The impact of a history of child abuse on cognitive performance: a cross-sectional study in older patients with a depressive, anxiety, or somatic symptom disorder.

BACKGROUND: Child abuse is a major global burden with an enduring negative impact on mental and physical health. A history of child abuse is consistently associated with worse cognitive performance among adults; data in older age groups are inconclusive. Since affective symptoms and cognitive functioning are interrelated among older persons, a synergistic effect can be assumed in patients with affective symptoms who also have suffered from child abuse. This study examines the association between a history of child abuse and cognitive performance in such patients. METHODS: Cross-sectional data were collected from the 'Routine Outcome Monitoring for Geriatric Psychiatry & Science' project, including 179 older adults (age 60-88 years) with either a unipolar depressive, any anxiety, or somatic symptom disorder referred to specialized geriatric mental health care. A history of physical, sexual, and psychological abuse, and emotional neglect was assessed with a structured interview. Cognitive functioning was measured with three paper and pencils tests (10-words verbal memory test, Stroop Colour-Word test, Digit Span) and four tests from the computerized Cogstate Test Battery (Detection Test, Identification Test, One Card Learning Test, One Back Test). The association between a history of child abuse and cognitive performance was examined by multiple linear regression analyses adjusted for covariates. RESULTS: Principal component analyses of nine cognitive parameters revealed four cognitive domains, i.e., visual-verbal memory, psychomotor speed, working memory and interference control. A history of child abuse was not associated with any of these cognitive domains. However, when looking at the specific types of child abuse separately, a history of physical abuse and emotional neglect were associated with poorer interference control. A history of physical abuse was additionally associated with better visual-verbal memory. CONCLUSIONS: The association between a history of child abuse and cognitive performance differs between the different types of abuse. A history of physical abuse might particularly be a key determinant of cognitive performance in older adults with a depressive, anxiety, or somatic symptom disorder. Future studies on the impact of these disorders on the onset of dementia should take child abuse into account. TRIAL REGISTRATION: ROM-GPS is registered at the Dutch Trial Register ( NL6704 at www.trialregister.nl ).

Benefit of sequential bilateral cochlear implantation in children between 5 to 18 years old: A prospective cohort study.

OBJECTIVE: To determine the benefit of sequential cochlear implantation after a long inter-implantation interval in children with bilateral deafness receiving their second implant between 5 and 18 years of age. STUDY DESIGN: Prospective cohort-study. SETTING: Tertiary multicenter. PATIENTS: 85 children with bilateral deafness and unilateral implantation receiving a contralateral cochlear implant at the age of 5 to 18 years. METHOD: The primary outcomes were speech recognition in quiet and noise (CVC) scores. The secondary outcomes were language outcomes and subjective hearing abilities, all measured before and 12 months after sequential bilateral cochlear implantation. Medians of the paired data were compared using the Wilcoxon signed-rank test. Univariable linear regression analyses was used to analyze associations between variables and performance outcomes. RESULTS: A significant benefit was found for speech recognition in quiet (96% [89-98] vs 91% [85-96]; p < 0.01) and noise (65% [57-75] vs 54% [47-71]; p = 0.01) in the bilateral CI condition compared to unilateral (n = 75, excluded 10 non-users). No benefit was seen for language outcomes. The subjective sound quality score was statistically significant higher in bilateral compared to the unilateral CI condition. Pre-operative residual hearing level in the ear of the second implant, the inter-implant interval and age at time of second implantation was not significantly associated with performance scores. CONCLUSION: After 12 months of use, sequential bilateral cochlear implantation showed improved speech perception in quiet and noise and improved subjective sound quality outcomes in children despite a great inter-implantation interval (median of 8 years [range 1-16 years]).

Structural and mechanistic insights into the interaction between Rho and mammalian Dia.

Formins are involved in a variety of cellular processes that require the remodelling of the cytoskeleton. They contain formin homology domains FH1 and FH2, which initiate actin assembly. The Diaphanous-related formins form a subgroup that is characterized by an amino-terminal Rho GTPase-binding domain (GBD) and an FH3 domain, which bind somehow to the carboxy-terminal Diaphanous autoregulatory domain (DAD) to keep the protein in an inactive conformation. Upon binding of activated Rho proteins, the DAD is released and the ability of the formin to nucleate and elongate unbranched actin filaments is induced. Here we present the crystal structure of RhoC in complex with the regulatory N terminus of mammalian Diaphanous 1 (mDia1) containing the GBD/FH3 region, an all-helical structure with armadillo repeats. Rho uses its 'switch' regions for interacting with two subdomains of GBD/FH3. We show that the FH3 domain of mDia1 forms a stable dimer and we also identify the DAD-binding site. Although binding of Rho and DAD on the N-terminal fragment of mDia1 are mutually exclusive, their binding sites are only partially overlapping. On the basis of our results, we propose a structural model for the regulation of mDia1 by Rho and DAD.

Impact of childhood trauma on multidimensional frailty in older patients with a unipolar depressive-, anxiety- or somatic symptom disorder.

OBJECTIVES: Frailty marks an increased risk for adverse health outcomes. Since childhood trauma is associated with the onset of physical and mental health diseases during the lifespan, we examined the link between childhood trauma and multidimensional frailty. METHOD: A cross-sectional study embedded in a clinical cohort study (ROM-GPS) of older (≥60 years) patients (n=182) with a unipolar depressive-, anxiety- and/or somatic symptom disorder according to DSM-criteria referred to specialized geriatric mental health care. Frailty was assessed with the Tilburg Frailty Indicator (TFI), comprising a physical, psychological, and social dimension. Physical, sexual and psychological abuse and emotional neglect before the age of 16 years was measured with a structured interview. RESULTS: Of 182 patients, 103 (56.6%) had experienced any childhood trauma and 154 (84.6%) were frail (TFI sum score ≥5). Linear regression analyses, adjusted for lifestyle, psychological and physical-health factors, showed that the presence of any type of childhood trauma was not associated with the TFI sum score, however when considered separately, physical abuse was (ß=0.16, p=.037). Regarding the specific frailty dimensions, any childhood trauma was associated with social frailty (ß=0.18, p=.019), with emotional neglect as main contributor. CONCLUSION: These findings demonstrate a complex link between different types of childhood trauma and multidimensional frailty among older psychiatric patients. Regarding the three dimensions of frailty, social frailty seems most affected by childhood trauma. This may have been underestimated until now and should receive more attention in clinical care and future research.

Autophagy lipidation machinery regulates axonal microtubule dynamics but is dispensable for survival of mammalian neurons.

Neurons maintain axonal homeostasis via employing a unique organization of the microtubule (MT) cytoskeleton, which supports axonal morphology and provides tracks for intracellular transport. Abnormal MT-based trafficking hallmarks the pathology of neurodegenerative diseases, but the exact mechanism regulating MT dynamics in axons remains enigmatic. Here we report on a regulation of MT dynamics by AuTophaGy(ATG)-related proteins, which previously have been linked to the autophagy pathway. We find that ATG proteins required for LC3 lipid conjugation are dispensable for survival of excitatory neurons and instead regulate MT stability via controlling the abundance of the MT-binding protein CLASP2. This function of ATGs is independent of their role in autophagy and requires the active zone protein ELKS1. Our results highlight a non-canonical role of ATG proteins in neurons and suggest that pharmacological activation of autophagy may not only promote the degradation of cytoplasmic material, but also impair axonal integrity via altering MT stability.

A Dutch day treatment program for anorexia and bulimia nervosa in comparison with internationally described programs.

A Dutch day treatment program for patients with anorexia and bulimia nervosa is described and compared to intensive day treatment programs for patients with eating disorders outlined in international literature. The 5-day program is described in terms of its general characteristics, intended outcome and specific treatment interventions. Along these parameters it is compared to the programs found in a systematic literature search of day hospitalization programs for eating disorders. Global inspection shows a lot of similarities between all the programs. Looking more closely, also many important differences exist (concerning, e.g. treatment duration, intensity of treatment, theoretical orientation, goals of treatment and weight gain regime). Because of the differences, it is hard to compare outcome data between centres. Besides, on many of these dimensions, the literature does not yet tell us unambiguously what is best for our patients. Therefore, it is necessary to keep the dialogue between treatment centres going.

Use of antiepileptic drugs in a community-dwelling Dutch population.

We compared the treatment policy for patients with epilepsy in six Dutch cities, comprising 302, 149 inhabitants, with the treatment policies of a secondary referral center (a university hospital) and tertiary referral centers (outpatient departments of epilepsy centers). By comparing the prevalence of individuals receiving antiepileptic drugs in the six cities with the epidemiologic data for epilepsy in Rochester, Minnesota, we concluded that prescription data offer a suitable means by which to estimate the prevalence of epilepsy in a community. To compare prescriptions in cases of polytherapy, we normalized data by using defined daily doses published by the WHO Collaborating Center for Drugs Statistics Methodology and the Nordic Council on Medicines and concluded that the defined daily doses of antiepileptic drugs should be further elaborated. There is a need to obtain complete dose-response curves of equivalent antiepileptic drugs in humans. The trend of drugs use found in the six cities, the university hospital, and the epilepsy centers is, however, in accord with the expectations regarding primary, secondary, and tertiary referral centers.

Patient-therapist interaction in the behavioral treatment of panic disorder with agoraphobia.

Although effective behavioral techniques have been developed, what aspects of the patient-therapist interaction affect treatment outcome remain largely unknown. This study hypothesized that the interaction between patient and therapist develops over several phases. Further, the association between behavior modes and treatment outcome was expected to alter as that interaction developed. Thirty patients diagnosed with panic disorder with agoraphobia were treated with a standardized behavioral treatment program of 12 sessions. The interpersonal verbal therapist and patient behavior modes were studied at Sessions 1, 3, and 10, using an observational instrument. It was found that behavior modes change over the course of treatment, in line with predictions derived from social-psychological models. The hypothesis that establishing a therapeutic relationship requires an empathic and nondirective stance by the therapist in Session 1 was partly confirmed.

Effects of stair-stepping exercise direction and cadence on EMG activity of selected lower extremity muscle groups.

Step ergometry has become a popular treatment mode in cardiovascular fitness and knee rehabilitation programs. The following study describes the effects of forward stair stepping at 35 and 95 steps/minute and forward and retrograde stair stepping at 60 steps/minute on the mean electromyographic (EMG) activity of the gluteus maximus, rectus femoris, vastus medialis, semimembranosus/semitendinosus, and gastrocnemius muscles. Thirty-three subjects without prior lower extremity pathology participated in the study. Analysis of variance was used to compare mean EMG activity during the knee extension phase of the different stepping conditions. Significant differences (p < 0.05) in mean EMGs of gluteus maximus, rectus femoris, vastus medialis, and gastrocnemius were noted across all cadences. The semimembranosus/semitendinosus EMG activity displayed a single significant difference between the cadences of 35 and 95. The comparison between forward and retrograde stepping identified only one significant difference in mean EMG (semimembranosus/semitendinosus). The effects of cadence on EMG activity should be considered when developing conditioning or rehabilitation programs for the lower extremity. Faster cadences result in increased peak activity of shorter duration for the gluteus maximus, quadriceps, and gastrocnemius. There is no apparent difference in EMG activity of the hamstrings due to cadence. Also, noting the minimal activation that occurs, stair-stepping exercise would not be recommended for strengthening of the hamstrings musculature.

Efficacy and safety of medical cannabinoids in older subjects: a systematic review.

This systematic review aims to integrate the evidence on indications, efficacy, safety and pharmacokinetics of medical cannabinoids in older subjects. The literature search was conducted using PubMed, EMBASE, CINAHL and Cochrane Library. We selected controlled trials including solely older subjects (≥65 years) or reporting data on older subgroups. 105 (74%) papers, on controlled intervention trials, reported the inclusion of older subjects. Five studies reported data on older persons separately. These were randomized controlled trials, including in total 267 participants (mean age 47-78 years). Interventions were oral tetrahydrocannabinol (THC) (n=3) and oral THC combined with cannabidiol (n=2). The studies showed no efficacy on dyskinesia, breathlessness and chemotherapy induced nausea and vomiting. Two studies showed that THC might be useful in treatment of anorexia and behavioral symptoms in dementia. Adverse events were more common during cannabinoid treatment compared to the control treatment, and were most frequently sedation like symptoms. Although trials studying medical cannabinoids included older subjects, there is a lack of evidence of its use specifically in older patients. Adequately powered trials are needed to assess the efficacy and safety of cannabinoids in older subjects, as the potential symptomatic benefit is especially attractive in this age group.

Rule based processing of the CD4000, CD3200 and CD Sapphire analyser output using the Cerner Discern Expert Module.

The latest version of our Laboratory Information System haematology laboratory expert system that handles the output of Abbott Cell-Dyn Sapphires, CD4000s and a CD3200 full blood count analyser in three high-volume haematology laboratories is described. The three hospital laboratories use Cerner Millennium Version 2007.02 software and the expert system uses Cerner Millennium Discern Expert rules and some small Cerner Command Language in-house programs. The entire expert system is totally integrated with the area-wide database and has been built and maintained by haematology staff members, as has the haematology database. Using patient demographic data, analyser numeric results, analyser error and morphology flags and previous results for the patient, this expert system decides whether to validate the main full blood count indices and white cell differential, or if the analyser results warrant further operator intervention/investigation before verifying, whether a blood film is required for microscopic review and if abnormal results require phoning to the staff treating the patient. The principles of this expert system can be generalized to different haematology analysers and haematology laboratories that have different workflows and different software.

Source levels and harmonic content of whistles in white-beaked dolphins (Lagenorhynchus albirostris).

Recordings of white-beaked dolphin whistles were made in Faxafl6i Bay (Iceland) using a three-hydrophone towed linear array. Signals from the hydrophones were routed through an amplifier to a lunch box computer on board the boat and digitized using a sample rate of 125 kHz per channel. Using this method more than 5000 whistles were recorded. All recordings were made in sea states 0-1 (Beaufort scale). Dolphins were located in a 2D horizontal plane by using the difference of arrival time to the three hydrophones, and source levels were estimated from these positions using two different methods (I and II). Forty-three whistles gave a reliable location for the vocalizing dolphin when using method II and of these 12 when using method I. Source level estimates on the center hydrophone were higher using method I [average source level 148 (rms) +/- 12 dB, n = 36] than for method II [average source level 139 (rms) +/- 12 dB, n = 36]. Using these rms values the maximum possible communication range for whistling dolphins given the local ambient noise conditions was then estimated. The maximum range was 10.5 km for a dolphin whistle with the highest source level (167 dB) and about 140 m for a whistle with the lowest source level (118 dB). Only two of the 43 whistles contained an unequal number of harmonics recorded at the three hydrophones judging from the spectrograms. Such signals could be used to calculate the directionality of whistles, but more recordings are necessary to describe the directionality of white-beaked dolphin whistles.

Deoxyribonucleotide biosynthesis in yeast: assay and properties of ribonucleotide reductase in permeabilized Saccharomyces cerevisiae cells.

Yeast cells permeabilized by freeze-thaw cycles in a sorbitol-containing medium provide an experimentally favorable system for the study of ribonucleotide reduction in a small number of cells or in mutant strains. Ribonucleotide reductase activities determined in such cells are about twice those found in cell extracts but properties of the enzyme, except pH optimum, are closely comparable in both assay procedures. In contrast with other organisms, the activities measured in permeabilized cells from both diploid or haploid strains exceed the demand for deoxyribonucleotide formation during replication of the yeast genome. The method has been applied to yeast cultures growing in the presence of the ribonucleotide reductase inhibitor hydroxyurea and a twofold increase of enzyme activity has been established in such cells. On the other hand, analysis of a series of hus mutants, selected for hydroxyurea sensitivity in the laboratory of Singer and Johnston did not reveal obvious alterations of the enzyme vs the parental strains, suggesting that the hus phenotype may be due to lesions other than in ribonucleotide reductase.

Deoxyribonucleotide biosynthesis in yeast (Saccharomyces cerevisiae). A ribonucleotide reductase system of sufficient activity for DNA synthesis.

Ribonucleotide reductase, the central enzyme of DNA precursor biosynthesis, has been isolated and characterized from baker's yeast. The enzyme activity, measured in extracts from three different, exponentially growing yeast strains, is high enough to meet the substrate requirement of DNA replication, in contrast to very low activities found in most other organisms. In thymidylate-permeable yeast cells ribonucleotide reductase activity is stimulated under both starvation and excess of intracellular dTMP. On the other hand growth of yeast in presence of 20 mM hydroxyurea did not increase enzyme activity. Yeast ribonucleotide reductase is composed of two non-identical subunits, inactive separately, of which one binds to immobilized dATP. The relative molecular mass of the holoenzyme is about 250 000. The enzyme reduces all four natural ribonucleoside diphosphates with comparable efficacy. GDP reduction requires dTTP as effector, ADP reduction is stimulated by dGTP, whereas pyrimidine nucleotide reduction is stimulated by any deoxyribonucleotide and ATP. Enzyme activity is independent of exogenous metal ions and is insensitive towards chelating agents. Hydroxyurea inactivates yeast ribonucleotide reductase in a slow reaction; half-inhibition (I50) is reached only at 2-6 mM hydroxyurea concentration. Up to 50% reactivation occurs spontaneously after removal of the inhibitor. In accord with previous attempts by others, extensive purification of the yeast enzyme has failed owing to its extreme instability in solution; the half-life of about 11 h could not be influenced by any protective measure. Taken together, yeast ribonucleotide reductase combines features known from Escherichia coli and mammalian enzymes with differing, individual properties.

Immunonephelometric quantification of free haemoglobin.

A fully mechanized immunonephelometric method for rapid and specific determination of free haemoglobin in serum, plasma, or aqueous haemolysates is described. It utilizes commercially available rabbit antiserum against human haemoglobin and the Behring Nephelometer Analyser. A single determination is performed within 6 minutes and requires 250 microliters total sample volume. The measuring range is about 9-2300 mg/ml haemoglobin. Precision is characterized by intraassay coefficients of variation of 3.4% and 1.6%, and interassay coefficients of variation of 8.2% and 5.6% for haemoglobin concentrations of 29 mg/l and 119 mg/l, respectively. Accuracy of the method is shown by close correlation to haemoglobin determination by cyanohaemiglobin spectrometry (r = 0.9837). Interference may occur for visibly lipaemic samples. A preliminary comparison of different specimens drawn in parallel shows lowest haemoglobin concentrations in citrate plasma, followed by heparin plasma and by serum, while EDTA-plasma is unsuitable for this analysis.

Binding of chondroitin sulfate, dermatan sulfate and fat-storing cell-derived proteoglycans to rat hepatocytes.

1. The interaction of isolated rat hepatocytes with exogenous 3H-labeled chondroitin-4-sulfate and dermatan sulfate and with biosynthetically 35S-labeled proteoglycans secreted by cultured rat liver fat-storing cells has been studied. 2. All ligands are bound by hepatocytes in a concentration-dependent manner. Scatchard-plot analysis of the data revealed the existence of high- and low-affinity binding modes. 3. The cell-bound exogenous [3H]glycosaminoglycans could be displaced by each unlabeled ligand and by heparin, whereas displacement of the endogenous material was less effective. 4. Binding of all ligands to hepatocytes increased with time. For the exogenous glycosaminoglycans the two- to threefold amount was retained at 37 degrees C as compared to 4 degrees C; it was markedly reduced by pretreatment of the cells with trypsin. 5. Degradation of the exogenous ligands could be detected neither for the cell-bound fraction nor for the free glycosaminoglycans in the culture medium. 6. The binding of the ligands to hepatocytes is viewed as a cell-matrix interaction. Its possible pathobiochemical relevance in liver fibrosis or neoplasia is discussed.

One-hydrophone method of estimating distance and depth of phonating dolphins in shallow water.

Previous attempts at localizing cetaceans have generally used multiple hydrophone arrays and multichannel recording systems. In this paper, a low-budget localization technique using only one hydrophone is described. The time delays of the signals traveling via the surface and bottom reflection paths to the hydrophone, relative to the direct signal, are used to calculate the distance and the depth of a phonating animal. Only two additional measures, the depth of the bottom and hydrophone, have to be taken. The method requires relatively shallow waters and a flat bottom surface. Echolocating and burst pulsing Hawaiian spinner dolphins (Stenella longirostris) at the Waianae coast of Oahu, Hawaii, were localized over different bottom substrates. A tracking range of up to 100 m was achieved. The accuracy of the method is estimated by the total error differential technique. The relative distance estimation error is below 35% and the absolute depth error below 0.7 m, so that the location method is sufficiently precise for examining source levels in our study area. Because of its simplicity, the method ideally complements sound recordings and visual sightings of marine mammals and could lead to a better understanding of the nature and use of click trains by dolphins.

The prognostic value of extracellular matrix component concentrations in serum during treatment of adult respiratory distress syndrome with extracorporeal CO2 removal.

The time-dependent concentrations of hyaluronan, aminoterminal propeptide of type III procollagen, and laminin were determined in sera of 16 patients with severe adult respiratory distress syndrome during treatment with an extracorporeal CO2 removal device. Patients were classified according to lung parameters as responders (n = 10) and non-responders (n = 6) to extracorporeal CO2 removal. At the beginning of treatment strongly elevated serum concentrations of all studied extracellular matrix components were found. During the first 6-11 days of treatment the concentrations of aminoterminal propeptide of type III procollagen and hyaluronan increased further in non-responders but decreased in the majority of responders, while laminin decreased in both groups. No significant correlations were found between the serum concentrations of connective tissue components and the parameters of lung function. By non-parametric analysis of variance, significant differences between responders and non-responders according to treatment time could be established. By analysing the time course of the serum concentrations of hyaluronan and aminoterminal propeptide of type III procollagen, a total differentiation between responders and nonresponders was made possible by the trends of these analytes as early as three days after the start of treatment. The determination of aminoterminal propeptide of type III procollagen and hyaluronan in serum of patients with adult respiratory distress syndrome might therefore have prognostic significance in extracorporeal CO2 removal.

Aurintricarboxylic acid and polynucleotides as novel inhibitors of ribonucleotide reductases.

Ribonucleoside diphosphate reductases isolated from Escherichia coli, baker's yeast, Ehrlich ascites tumor cells, and unicellular green alga (Scenedesmus obliquus) are inhibited strongly and uniformly by the polymeric triphenylmethane dye, aurintricarboxylic acid. The molecule appears to interact simultaneously with the enzyme's various nucleotide and catalytic (iron-organic radical) sites. Oligo- and polyribonucleotides are also inhibitory. These reactions serve as models of the probably physiologic regulation of ribonucleotide reduction exerted by natural inhibitors. Partial characterization of an inhibitor fraction found in wheat seed embryo is described.