Antipsychotic medication exposure, clozapine, and pneumonia: results from a self-controlled study.

OBJECTIVE: By using a self-controlled design, we investigated whether antipsychotic medication exposure was associated with increased pneumonia risk and whether patients receiving clozapine were more likely to develop pneumonia than patients receiving other antipsychotic medications. METHODS: Through nationwide health registers, we identified all out-patients with schizophrenia initiating antipsychotic treatment. First, we estimated whether antipsychotic-naïve patients with schizophrenia increased their risk of pneumonia after initiation of either a first- or second-generation antipsychotic medication using a one-year mirror-image model. Afterward, similar analyses were made for individual second-generation antipsychotics. Lastly, the rate of pneumonia for patients initiated on clozapine was compared to patients commenced on other second-generation antipsychotics. RESULTS: In total, 8355 antipsychotic-naïve patients with schizophrenia were initiated on a first-generation antipsychotic medication; 0.95% of the patients had developed pneumonia before exposure, compared to 0.68% after exposure (P = 0.057). Similar findings were made for the 8001 antipsychotic-naïve patients with schizophrenia initiated on second-generation antipsychotic medications, with 0.56% developing pneumonia before exposure compared to 0.55% after exposure (P = 1.00). Second-generation antipsychotic medications did not increase the pneumonia risk, except for risperidone (increased by 0.32%; P = 0.007) and clozapine, which gave the largest absolute increase in pneumonia risk although not significant (increased by 0.64%; P = 0.10). The rate of pneumonia was higher after initiation of clozapine than for other second-generation antipsychotic medications. CONCLUSION: Most antipsychotic medications were not found to increase the risk of pneumonia. Clozapine exposure might be associated with increased risk of developing pneumonia.

Adverse cardiac events in out-patients initiating clozapine treatment: a nationwide register-based study.

OBJECTIVE: Using national Danish registers, we estimated rates of clozapine-associated cardiac adverse events. Rates of undiagnosed myocarditis were estimated by exploring causes of death after clozapine initiation. METHOD: Through nationwide health registers, we identified all out-patients initiating antipsychotic treatment (January 1, 1996-January 1, 2015). Rates of clozapine-associated myocarditis and pericarditis within 2 months from clozapine initiation and rates of cardiomyopathy within 1-2 years from clozapine initiation were compared to rates for other antipsychotics. Mortality within 2 months from clozapine initiation was extracted. RESULTS: Three thousand two hundred and sixty-two patients of a total 7932 patients initiated clozapine as out-patients (41.12%). One patient (0.03%) developed myocarditis, and no patients developed pericarditis within 2 months from clozapine initiation. Two (0.06%) and four patients (0.12%) developed cardiomyopathy within 1 and 2 years respectively. Rates were similar for other antipsychotics. Twenty-six patients died within 2 months from clozapine initiation. Pneumonia (23.08%) and stroke (11.54%) were the main causes of death. We estimated the maximum rate of clozapine-associated fatal myocarditis to 0.28%. CONCLUSION: Cardiac adverse effects in Danish out-patients initiating clozapine treatment are extremely rare and these rates appear to be comparable to those observed for other antipsychotic drugs.

Exposure to selective serotonin reuptake inhibitors in utero and early elementary school outcomes.

OBJECTIVE: Data on special education in offspring exposed to selective serotonin reuptake inhibitors (SSRIs) in utero are lacking. We examined associations of in utero SSRI exposure with special education needs and delayed elementary school start. METHODS: A population-based case-cohort study using Danish nationwide birth and prescription registry data from 2005 to 2008. Follow-up ends during 2011-2015 to capture special education needs during and delayed entry to the first elementary school year. Cases were in utero SSRI-exposed offspring. Cohort-controls were SSRI-unexposed offspring of mothers previously on SSRIs. We reported odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for relevant potential confounders. RESULTS: Of 117 475 first-incident non-multiple pregnancy births, 3314 were SSRI-exposed, and 3536 were unexposed. Among SSRI-exposed offspring, 3.2% (n = 98) had special school needs vs. 2.4% (n = 77) in unexposed offspring, P-value=0.048. Correspondingly, 12.3% (n = 383) among SSRI-exposed children had delayed school entry vs. 9.4% (n = 308) in unexposed offspring, P-value < 0.001. Adjusted OR for the association with special school needs was 1.12 (95% CI 0.82-1.55; P-value = 0.48) and 1.38 (95% CI 0.90-2.13; P-value = 0.14) for exposure in all three trimesters. The corresponding adjusted ORs for delayed school entry were 1.17 (95% CI 0.99-1.38; P-value = 0.073) and 1.40 (95% CI 1.11-1.76; P-value = 0.004). CONCLUSION: In utero SSRI exposure in all three trimesters was associated with delayed elementary school start but not special education needs.

Effects of seasonality on drosophilids (Insecta, Diptera) in the northern part of the Atlantic Forest, Brazil.

Seasonality is an important aspect associated with population dynamic and structure of tropical insect assemblages. This study evaluated the effects of seasonality on abundance, richness, diversity and composition of an insect group, drosophilids, including species native to the Neotropical region and exotic ones. Three preserved fragments of the northern Atlantic Forest were surveyed, where temperatures are above 20 °C throughout the year and rainfall regimes define two seasons (dry and rainy). As opposed to other studies about arthropods in tropical regions, we observed that abundance of drosophilids was significantly higher in the dry season, possibly due to biological aspects and the colonization strategy adopted by the exotic species in these environments. Contrarily to abundance, we did not observe a seasonal pattern for richness. As for other parts of the Atlantic Forest, the most representative Neotropical species (Drosophila willistoni, D. sturtevanti, D. paulistorum and D. prosaltans) were significantly more abundant in the rainy season. Among the most abundant exotic species, D. malerkotliana, Zaprionus indianus and Scaptodrosophila latifasciaeformis were more importantly represented the dry season, while D. simulans was more abundant in the rainy period. The seasonality patterns exhibited by the most abundant species were compared to findings published in other studies. Our results indicate that exotic species were significantly more abundant in the dry season, while native ones exhibited an opposite pattern.

Management of Mycobacterium abscessus post abdominoplasty.

UNLABELLED: Atypical mycobacterium is the source of a recent outbreak of cosmetic surgery infections [1]. Such an infection is difficult to eradicate and presents unique challenges in its management after esthetic surgery. Delays in appropriate treatment are frequent because of difficulty in diagnosis and unfamiliarity with this type of infection. We present cases of our management of Mycobacterial abscessus abdominoplasty infections following cosmetic surgery in the Dominican Republic. Rapid initial recognition of this problem and the frequent need for surgical treatment of atypical mycobacterium abdominoplasty infection may aid in the treatment of this rare but increasingly encountered infection. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Dietary management of urea cycle disorders: European practice.

BACKGROUND: There is no published data comparing dietary management of urea cycle disorders (UCD) in different countries. METHODS: Cross-sectional data from 41 European Inherited Metabolic Disorder (IMD) centres (17 UK, 6 France, 5 Germany, 4 Belgium, 4 Portugal, 2 Netherlands, 1 Denmark, 1 Italy, 1 Sweden) was collected by questionnaire describing management of patients with UCD on prescribed protein restricted diets. RESULTS: Data for 464 patients: N-acetylglutamate synthase (NAGS) deficiency, n=10; carbamoyl phosphate synthetase (CPS1) deficiency, n=29; ornithine transcarbamoylase (OTC) deficiency, n=214; citrullinaemia, n=108; argininosuccinic aciduria (ASA), n=80; arginase deficiency, n=23 was reported. The majority of patients (70%; n=327) were aged 0-16y and 30% (n=137) >16y. Prescribed median protein intake/kg body weight decreased with age with little variation between disorders. The UK tended to give more total protein than other European countries particularly in infancy. Supplements of essential amino acids (EAA) were prescribed for 38% [n=174] of the patients overall, but were given more commonly in arginase deficiency (74%), CPS (48%) and citrullinaemia (46%). Patients in Germany (64%), Portugal (67%) and Sweden (100%) were the most frequent users of EAA. Only 18% [n=84] of patients were prescribed tube feeds, most commonly for CPS (41%); and 21% [n=97] were prescribed oral energy supplements. CONCLUSIONS: Dietary treatment for UCD varies significantly between different conditions, and between and within European IMD centres. Further studies examining the outcome of treatment compared with the type of dietary therapy and nutritional support received are required.

Tetrahydrobiopterin (BH4) in PKU: effect on dietary treatment, metabolic control, and quality of life.

BACKGROUND: Tetrahydrobiopterin (BH(4))-sensitive phenylketonuria (PKU) can be treated with sapropterin dihydrochloride. We studied metabolic control and health-related quality of life (HRQoL) in PKU patients treated with BH(4). SUBJECTS AND METHODS: Based on the review of neonatal BH(4) test results and mutation analysis in 41 PKU patients, 19 were identified as potentially BH(4)-sensitive (9 females, 10 males, age 4-18 years). We analyzed phenylalanine (phe) concentrations in dried blood samples, nutrition protocols, and HRQoL questionnaires (KINDL(®)) beginning from 1 year before, during the first 42 days, and after 3 months of BH(4) therapy. RESULTS: Eight BH(4)-sensitive patients increased their phe tolerance (629 ± 476 vs. 2131 ± 1084 mg, p = 0.006) while maintaining good metabolic control (phe concentration in dried blood 283 ± 145 vs. 304 ± 136 µM, p = 1.0). Six of them were able to stop dietary protein restriction entirely. BH(4)-sensitive patients had average HRQoL scores that were comparable to age-matched healthy children. There was no improvement in HRQoL scores after replacing classic dietary treatment with BH(4) supply, although personal reports given by the patients and their parents suggest that available questionnaires are inappropriate to detect aspects relevant to inborn metabolic disorders. DISCUSSION: BH(4) can allow PKU patients to increase their phe consumption significantly or even stop dietary protein restrictions. Unexpectedly, this does not improve HRQoL as assessed with KINDL(®), partly due to high scores even before BH(4) therapy. Specific questionnaires should be developed for inborn metabolic disorders.

Social impairments in Rett syndrome: characteristics and relationship with clinical severity.

BACKGROUND: While behavioural abnormalities are fundamental features of Rett syndrome (RTT), few studies have examined the RTT behavioural phenotype. Most of these reports have focused on autistic features, linked to the early regressive phase of the disorder, and few studies have applied standardised behavioural measures. We used a battery of standardised measures of behaviour and functioning to test the following hypotheses: (1) autistic behaviour is prominent throughout childhood in RTT; (2) autistic features are more salient in individuals with milder presentation; (3) severity of autistic behaviour is associated with a wider range of behavioural problems; and (4) specific MECP2 mutations are linked to more severe autistic behaviour. METHODS: Eighty MECP2 mutation-positive girls with RTT (aged 1.6-14.9 years) were administered: (1) the Screen for Social Interaction (SSI), a measure of autistic behaviour suited for individuals with severe communication and motor impairment; (2) the Rett Syndrome Behaviour Questionnaire (RSBQ), covering a wide range of abnormal behaviours in RTT; (3) the Vineland Adaptive Behavior Scales (VABS); and (4) a modified version of the Rett Syndrome Severity Scale (RSSS). Regression analyses examined the predictive value of age and RSSS on autistic behaviour and other behavioural abnormalities. T-tests further characterised the behavioural phenotype of individual MECP2 mutations. RESULTS: While age had no significant effect on SSI or RSBQ total scores in RTT, VABS Socialization and Composite scores decreased over time. Clinical severity (i.e. RSSS) also increased with age. Surprisingly, SSI performance was not related to either RSSS or VABS Composite scores. Autistic behaviour was weakly linked with the RSBQ Hand behaviour factor scores, but not with the RSBQ Fear/Anxiety factor. Clinical (neurological) severity did not predict RSBQ scores, as evidenced by the analysis of individual MECP2 mutations (e.g. p.R106W, p.R270X and p.R294X). CONCLUSIONS: Our data suggest that in RTT, autistic behaviour persists after the period of regression. It also demonstrated that neurological and behavioural impairments, including autistic features, are relatively independent of one another. Consistent with previous reports of the RTT phenotype, individual MECP2 mutations demonstrate complex associations with autistic features. Evidence of persistent autistic behaviour throughout childhood, and of a link between hand function and social skills, has important implications not only for research on the RTT behavioural phenotype, but also for the clinical management of the disorder.

Planctopirus ephydatiae, a novel Planctomycete isolated from a freshwater sponge.

The microbiome of freshwater sponges is rarely studied, and not a single novel bacterial species has been isolated and subsequently characterized from a freshwater sponge to date. A previous study showed that 14.4% of the microbiome from Ephydatia fluviatilis belong to the phylum Planctomycetes. Therefore, we sampled an Ephydatia sponge from a freshwater lake and employed enrichment techniques targeting bacteria from the phylum Planctomycetes. The obtained strain spb1T was subject to genomic and phenomic characterization and found to represent a novel planctomycetal species proposed as Planctopirus ephydatiae sp. nov. (DSM 106606 = CECT 9866). In the process of differentiating spb1T from its next relative Planctopirus limnophila DSM 3776T, we identified and characterized the first phage - Planctopirus phage vB_PlimS_J1 - infecting planctomycetes that was only mentioned anecdotally before. Interestingly, classical chemotaxonomic methods would have failed to distinguish Planctopirus ephydatiae strain spb1T from Planctopirus limnophila DSM 3776T. Our findings demonstrate and underpin the need for whole genome-based taxonomy to detect and differentiate planctomycetal species.

Phage therapy against Achromobacter xylosoxidans lung infection in a patient with cystic fibrosis: a case report.

Respiratory infections can lead to serious complications in CF patients, especially when infected with antibiotic resistant bacteria. Alternative treatments for these infections are being sought out to help address this problem. We present a clinical case of a cystic fibrosis (CF) patient, with multi-drug resistant (MDR) Achromobacter xylosoxidans chronic lung infection who was successfully managed with bacteriophage therapy.

Environmental lead exposure during early life alters granule cell neurogenesis and morphology in the hippocampus of young adult rats.

Exposure to environmentally relevant levels of lead (Pb(2+)) during early life produces deficits in hippocampal synaptic plasticity in the form of long-term potentiation (LTP) and spatial learning in young adult rats [Nihei MK, Desmond NL, McGlothan JL, Kuhlmann AC, Guilarte TR (2000) N-methyl-D-aspartate receptor subunit changes are associated with lead-induced deficits of long-term potentiation and spatial learning. Neuroscience 99:233-242; Guilarte TR, Toscano CD, McGlothan JL, Weaver SA (2003) Environmental enrichment reverses cognitive and molecular deficits induced by developmental lead exposure. Ann Neurol 53:50-56]. Other evidence suggests that the performance of rats in the Morris water maze spatial learning tasks is associated with the level of granule cell neurogenesis in the dentate gyrus (DG) [Drapeau E, Mayo W, Aurousseau C, Le Moal M, Piazza P-V, Abrous DN (2003) Spatial memory performance of aged rats in the water maze predicts level of hippocampal neurogenesis. Proc Natl Acad Sci U S A 100:14385-14390]. In this study, we examined whether continuous exposure to environmentally relevant levels of Pb(2+) during early life altered granule cell neurogenesis and morphology in the rat hippocampus. Control and Pb(2+)-exposed rats received bromodeoxyuridine (BrdU) injections (100 mg/kg; i.p.) for five consecutive days starting at postnatal day 45 and were killed either 1 day or 4 weeks after the last injection. The total number of newborn cells in the DG of Pb(2+)-exposed rats was significantly decreased (13%; P<0.001) 1 day after BrdU injections relative to controls. Further, the survival of newborn cells in Pb(2+)-exposed rats was significantly decreased by 22.7% (P<0.001) relative to control animals. Co-localization of BrdU with neuronal or astrocytic markers did not reveal a significant effect of Pb(2+) exposure on cellular fate. In Pb(2+)-exposed rats, immature granule cells immunolabeled with doublecortin (DCX) displayed aberrant dendritic morphology. That is, the overall length-density of the DCX-positive apical dendrites in the outer portion of the DG molecular layer was significantly reduced up to 36% in the suprapyramidal blade only. We also found that the area of Timm's-positive staining representative of the mossy fibers terminal fields in the CA3 stratum oriens (SO) was reduced by 26% in Pb(2+)-exposed rats. These findings demonstrate that exposure to environmentally relevant levels of Pb(2+) during early life alters granule cell neurogenesis and morphology in the rat hippocampus. They provide a cellular and morphological basis for the deficits in synaptic plasticity and spatial learning documented in Pb(2+)-exposed animals.

Dietary practices in isovaleric acidemia: A European survey.

BACKGROUND: In Europe, dietary management of isovaleric acidemia (IVA) may vary widely. There is limited collective information about dietetic management. AIM: To describe European practice regarding the dietary management of IVA, prior to the availability of the E-IMD IVA guidelines (E-IMD 2014). METHODS: A cross-sectional questionnaire was sent to all European dietitians who were either members of the Society for the Study of Inborn Errors of Metabolism Dietitians Group (SSIEM-DG) or whom had responded to previous questionnaires on dietetic practice (n = 53). The questionnaire comprised 27 questions about the dietary management of IVA. RESULTS: Information on 140 patients with IVA from 39 centres was reported. 133 patients (38 centres) were given a protein restricted diet. Leucine-free amino acid supplements (LFAA) were routinely used to supplement protein intake in 58% of centres. The median total protein intake prescribed achieved the WHO/FAO/UNU [2007] safe levels of protein intake in all age groups. Centres that prescribed LFAA had lower natural protein intakes in most age groups except 1 to 10 y. In contrast, when centres were not using LFAA, the median natural protein intake met WHO/FAO/UNU [2007] safe levels of protein intake in all age groups. Enteral tube feeding was rarely prescribed. CONCLUSIONS: This survey demonstrates wide differences in dietary practice in the management of IVA across European centres. It provides unique dietary data collectively representing European practices in IVA which can be used as a foundation to compare dietary management changes as a consequence of the first E-IMD IVA guidelines availability.

Dietary practices in propionic acidemia: A European survey.

BACKGROUND: The definitive dietary management of propionic acidaemia (PA) is unknown although natural protein restriction with adequate energy provision is of key importance. AIM: To describe European dietary practices in the management of patients with PA prior to the publication of the European PA guidelines. METHODS: This was a cross-sectional survey consisting of 27 questions about the dietary practices in PA patients circulated to European IMD dietitians and health professionals in 2014. RESULTS: Information on protein restricted diets of 186 PA patients from 47 centres, representing 14 European countries was collected. Total protein intake [PA precursor-free L-amino acid supplements (PFAA) and natural protein] met WHO/FAO/UNU (2007) safe protein requirements for age in 36 centres (77%). PFAA were used to supplement natural protein intake in 81% (n = 38) of centres, providing a median of 44% (14-83%) of total protein requirement. Seventy-four per cent of patients were prescribed natural protein intakes below WHO/FAO/UNU (2007) safe levels in one or more of the following age groups: 0-6 m, 7-12 m, 1-10 y, 11-16 y and > 16 y. Sixty-three per cent (n = 117) of patients were tube fed (74% gastrostomy), but only 22% received nocturnal feeds. CONCLUSIONS: There was high use of PFAA with intakes of natural protein commonly below WHO/FAO/UNU (2007) safe levels. Optimal dietary management can only be determined by longitudinal, multi-centre, prospective case controlled studies. The metabolic instability of PA and small patient cohorts in each centre ensure that this is a challenging undertaking.

High Diversity of Drosophilidae in High-Altitude Wet Forests in Northeastern Brazil.

The high-altitude wet forests of northeastern Brazil, locally known as "Brejos de Altitude," are enclaves of the Atlantic Forest situated above 500 m, surrounded by dryland vegetation, the Caatinga. The aim of this study was to characterize drosophilid communities in these upland forests, since few ecological studies on drosophilid communities have been conducted in northeastern Brazil. Four sites were investigated in three different times of the year throughout standardized traps. The results reveal the presence of 55 different species in a total of 13,064 specimens collected. The data were evaluated using ecological diversity measurements and compared with those obtained for other environments in the same geographic region. As for species composition, the Bonito upland forest, in a boundary forest location, stood out as having high species richness.

Contributions of Dryland Forest (Caatinga) to Species Composition, Richness and Diversity of Drosophilidae.

In this study, semi-arid environments were tested to see if they support insect diversity. This was evaluated through the structure of the composition of assemblies of drosophilids in three conservation units placed in three different ecoregions in the dryland forests, Caatinga. This is a unique biome in northeast Brazil, comprising approximately 10% of the country. Species richness was investigated over 2 years during a prolonged drought, considered the worst affliction the Caatinga ecosystem had experienced in the last 50 years. Alpha diversity indices and the ecological similarity between the samples were calculated to determine how the environments drive the composition of Drosophilidae in such semi-arid places. A total of 7352 specimens were sampled. They were classified into 20 species belonging to four genera: Drosophila, Rhinoleucophenga, Scaptodrosophila, and Zaprionus. Drosophila nebulosa Sturtevant (44.5%) and Drosophila cardini Sturtevant (12.5%) were the most abundant species. The occurrences and abundances of all the species differed greatly between sites. These results and other ecological analyses indicate that although placed in the same biome, there are great variability in the drosophilid species and abundance among the three protected and conserved dryland environments.

Enantiomer-specific and paracrine leukemogenicity of mutant IDH metabolite 2-hydroxyglutarate.

Canonical mutations in IDH1 and IDH2 produce high levels of the R-enantiomer of 2-hydroxyglutarate (R-2HG), which is a competitive inhibitor of α-ketoglutarate (αKG)-dependent enzymes and a putative oncometabolite. Mutant IDH1 collaborates with HoxA9 to induce monocytic leukemia in vivo. We used two mouse models and a patient-derived acute myeloid leukemia xenotransplantation (PDX) model to evaluate the in vivo transforming potential of R-2HG, S-2HG and αKG independent of the mutant IDH1 protein. We show that R-2HG, but not S-2HG or αKG, is an oncometabolite in vivo that does not require the mutant IDH1 protein to induce hyperleukocytosis and to accelerate the onset of murine and human leukemia. Thus, circulating R-2HG acts in a paracrine manner and can drive the expansion of many different leukemic and preleukemic clones that may express wild-type IDH1, and therefore can be a driver of clonal evolution and diversity. In addition, we show that the mutant IDH1 protein is a stronger oncogene than R-2HG alone when comparable intracellular R-2HG levels are achieved. We therefore propose R-2HG-independent oncogenic functions of mutant IDH1 that may need to be targeted in addition to R-2HG production to exploit the full therapeutic potential of IDH1 inhibition.

Mating activity of yellow and sepia Drosophila willistoni mutants.

By analyzing the mating activity of newly isolated yellow and sepia mutants of Drosophila willistoni no difference in behavior between sepia and wild-type flies were observed, whereas yellow males were less successful than wild-type males when competing for females. These results are in agreement with those reported for other Drosophila species. D. willistoni was different in the 'females-competing' crosses because wild-type males mated more frequently with wild-type females whereas yellow males mated successfully with both phenotypes. These results indicate the complexity of the courtship behavior in D. willistoni and provide data for comparative and evolutionary research into the genus.

Increase of the purification efficiency of biofilters by the use of a complementary ionisation step.

The biofilter and the ionisation system are two oxidative treatment techniques for purification of waste gas streams with low concentrations of volatile organic compounds. In this paper, the authors present the investigations of an ionisation technique aimed at increasing the efficiency of the reduction of the odorant concentration in waste gas streams from biological waste treatment plants. The objective is to enable advanced odour emission reduction and to adjust the existing biofilters to stricter requirements. In a first step, the odorous substances which are major contributors to the overall odorant concentration are identified on basis of various emission data sets with the help of a method of life cycle impact assessment. Thereby limonene, alpha-pinene, ethyl butyrate and dimethyl disulphide were identified as crucial indicators. In a second step, experimental investigations using limonene as a model compound were conducted to gain an understanding of the ionisation process itself and at last for the evaluation of the system.