Associations between disturbed sleep and attenuated psychotic experiences in people at clinical high risk for psychosis.

BACKGROUND: Pre-diagnostic stages of psychotic illnesses, including 'clinical high risk' (CHR), are marked by sleep disturbances. These sleep disturbances appear to represent a key aspect in the etiology and maintenance of psychotic disorders. We aimed to examine the relationship between self-reported sleep dysfunction and attenuated psychotic symptoms (APS) on a day-to-day basis. METHODS: Seventy-six CHR young people completed the Experience Sampling Methodology (ESM) component of the European Union Gene-Environment Interaction Study, collected through PsyMate® devices, prompting sleep and symptom questionnaires 10 times daily for 6 days. Bayesian multilevel mixed linear regression analyses were performed on time-variant ESM data using the brms package in R. We investigated the day-to-day associations between sleep and psychotic experiences bidirectionally on an item level. Sleep items included sleep onset latency, fragmentation, and quality. Psychosis items assessed a range of perceptual, cognitive, and bizarre thought content common in the CHR population. RESULTS: Two of the seven psychosis variables were unidirectionally predicted by previous night's number of awakenings: every unit increase in number of nightly awakenings predicted a 0.27 and 0.28 unit increase in feeling unreal or paranoid the next day, respectively. No other sleep variables credibly predicted next-day psychotic symptoms or vice-versa. CONCLUSION: In this study, the relationship between sleep disturbance and APS appears specific to the item in question. However, some APS, including perceptual disturbances, had low levels of endorsement amongst this sample. Nonetheless, these results provide evidence for a unidirectional relationship between sleep and some APS in this population.

Increased illness burden in women with comorbid bipolar and premenstrual dysphoric disorder: data from 1 099 women from STEP-BD study.

BACKGROUND: The impact of comorbid premenstrual dysphoric disorder (PMDD) in women with bipolar disorder (BD) is largely unknown. AIMS: We compared illness characteristics and female-specific mental health problems between women with BD with and without PMDD. MATERIALS & METHODS: A total of 1 099 women with BD who participated in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were studied. Psychiatric diagnoses and illness characteristics were assessed using the Mini International Neuropsychiatric Interview. Female-specific mental health was assessed using a self-report questionnaire developed for STEP-BD. PMDD diagnosis was based on DSM-5 criteria. RESULTS: Women with comorbid BD and PMDD had an earlier onset of bipolar illness (P < 0.001) and higher rates of rapid cycling (P = 0.039), and increased number of past-year hypo/manic (P = 0.003), and lifetime/past-year depressive episodes (P < 0.05). Comorbid PMDD was also associated with higher proportion of panic disorder, post-traumatic stress disorder, generalized anxiety disorder, bulimia nervosa, substance abuse, and adult attention deficit disorder (all P < 0.05). There was a closer gap between BD onset and age of menarche in women with comorbid PMDD (P = 0.003). Women with comorbid PMDD reported more severe mood symptoms during the perinatal period and while taking oral contraceptives (P < 0.001). DISCUSSION: The results from this study is consistent with research suggesting that sensitivity to endogenous hormones may impact the onset and the clinical course of BD. CONCLUSIONS: The comorbidity between PMDD and BD is associated with worse clinical outcomes and increased illness burden.

The binding selectivity of vonoprazan (TAK-438) to the gastric H+, K+ -ATPase.

BACKGROUND: The gastric H(+) ,K(+) -ATPase is the preferred target for acid suppression. Until recently, the only drugs that effectively inhibited this ATPase were the proton pump inhibitors (PPIs). PPIs are acid-activated prodrugs that require acid protection. Once acid-activated, PPIs bind to cysteines of the ATPase, resulting in covalent, long-lasting inhibition. The short plasma half-life of PPIs and continual de novo synthesis of the H(+) ,K(+) -ATPase result in difficulty controlling night-time acid secretion. A new alternative to PPIs is the pyrrolo-pyridine, vonoprazan (TAK-438), a potassium-competitive acid blocker (PCAB) that does not require acid protection. In contrast to other PCABs, vonoprazan has a long duration of action, resulting in 24-h control of acid secretion, a high pKa of 9.37 and high affinity (Ki = 3.0 ηmol/L). AIM: To determine binding selectivity of vonoprazan for the gastric H(+) ,K(+) -ATPase and to explain its slow dissociation. METHODS: Gastric gland and parietal cell binding of vonoprazan was determined radiometrically. Molecular modelling explained the slow dissociation of vonoprazan from the H(+) ,K(+) -ATPase. RESULTS: Vonoprazan binds selectively to the parietal cell, independent of acid secretion. Vonoprazan binds in a luminal vestibule between the surfaces of membrane helices 4, 5 and 6. Exit of the drug to the lumen is hindered by asp137 and asn138 in the loop between TM1 and TM2, which presents an electrostatic barrier to movement of the sulfonyl group of vonoprazan. This may explain its slow dissociation from the H(+) ,K(+) -ATPase and long-lasting inhibition. CONCLUSION: The binding model provides a template for design of novel potassium-competitive acid blockers.

Colloidal bismuth subcitrate impedes proton entry into Helicobacter pylori and increases the efficacy of growth-dependent antibiotics.

BACKGROUND: Successful eradication of Helicobacter pylori is becoming more difficult, mainly due to emerging antibiotic resistance. Treatment regimens containing bismuth have increased efficacy, but the mechanism is unknown. Helicobacter pylori is a neutralophile adapted to survive the acidic gastric environment via acid acclimation, but demonstrates more robust growth at neutral pH. Many antibiotics used to treat H. pylori rely on bacterial growth. AIM: To investigate the mechanism of increased efficacy of bismuth-containing H. pylori treatment regimens. METHODS: RNAseq and qPCR, urease activity in permeabilised and intact bacteria, internal pH and membrane potential were measured with and without colloidal bismuth subcitrate (CBS). Bacterial survival was assessed with CBS and/or ampicillin. RESULTS: Genes involved with metabolism and growth were upregulated in the presence of CBS at acidic pH. Urease activity of permeabilised H. pylori at pH 7.4 and 4.5 decreased in the presence of CBS, but intact urease activity decreased only at acidic pH. The fall in cytoplasmic pH with external acidification was diminished by CBS. The increase in membrane potential in response to urea addition at acidic medium pH was unaffected by CBS. The impact of CBS and ampicillin on H. pylori survival was greater than either agent alone. CONCLUSIONS: Bismuth is not acting directly on urease or the urea channel. Colloidal bismuth subcitrate impedes proton entry into the bacteria, leading to a decrease in the expected fall in cytoplasmic pH. With cytoplasmic pH remaining within range for increased metabolic activity of a neutralophile, the efficacy of growth-dependent antibiotics is augmented.

Polypharmacy and bipolar disorder: what's personality got to do with it?

The majority of patients treated for bipolar disorder receive multiple psychotropic medications concurrently (polypharmacy), despite a lack of empirical evidence for any combination of three or more medications. Some patients benefit from the skillful management of a complex medication regimen, but iterative additions to a treatment regimen often do not lead to clinical improvement, are expensive, and can confound assessment of the underlying mood disorder. Given these potential problems of polypharmacy, this paper reviews the evidence supporting the use of multiple medications and seeks to identify patient personality traits that may put patients at a greater risk for ineffective complex chronic care. Patients with bipolar disorder (n = 89), ages 18 and older, were assessed on the Montgomery Asberg Depression Rating Scale (MADRS), Young Mania Rating Scale (YMRS), and the NEO Five Factor Inventory (NEO-FFI), and completed a treatment history questionnaire to report psychotropic medication use. We found that patients with lower scores on openness had significantly more current psychotropic medications than patients with higher scores on openness (3.7 ± 1.9 vs. 2.8 ± 1.8, p < 0.05). Patients with the highest lifetime medication use had significantly lower extraversion (21.8 ± 8.9 vs. 25.4 ± 7.6, p < 0.05) and lower conscientiousness (21.9 ± 8.2 vs. 27.9 ± 8.2, p < 0.01) than those reporting lower lifetime medication use. Low levels of openness, extraversion, and conscientiousness may be associated with increased psychotropic medication use. Investigating the role of individual differences, such as patient personality traits, in moderating effective polypharmacy warrants future research.

Experimental verification of dynamic soaring in albatrosses.

Dynamic soaring is a small-scale flight manoeuvre which is the basis for the extreme flight performance of albatrosses and other large seabirds to travel huge distances in sustained non-flapping flight. As experimental data with sufficient resolution of these small-scale movements are not available, knowledge is lacking about dynamic soaring and the physical mechanism of the energy gain of the bird from the wind. With new in-house developments of GPS logging units for recording raw phase observations and of a dedicated mathematical method for postprocessing these measurements, it was possible to determine the small-scale flight manoeuvre with the required high precision. Experimental results from tracking 16 wandering albatrosses (Diomedea exulans) in the southern Indian Ocean show the characteristic pattern of dynamic soaring. This pattern consists of four flight phases comprising a windward climb, an upper curve, a leeward descent and a lower curve, which are continually repeated. It is shown that the primary energy gain from the shear wind is attained in the upper curve where the bird changes the flight direction from windward to leeward. As a result, the upper curve is the characteristic flight phase of dynamic soaring for achieving the energy gain necessary for sustained non-flapping flight.

The effects of varying acidity on Helicobacter pylori growth and the bactericidal efficacy of ampicillin.

BACKGROUND: Penicillins inhibit cell wall synthesis; therefore, Helicobacter pylori must be dividing for this class of antibiotics to be effective in eradication therapy. Identifying growth responses to varying medium pH may allow design of more effective treatment regimens. AIM: To determine the effects of acidity on bacterial growth and the bactericidal efficacy of ampicillin. METHODS: H. pylori were incubated in dialysis chambers suspended in 1.5-L of media at various pHs with 5 mM urea, with or without ampicillin, for 4, 8 or 16 h, thus mimicking unbuffered gastric juice. Changes in gene expression, viability and survival were determined. RESULTS: At pH 3.0, but not at pH 4.5 or 7.4, there was decreased expression of ~400 genes, including many cell envelope biosynthesis, cell division and penicillin-binding protein genes. Ampicillin was bactericidal at pH 4.5 and 7.4, but not at pH 3.0. CONCLUSIONS: Ampicillin is bactericidal at pH 4.5 and 7.4, but not at pH 3.0, due to decreased expression of cell envelope and division genes with loss of cell division at pH 3.0. Therefore, at pH 3.0, the likely pH at the gastric surface, the bacteria are nondividing and persist with ampicillin treatment. A more effective inhibitor of acid secretion that maintains gastric pH near neutrality for 24 h/day should enhance the efficacy of amoxicillin, improving triple therapy and likely even allowing dual amoxicillin-based therapy for H. pylori eradication.

Training of affect recognition (TAR) in schizophrenia--impact on functional outcome.

Deficits in facial affect recognition as one aspect of social cognitive deficits are treatment targets to improve functional outcome in schizophrenia. According to preliminary results antipsychotics alone show little effects on affect recognition. A few randomized intervention studies have evaluated special psychosocial treatment programs on social cognition. In this study, the effects of a computer-based training of affect recognition were investigated as well as its impact on facial affect recognition and functional outcome, particularly on patients' quality of life. Forty clinically stabilized schizophrenic patients were randomized to a six-week training on affect recognition (TAR) or treatment as usual including occupational therapy (TAU) and completed pre- and post-treatment assessments of emotion recognition, cognition, quality of life and clinical symptoms. Between pre- and post treatment, the TAR group achieved significant improvements in facial affect recognition, in particular in recognizing sad faces and, in addition, in the quality of life domain social relationship. These changes were not found in the TAU group. Furthermore, the TAR training contributes to enhancing some aspects of cognitive functioning and negative symptoms. These improvements in facial affect recognition and quality of life were independent of changes in clinical symptoms and general cognitive functions. The findings support the efficacy of an affect recognition training for patients with schizophrenia and the generalization to social relationship. Further development is needed in the impact of a psychosocial intervention in other aspects of social cognition and functional outcome.

Aims and results of the NIMH systematic treatment enhancement program for bipolar disorder (STEP-BD).

The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was funded as part of a National Institute of Mental Health initiative to develop effectiveness information about treatments, illness course, and assessment strategies for severe mental disorders. STEP-BD studies were planned to be generalizable both to the research knowledge base for bipolar disorder and to clinical care of bipolar patients. Several novel methodologies were developed to aid in illness characterization, and were combined with existing scales on function, quality of life, illness burden, adherence, adverse effects, and temperament to yield a comprehensive data set. The methods integrated naturalistic treatment and randomized clinical trials, which a portion of STEP-BD participants participated. All investigators and other researchers in this multisite program were trained in a collaborative care model with the objective of retaining a high percentage of enrollees for several years. Articles from STEP-BD have yielded evidence on risk factors impacting outcomes, suicidality, functional status, recovery, relapse, and caretaker burden. The findings from these studies brought into question the widely practiced use of antidepressants in bipolar depression as well as substantiated the poorly responsive course of bipolar depression despite use of combination strategies. In particular, large studies on the characteristics and course of bipolar depression (the more pervasive pole of the illness), and the outcomes of treatments concluded that adjunctive psychosocial treatments but not adjunctive antidepressants yielded outcomes superior to those achieved with mood stabilizers alone. The majority of patients with bipolar depression concurrently had clinically significant manic symptoms. Anxiety, smoking, and early age of bipolar onset were each associated with increased illness burden. STEP-BD has established procedures that are relevant to future collaborative research programs aimed at the systematic study of the complex, intrinsically important elements of bipolar disorders.

Selective gene expression by rat gastric corpus epithelium.

The gastrointestinal (GI) tract is divided into several segments that have distinct functional properties, largely absorptive. The gastric corpus is the only segment thought of as largely secretory. Microarray hybridization of the gastric corpus mucosal epithelial cells was used to compare gene expression with other segments of the columnar GI tract followed by statistical data subtraction to identify genes selectively expressed by the rat gastric corpus mucosa. This provides a means of identifying less obvious specific functions of the corpus in addition to its secretion-related genes. For example, important properties found by this GI tract comparative transcriptome reflect the energy demand of acid secretion, a role in lipid metabolism, the large variety of resident neuroendocrine cells, responses to damaging agents and transcription factors defining differentiation of its epithelium. In terms of overlap of gastric corpus genes with the rest of the GI tract, the distal small bowel appears to express many of the gastric corpus genes in contrast to proximal small and large bowel. This differential map of gene expression by the gastric corpus epithelium will allow a more detailed description of major properties of the gastric corpus and may lead to the discovery of gastric corpus cell differentiation genes and those mis-regulated in gastric carcinomas.

Personality and bipolar disorder: dissecting state and trait associations between mood and personality.

BACKGROUND: Some personality characteristics have previously been associated with an increased risk for psychiatric disorder. Longitudinal studies are required in order to tease apart temporary (state) and enduring (trait) differences in personality among individuals with bipolar disorder (BD). This study aimed to determine whether there is a characteristic personality profile in BD, and whether associations between BD and personality are best explained by state or trait effects. METHOD: A total of 2247 participants in the Systematic Treatment Enhancement Program for Bipolar Disorder study completed the NEO Five-Factor Inventory administered at study entry, and at 1 and 2 years. RESULTS: Personality in BD was characterized by high neuroticism (N) and openness (O), and low agreeableness (A), conscientiousness (C) and extraversion (E). This profile was replicated in two independent samples, and openness was found to distinguish BD from major depressive disorder. Latent growth modeling demonstrated that manic symptoms were associated with increased E and decreased A, and depressed symptoms with higher N and lower E, A, C and O. During euthymic phases, high N and low E scores predicted a future depression-prone course. CONCLUSIONS: While there are clear state effects of mood on self-reported personality, personality variables during euthymia predict future course of illness. Personality disturbances in extraversion, neuroticism and openness may be enduring characteristics of patients with BD.

Validation of the German version of the brief assessment of cognition in Schizophrenia (BACS) - preliminary results.

The German version of the BACS showed high test-retest reliability. Sensitivity and specificity scores demonstrated good ability to differentiate between patients and controls. The study suggests that the German Version of the BACS is a useful scale to evaluate cognitive functioning.

[Functional MRI in schizophrenia. Diagnostics and therapy monitoring of cognitive deficits of schizophrenic patients by functional MRI]. / Funktionelle MRT bei Schizophreniepatienten. Diagnostik und Therapiemonitoring kognitiver Defizite schizophrener Patienten mittels funktioneller MRT.

Cognitive impairments are core psychopathological components of the symptomatic of schizophrenic patients. These dysfunctions are generally related to attention, executive functions and memory. This report provides information on the importance of using functional magnetic resonance imaging (fMRI) for the diagnostics and therapy monitoring of the different subtypes of cognitive dysfunctions. Furthermore, it describes the typical differences in the activation of individual brain regions between schizophrenic patients and healthy control persons. This information should be helpful in identifying the deficit profile of each patient and create an individual therapy plan.

Cerebellar pial arteriovenous malformations presenting with medullary venous hypertension: imaging and endovascular treatment.

A patient in their 60s presented with headache and progressive lower extremity weakness over 1 week. Initial MRI was thought to represent venous hypertension secondary to a dural arteriovenous fistula. However, angiography revealed a cerebellar pial arteriovenous malformation with medullary venous hypertension. The imaging and endovascular treatment of this unusual case of a pial cerebellar arteriovenous malformation presenting in that manner is presented.

Impact of chronic obstructive pulmonary disease (COPD) on attention functions.

The present study investigates the influence of COPD on attention functions, learning, and logical thinking. Therefore, 60 COPD patients and 60 healthy controls were recruited into a cross-sectional study and underwent extensive neuropsychological testing. The Attention Network Test was used for assessment of tonic and phasic alertness, orienting, and executive attention. Logical thinking and learning were determined with the Standard Progressive Matrices and the Verbal and Nonverbal Learning Test, respectively. Significant group differences were found in phasic alertness (p=0.001) and orienting (p=0.01) but not in executive attention. In addition overall reaction time was significantly slower in the COPD group (p=0.001). Further group differences were found in verbal (p<0.001) and visual learning (p<0.001) and logical thinking (p<0.001). Regression analysis revealed significant correlations for age (p=0.024) and blood carbon dioxide levels (p=0.043) in reaction time, a correlation for age and orienting (p=0.019) and finally for age (p=0.011) as well as for blood carbon dioxide values (p=0.048) and performance in logical thinking. Results are indicating a global impairment in cognitive functions of COPD patients which is negatively influenced by accelerated aging and increasing with disease severity.

Identification and pharmacological characterization of the prostaglandin FP receptor and FP receptor variant complexes.

BACKGROUND AND PURPOSE: A prostamide analogue, bimatoprost, has been shown to be effective in reducing intraocular pressure, but its precise mechanism of action remains unclear. Hence, to elucidate the molecular mechanisms of this effect of bimatoprost, we focused on pharmacologically characterizing prostaglandin FP receptor (FP) and FP receptor variant (altFP) complexes. EXPERIMENTAL APPROACH: FP receptor mRNA variants were identified by reverse transcription-polymerase chain reaction. The FP-altFP4 heterodimers were established in HEK293/EBNA cells co-expressing FP and altFP4 receptor variants. A fluorometric imaging plate reader was used to study Ca2+ mobilization. Upregulation of cysteine-rich angiogenic protein 61 (Cyr61) mRNA was measured by Northern blot analysis, and phosphorylation of myosin light chain (MLC) by western analysis. KEY RESULTS: Six splicing variants of FP receptor mRNA were identified in human ocular tissues. Immunoprecipitation confirmed that the FP receptor is dimerized with altFP4 receptors in HEK293/EBNA cells co-expressing FP and altFP4 receptors. In the studies of the kinetic profile for Ca2+ mobilization, prostaglandin F2alpha (PGF2alpha) elicited a rapid increase in intracellular Ca2+ followed by a steady state phase. In contrast, bimatoprost elicited an immediate increase in intracellular Ca2+ followed by a second phase. The prostamide antagonist, AGN211335, selectively and dose-dependently inhibited the bimatoprost-initiated second phase of Ca2+ mobilization, Cyr61 mRNA upregulation and MLC phosphorylation, but did not block the action of PGF2alpha. CONCLUSION AND IMPLICATIONS: Bimatoprost lacks effects on the FP receptor but may interact with the FP-altFP receptor heterodimer to induce alterations in second messenger signalling. Hence, FP-altFP complexes may represent the underlying basis of bimatoprost pharmacology.

Correlates of subjective and objective burden among caregivers of patients with bipolar disorder.

OBJECTIVE: We examined the relationship between mood symptoms and episodes in patients with bipolar disorder and burden reported by their primary caregivers. METHOD: Data on subjective and objective burden reported by 500 primary caregivers for 500 patients with bipolar disorder participating in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were collected using semistructured interviews. Patient data were collected prospectively over 1 year. The relationship between patient course and subsequent caregiver burden was examined. RESULTS: Episodes of patient depression, but not mood elevation, were associated with greater objective and subjective caregiver burden. Burden was associated with fewer patient days well over the previous year. Patient depression was associated with caregiver burden even after controlling for days well. CONCLUSION: Patient depression, after accounting for chronicity of symptoms, independently predicts caregiver burden. This study underscores the important impact of bipolar depression on those most closely involved with those whom it affects.