to a large extent, abandoned. The present study is based on a sample of 300 mothers in the city of Aracaju in the Northeast of Brazil. Through interviews, the differences and similarities between knowledge and practice with respect to infant feeding were established. An explanation of these differences is developed on the basis of a processual analysis of the qualitative and quantitative results of the interview data. Nearly all mothers were knowledgeable of the need to breastfeed, and nearly all mothers had initiated breastfeeding. However, only a minority was exclusively breastfeeding at the time of the interview. A distinction is made between a breastfeeding process and a de-breastfeeding process. The data suggest that mothers, in general, start the de-breastfeeding process with the positive intention of ameliorating the infant's situation without realizing the negative processual consequences that most likely ends in a cessation of breastfeeding. The study supports the view that health policy should underline the processual character of both breastfeeding and de-breastfeeding when promoting the importance of exclusive breastfeeding.

Inexpensive one-step purification of polypeptides expressed in Escherichia coli as fusions with the family 9 carbohydrate-binding module of xylanase 10A from T. maritima.

A novel inexpensive affinity purification technology is described based on recombinant expression in Escherichia coli of the polypeptide or protein target fused through its N-terminus to TmXyn10ACBM9-2 (CBM9), the C-terminal family 9 carbohydrate-binding module of xylanase 10A from Thermotoga maritima. Measured association constants (K(a)) for adsorption of CBM9 to insoluble allomorphs of cellulose are between 2 x 10(5) and 8 x 10(6) M(-1). CBM9 also binds a range of soluble sugars, including glucose. As a result, a 1M glucose solution is effective in eluting CBM9 and CBM9-tagged fusion proteins from a very inexpensive commercially-available cellulose-based capture column. A processing site is encoded at the C-terminus of the tag to facilitate its rapid and quantitative removal by Factor X(a) to recover the desired target protein sequence following affinity purification. Fusion of the CBM9 affinity tag to the N-terminus of green fluorescent protein (GFP) from the jellyfish, Aquorin victoria, is shown to yield >200 mgl(-1) of expressed soluble fusion protein that can be affinity separated from clarified cell lysate to a purity of >95% at a yield of 86%.