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.

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.

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.

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.

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.

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.

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.

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.

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.

Staging resection and reconstruction with temporary wound VAC coverage in a case of giant cystosarcoma phyllodes of the breast.

INTRODUCTION: Cystosarcoma phyllodes (CP) is a rare breast tumor occurring most often in females in their fifth decade. While usually benign, some CP tumors exhibit aggressive growth patterns and extensively invade chest wall structures; resecting these tumors to negative surgical margins can be challenging. We present a case of malignant CP involving the chest wall where using a negative pressure vacuum-assisted closure (VAC) system after resection enabled complete histopathologic margin assessment prior to reconstruction. This is the first known report of staged breast tumor resection and reconstruction with interim VAC coverage. CASE PRESENTATION: A 48 year-old woman presented with rapidly increasing left breast size, fevers, and fatigue. On examination, the left breast was massively enlarged with engorged vessels and skin necrosis. Lab analyses revealed unusual metabolic abnormalities requiring preoperative hospitalization. We performed a left modified radical mastectomy with partial resection of pectoralis major and minor muscles, temporarily sealing the wound with a VAC due to concern for deeper tumor extension that could require further resection. Pathology revealed malignant CP with a negative deep margin. The 38cm defect was then repaired with latissimus myocutaneous flap plus skin graft. At three-year follow up the patient remains free of disease. CONCLUSION: In cases of malignant CP involving the chest wall, minimizing the extent of chest wall resection is critical for reducing morbidity, while completely clearing tumor margins is essential for reducing recurrence risk. Using temporary wound VAC coverage enables cautious debulking followed by histopathologic margin assessment prior to definitively reconstructing the breast.

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.

Unrestricted fruits and vegetables in the PKU diet: a 1-year follow-up.

Phenylketonuria (PKU) therapy demands phenylalanine (Phe) calculation. In most countries, almost all food is taken into account, even fruits and vegetables. We investigated whether unrestricted consumption of fruits and vegetables negatively influences metabolic control. Nineteen PKU children (2-10 years) started with 2 weeks of free or restricted fruit and vegetable intake. After 2 weeks, the regime changed from free to restricted or restricted to free (cross-over design). Over the first 4 weeks, dried blood Phe concentration was measured, fruit and vegetable consumption recorded and nutrient intake calculated from diet records. Thereafter the diet was changed to free use of fruits and vegetables for all patients. Six and 12 months later, diet and Phe concentrations were monitored. Median Phe intake increased significantly by 65 mg/day (week 4, P<0.001), 68 mg/day (month 6, P<0.001) and 70 mg/day (month 12, P<0.001). Dried blood Phe concentrations remained stable (P=0.894), as did the frequency of Phe concentrations above the recommended range (P=0.592). In conclusion, PKU diet liberalization for fruits and vegetables seems unproblematic.

PKU patients on a relaxed diet may be at risk for micronutrient deficiencies.

OBJECTIVE: To investigate micronutrient supply in phenylketonuria (PKU) patients on a relaxed diet. SUBJECTS/METHODS: Sixty-seven patients (6-45 years) with a phenylalanine tolerance ≥ 600 mg/day were included in the study. From a 3-day diet record, protein supply as well as consumption of essential amino acids and several micronutrients were assessed and compared with the current recommendations and data for the healthy population. RESULTS: Protein supply and consumption of all essential amino acids were sufficient in all patients. Supply of micronutrients depended on dietary regime. Patients with a total protein supply of 120% or more of the recommended amount and at least 0.5 g protein per kg body weight from amino-acid mixture (AAM) were sufficiently supplied with all investigated micronutrients. All patients without AAM supplement showed severe micronutrient deficiencies in their diet records. CONCLUSION: PKU patients under a relaxed diet are at risk of an insufficient nutrient supply, if they have first no substitution with AAM, second a protein supply less than 0.5 g per kg body weight from AAM or third a total protein supply less than 120% of the recommendations. Therefore, close monitoring, specific dietary counseling and potential supplementation is mandatory to prevent micronutrient deficiencies in PKU patients.

Low cost, patterning of human hNT brain cells on parylene-C with UV & IR laser machining.

This paper describes the use of 800nm femtosecond infrared (IR) and 248nm nanosecond ultraviolet (UV) laser radiation in performing ablative micromachining of parylene-C on SiO2 substrates for the patterning of human hNT astrocytes. Results are presented that support the validity of using IR laser ablative micromachining for patterning human hNT astrocytes cells while UV laser radiation produces photo-oxidation of the parylene-C and destroys cell patterning. The findings demonstrate how IR laser ablative micromachining of parylene-C on SiO2 substrates can offer a low cost, accessible alternative for rapid prototyping, high yield cell patterning.

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.

Adult motor axons preferentially reinnervate predegenerated muscle nerve.

Preferential motor reinnervation (PMR) is the tendency for motor axons regenerating after repair of mixed nerve to reinnervate muscle nerve and/or muscle rather than cutaneous nerve or skin. PMR may occur in response to the peripheral nerve pathway alone in juvenile rats (Brushart, 1993; Redett et al., 2005), yet the ability to identify and respond to specific pathway markers is reportedly lost in adults (Uschold et al., 2007). The experiments reported here evaluate the relative roles of pathway and end organ in the genesis of PMR in adult rats. Fresh and 2-week predegenerated femoral nerve grafts were transferred in correct or reversed alignment to replace the femoral nerves of previously unoperated Lewis rats. After 8 weeks of regeneration the motoneurons projecting through the grafts to recipient femoral cutaneous and muscle branches and their adjacent end organs were identified by retrograde labeling. Motoneuron counts were subjected to Poisson regression analysis to determine the relative roles of pathway and end organ identity in generating PMR. Transfer of fresh grafts did not result in PMR, whereas substantial PMR was observed when predegenerated grafts were used. Similarly, the pathway through which motoneurons reached the muscle had a significant impact on PMR when grafts were predegenerated, but not when they were fresh. Comparison of the relative roles of pathway and end organ in generating PMR revealed that neither could be shown to be more important than the other. These experiments demonstrate unequivocally that adult muscle nerve and cutaneous nerve differ in qualities that can be detected by regenerating adult motoneurons and that can modify their subsequent behavior. They also reveal that two weeks of Wallerian degeneration modify the environment in the graft from one that provides no modality-specific cues for motor neurons to one that actively promotes PMR.