BRAF V600E mutation in Juvenile Xanthogranuloma family neoplasms of the central nervous system (CNS-JXG): a revised diagnostic algorithm to include pediatric Erdheim-Chester disease.

The family of juvenile xanthogranuloma family neoplasms (JXG) with ERK-pathway mutations are now classified within the "L" (Langerhans) group, which includes Langerhans cell histiocytosis (LCH) and Erdheim Chester disease (ECD). Although the BRAF V600E mutation constitutes the majority of molecular alterations in ECD and LCH, only three reported JXG neoplasms, all in male pediatric patients with localized central nervous system (CNS) involvement, are known to harbor the BRAF mutation. This retrospective case series seeks to redefine the clinicopathologic spectrum of pediatric CNS-JXG family neoplasms in the post-BRAF era, with a revised diagnostic algorithm to include pediatric ECD. Twenty-two CNS-JXG family lesions were retrieved from consult files with 64% (n = 14) having informative BRAF V600E mutational testing (molecular and/or VE1 immunohistochemistry). Of these, 71% (n = 10) were pediatric cases (≤18 years) and half (n = 5) harbored the BRAF V600E mutation. As compared to the BRAF wild-type cohort (WT), the BRAF V600E cohort had a similar mean age at diagnosis [BRAF V600E: 7 years (3-12 y), vs. WT: 7.6 years (1-18 y)] but demonstrated a stronger male/female ratio (BRAF V600E: 4 vs WT: 0.67), and had both more multifocal CNS disease ( BRAFV600E: 80% vs WT: 20%) and systemic disease (BRAF V600E: 40% vs WT: none). Radiographic features of CNS-JXG varied but typically included enhancing CNS mass lesion(s) with associated white matter changes in a subset of BRAF V600E neoplasms. After clinical-radiographic correlation, pediatric ECD was diagnosed in the BRAF V600E cohort. Treatment options varied, including surgical resection, chemotherapy, and targeted therapy with BRAF-inhibitor dabrafenib in one mutated case. BRAF V600E CNS-JXG neoplasms appear associated with male gender and aggressive disease presentation including pediatric ECD. We propose a revised diagnostic algorithm for CNS-JXG that includes an initial morphologic diagnosis with a final integrated diagnosis after clinical-radiographic and molecular correlation, in order to identify cases of pediatric ECD. Future studies with long-term follow-up are required to determine if pediatric BRAF V600E positive CNS-JXG neoplasms are a distinct entity in the L-group histiocytosis category or represent an expanded pediatric spectrum of ECD.

Non-fermentative Gram-negative rods bacteremia in children with cancer: a 14-year single-center experience.

PURPOSE: Data on non-fermentative Gram-negative rods (NFGNR) bacteremia in children with malignancies are limited. The aim of this study was to present clinical picture, antimicrobial susceptibility pattern, risk factors for resistance and outcome in NFGNR bacteremia in children with cancer. METHODS: All episodes of NFGNR bacteremia occurring during 2001-2014 in children with cancer in a tertiary-care hospital were retrospectively analyzed. Pseudomonas and Acinetobacter spp. resistant to three or more antibiotic classes and all Stenotrophomonas maltophilia (SM) were defined as multidrug-resistant bacteria (MDR). RESULTS: A total of 80 children (44 males, 0.8-18 years, median 5 years) developed 107 episodes (116 pathogens) of NFGNR bacteremia; Pseudomonas aeruginosa (PA) (51; 43.9%), Acinetobacter baumannii (AB) (21, 18.1%), SM (18, 15.5%); and others (27, 25.2%). The rate of NFGNR bacteremia in children with certain solid tumors (e.g. sarcoma, 12/134 (9.0%)) was comparable to that of hematological malignancies (52/429 (12.2%). Focal infection and septic shock occurred in 16 (14.9%) and four (3.7%) episodes, respectively. Thirty (25.8%) of 116 NFGNR were MDR. The most significant predictors of bacteremia with MDR PA or AB were severe neutropenia (<100 cells/mm3; OR 7.8, p = 0.002), hospital-acquired (OR 16.9, p < 0.0001) and breakthrough (OR 11.2, p < 0.0001) infection. Infection with MDR bacteria was associated with inappropriate empirical therapy. The 30-day mortality was 3/107 (2.8%), all in neutropenic patients with hematological malignancies. CONCLUSIONS: NFGNR bacteremia can present with nonspecific signs or symptoms. MDR NFGNRs are common and compromise treatment options, but mortality is relatively low. Knowledge of local epidemiology, pattern and risk factors for resistance is important to guide empirical therapy.

The use of whole exome sequencing for the diagnosis of autosomal recessive malignant infantile osteopetrosis.

Autosomal recessive malignant infantile osteopetrosis is a congenital disease characterized by pathologically increased bone density. Recently, the use of whole exome sequencing has been utilized as a clinical diagnostic tool in a number of Mendelian disorders. In this study, whole exome sequencing (WES) was successfully used in six patients with malignant infantile osteopetrosis (MIOP) and identified mutations in four MIOP-related genes (CLCN7, TCIRG1, SNX10, and TNFRSF11A). We report these patients, describe the mutations and review the current literature.

Free will perceptions and psychiatric symptoms in patients diagnosed with schizophrenia.

WHAT IS KNOWN ON THE SUBJECT?: Some research suggests that holding a free will perspective may offer mental health and physical health benefits. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: This study is the first to examine links between free will perceptions and psychiatric symptoms in patients diagnosed with schizophrenia. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Study results suggest that helping people with a diagnosis of schizophrenia to recognize situations where they do have some freedom of choice over their actions and emotional reactions (free will) may assist them in improving their experiences and better managing their symptoms. ABSTRACT: Introduction Some research indicates that having a strong sense that one possesses free will may be associated with better psychological and physical health. This study is the first to examine the relationship between free will perceptions and psychiatric symptoms in patients with a diagnosis of schizophrenia. Method Thirty-two participants were interviewed using the Brief Psychiatric Rating Scale to assess symptom severity and the Free Will Subscale of the Free Will and Determinism Scale to assess free will perceptions. Results As hypothesized, a negative association was found between free will perceptions and total symptom severity, though it appears that this was mainly accounted for by positive symptoms. A content analysis was also conducted to qualitatively examine how patients conceptualize the construct of free will and its role in coping with their own mental illness. Discussion Study results suggest that holding a free will perspective may mitigate psychiatric symptoms in patients with a diagnosis of schizophrenia. Thus, psychiatric nurses and other mental health clinicians may improve current treatments for schizophrenia by helping patients recognize situations where they do have some freedom of choice over their actions and emotional reactions (free will) to stressful life events.

Pre-treatment of C57BL6/J mice with the TLR4 agonist monophosphoryl lipid A prevents LPS-induced sickness behaviors and elevations in dorsal hippocampus interleukin-1ß, independent of interleukin-4 expression.

Peripheral administration of lipopolysaccharide (LPS) elevates production of pro-inflammatory cytokines, and motivates the expression of sickness behaviors. In this study, we tested the ability of an LPS-derived adjuvant, monophosphoryl lipid A (MPLA), to prevent LPS-induced sickness behaviors in a burrowing paradigm. Testing occurred over a three-day period. Animals received a single injection of either MPLA or saline the first two days of testing. On day three, animals received either LPS or saline. Tissue from the dorsal hippocampus was collected for qRT-PCR to assess expression of IL-1ß and IL-4. Results indicate that, during the pre-treatment phase, administration of MPLA induces an immune response sufficient to trigger sickness behaviors. However, we observed that animals pre-treated with MPLA for two days were resistant to LPS-induced sickness behaviors on day three. Results from the qRT-PCR analysis indicated that LPS-treated animals pre-treated with MPLA expressed significantly less IL-1ß compared to LPS-treated animals pre-treated with saline. However, we did not observe a significant difference in IL-4 expression between groups. Therefore, results indicate that under the given parameters of the study, MPLA pre-treatment protects against LPS-induced sickness behaviors, at least in part, by decreasing expression of the pro-inflammatory cytokine IL-1ß.

Administration of the inverse benzodiazepine agonist MRK-016 rescues acquisition and memory consolidation following peripheral administration of bacterial endotoxin.

Recent evidence suggests that inflammation-induced decrements in cognitive function can be mitigated via manipulation of excitatory or inhibitory transmission. We tested the ability of the inverse benzodiazepine agonist, MRK-016 (MRK) to protect against LPS-induced deficits in memory acquisition and consolidation, using a contextual fear conditioning (CFC) paradigm. In Experiment One, mice received lipopolysaccharide (LPS) and/or MRK injections prior to CFC training, and were then tested 24h after training. In Experiment Two, animals received similar treatment injections immediately after training, and were tested 24h later. Additionally, hippocampal samples were collected 4h after LPS injections and immediately after testing, to evaluate brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1) mRNA expression. Results indicate that MRK can protect against LPS-induced learning/memory decrements in both paradigms. We also found, in both paradigms, that animals treated with LPS/Saline expressed significantly less BDNF mRNA when compared to Saline/Saline-treated animals 4h after LPS administration, but that MRK did not restore BDNF expression levels. Further, treatment administrations had no effect on IGF-1 mRNA expression at any collection time-point. In summary, MRK-016 can protect against LPS-induced deficits in memory acquisition and consolidation, in this hippocampus-dependent paradigm, though this protection occurs independently of recovery of BDNF expression.

Post-thrombotic syndrome after central venous catheter removal in childhood cancer survivors: A prospective cohort study.

BACKGROUND: Although the use of central venous catheters (CVCs) has greatly improved the quality of care of children with cancer, these catheters increase the risk of deep vein thrombosis (DVT) and the potential long-term complication of post-thrombotic syndrome (PTS). We aimed to study PTS post-CVC removal using physical, functional and health related quality of life (HRQoL) domains in childhood cancer and bone marrow transplantation (BMT) survivors. PROCEDURE: We conducted a prospective study in a cohort of childhood cancer and BMT survivors post-CVC use. Participants were evaluated for PTS with the Modified Villalta Score (MVS) and the Manco-Johnson Instrument (MJI). HRQoL was assessed using the PedsQL™ questionnaire. RESULTS: A total of 158 children were enrolled at a median of 41 (4-149) months from CVC removal. Signs and symptoms of PTS were present in 34% (95% confidence interval [CI] 27-43%) (MVS criteria) and 30.5% (95% CI 23.1-37.8%) (MJI criteria). Diagnosis of PTS was associated with history of CVC occlusion, history of CVC-related DVT and the use of ≥2 CVCs. The presence of signs and symptoms of PTS was a predictor for low HRQoL tested by the PedsQL™ Total Scale scores and Physical Health Summary scores. CONCLUSIONS: PTS post-CVC removal in pediatric cancer survivors is not a rare event. The association between PTS and the history of CVC occlusion confirms earlier findings, and suggests that CVC occlusion may indicate asymptomatic DVT. PTS is also associated with lower HRQoL scores highlighting the need to study preventive measures, especially for high risk groups. Pediatr Blood Cancer 2015;62:285-290. © 2014 Wiley Periodicals, Inc.

Dynamic relationships between microbial biomass, respiration, inorganic nutrients and enzyme activities: informing enzyme-based decomposition models.

We re-examined data from a recent litter decay study to determine if additional insights could be gained to inform decomposition modeling. Rinkes et al. (2013) conducted 14-day laboratory incubations of sugar maple (Acer saccharum) or white oak (Quercus alba) leaves, mixed with sand (0.4% organic C content) or loam (4.1% organic C). They measured microbial biomass C, carbon dioxide efflux, soil ammonium, nitrate, and phosphate concentrations, and ß-glucosidase (BG), ß-N-acetyl-glucosaminidase (NAG), and acid phosphatase (AP) activities on days 1, 3, and 14. Analyses of relationships among variables yielded different insights than original analyses of individual variables. For example, although respiration rates per g soil were higher for loam than sand, rates per g soil C were actually higher for sand than loam, and rates per g microbial C showed little difference between treatments. Microbial biomass C peaked on day 3 when biomass-specific activities of enzymes were lowest, suggesting uptake of litter C without extracellular hydrolysis. This result refuted a common model assumption that all enzyme production is constitutive and thus proportional to biomass, and/or indicated that part of litter decay is independent of enzyme activity. The length and angle of vectors defined by ratios of enzyme activities (BG/NAG vs. BG/AP) represent relative microbial investments in C (length), and N and P (angle) acquiring enzymes. Shorter lengths on day 3 suggested low C limitation, whereas greater lengths on day 14 suggested an increase in C limitation with decay. The soils and litter in this study generally had stronger P limitation (angles >45°). Reductions in vector angles to <45° for sand by day 14 suggested a shift to N limitation. These relational variables inform enzyme-based models, and are usually much less ambiguous when obtained from a single study in which measurements were made on the same samples than when extrapolated from separate studies.

Risk factors for central venous catheter thrombotic complications in children and adolescents with cancer.

BACKGROUND: The use of central venous catheters (CVCs) has greatly improved the quality of care in children with cancer, yet these catheters may cause serious infectious and thrombotic complications. The aim of this prospective registry study was to assess the host and CVC-related risk factors for CVC-created thrombotic complications. METHODS: Patients undergoing CVC insertion for chemotherapy were followed prospectively for CVC complications. At the time of enrollment, demographic, clinical, and CVC-related data, and family history of thrombosis were collected. Survival and Cox regression analyses were performed. RESULTS: A total of 423 CVCs were inserted into 262 patients for a total of 76,540 catheter days. The incidence of CVC-related deep-vein thrombosis (DVT) was 0.13 per 1000 catheter-days (95% confidence interval [CI], 0.06-0.24). Insertion of peripherally inserted central catheters (PICCs) and insertion in an angiography suite significantly increased the risk of symptomatic CVC-related DVT. The incidence of CVC occlusion was 1.35 per 1000 catheter-days (95% CI, 1.1-1.63). Positive family history of thrombosis significantly increased the risk of CVC occlusion (hazard ratio [HR], 2.16; 95% CI, 1.2-3.8). The CVC-related risk factors were insertion of Hickman catheters, insertion in angiography suite, and proximal-tip location. Patients developing at least 1 episode of both CVC occlusion and infection had an increased risk for developing symptomatic CVC-related DVT (HR, 4.15; 95% CI, 1.2-14.4). CONCLUSIONS: Both patient-related and CVC-related factors are associated with higher risk of symptomatic thrombotic complications. These risk factors could be used in the clinical setting and in developing future studies for CVC thromboprophylaxis.

Evaluation of children with a suspected bleeding disorder applying the Impact-R [Cone and Plate(let) Analyzer].

BACKGROUND: A convenient screening test for children with bleeding symptoms before more labor-intensive diagnostic steps are taken would be of value. The Impact-R was designed in an attempt to analyse platelet function under near physiological conditions. Results are presented as surface coverage (SC, %) and average size (AS, microm(2)). OBJECTIVE: In this cross-sectional retrospective study, we assessed the use of the Impact-R in the evaluation of children with a suspected bleeding disorder (BD). METHODS: The hospital charts of 110 children referred to the coagulation laboratory were reviewed for personal and family bleeding history (BH) as well as results of the laboratory evaluation. RESULTS: A laboratory 'diagnosable' BD (LBD) was found in 23 children (21%, 95% CI 14-30%). A diagnosis of LBD was associated with the severity of bleeding but not with family BH. By receiver-operating characteristic (ROC) curve analysis, the SC was superior to the AS for diagnosis of a LBD. The Impact-R was abnormal in 43/97 children (44.3%, 95% CI 34-55%). The predictive values of a normal and abnormal Impact-R were 96% (95% CI 92-97%) and 42% (95% CI 28-56%), respectively. When considering the personal and family BH, the post-test probability for LBD after a normal Impact-R was reduced from 20% to 3.5% (95% CI 2.5-7%). CONCLUSIONS: A normal Impact-R test is highly effective in excluding LBDs. Yet, in case of an abnormal Impact-R test, further testing is needed. An algorithm that includes the personal and family BH and the results of a screening test may improve the diagnostic process. Prospective studies are now needed to confirm these findings.

Biogeochemical consequences of rapid microbial turnover and seasonal succession in soil.

Soil microbial communities have the metabolic and genetic capability to adapt to changing environmental conditions on very short time scales. In this paper we combine biogeochemical and molecular approaches to reveal this potential, showing that microbial biomass can turn over on time scales of days to months in soil, resulting in a succession of microbial communities over the course of a year. This new understanding of the year-round turnover and succession of microbial communities allows us for the first time to propose a temporally explicit N cycle that provides mechanistic hypotheses to explain both the loss and retention of dissolved organic N (DON) and inorganic N (DIN) throughout the year in terrestrial ecosystems. In addition, our results strongly support the hypothesis that turnover of the microbial community is the largest source of DON and DIN for plant uptake during the plant growing season. While this model of microbial biogeochemistry is derived from observed dynamics in the alpine, we present several examples from other ecosystems to indicate that the general ideas of biogeochemical fluxes being linked to turnover and succession of microbial communities are applicable to a wide range of terrestrial ecosystems.

B-cell lymphoma developing in the donor 9 years after donor-origin acute myeloid leukemia post bone marrow transplantation.

Donor-cell leukemia post bone marrow transplantation is a rare event. Most of the cases reported to date have developed in cells from an HLA-matched sibling, who had no evidence of malignant disease before or following the occurrence of donor-origin leukemia. We describe a 17-year-old female who developed B-cell lymphoma 9 years following the occurrence of donor-origin acute myeloid leukemia in her brother for whom she had donated marrow. Cytogenetic analysis of the tumor revealed multiple chromosomal aberrations. The donor was heterozygous for the Ashkenazi mutation of Bloom's syndrome, suggesting that donor-type leukemia could have resulted from genomic instability in the donor cells.

Hypopituitarism in langerhans cell histiocytosis: seven cases and literature review.

Central nervous system (CNS) involvement and, in particular, hypothalamic-pituitary involvement are well described features of Langerhans cell histiocytosis (LCH). The actual incidence of CNS-LCH disease is unknown and the natural history is poorly understood. Diabetes insipidus (DI) is reported to be the most common and well described manifestation of hypothalamic-pituitary involvement (up to 50%). Anterior pituitary dysfunction has been reported in up to 20% of patients with LCH, and occurs almost exclusively concurrently with DI. In the current paper we describe our experience with 7 patients (6 females and 1 male) in whom hypothalamicpituitary involvement was a major feature of LCH. Diagnosis was made in 4 patients during childhood or adolescence, and 3 patients were over 18 years old at the time of diagnosis. Our series exemplifies the wide spectrum of LCH-induced hypopituitarism, and demonstrates some unique features, including a higher incidence of CRH/ACTH deficiency compared to other reports (4/7 patients), and massive obesity in 2 of our patients. Endocrine function was not improved in any of our patients following medical treatment of LCH with chemotherapy and glucocorticoids. We conclude that pituitary-hypothalamic dysfunction is a common feature of LCH, and therefore all LCH patients should undergo a thorough endocrine evaluation periodically.

Pantagruelism: a Rabelaisian inspiration for understanding poisoning, euthanasia and abortion in the Hippocratic oath and in contemporary clinical practice.

Contrary to the common view, this paper suggests that the Hippocratic oath does not directly refer to the controversial subjects of euthanasia and abortion. We interpret the oath in the context of establishing trust in medicine through departure from Pantagruelism. Pantagruelism is coined after Rabelais' classic novel Gargantua and Pantagruel. His satire about a wonder herb, Pantagruelion, is actually a sophisticated model of anti-medicine in which absence of independent moral values and of properly conducted research fashion a flagrant over-medicalization of human problems. Ultimately this undermines the therapeutic core of medicine itself. We contend that PAS is a case of such over-medicalization and that its institution creates medicophobia. This article does not express an opinion about euthanasia in general. Rather, we claim that physicians should learn from the oath and from Rabelais that they should keep their practice to medical care and not to exploit their expertise and social privileges for the sake of ulterior motives, even when their patients desire those goals.

Transthoracic monitoring of the impedance of the right lung in patients with cardiogenic pulmonary edema.

OBJECTIVE: To evaluate the suitability of the new electrical impedance monitor RS-205 for monitoring of cardiogenic pulmonary edema (CPE). DESIGN: Prospective, controlled study. SETTING: A department of internal medicine in a 1,200-bed university-affiliated, teaching hospital. PATIENTS: Sixty patients, aged 52-80 yrs, 30 without CPE (controls) and 30 with or at high risk for CPE. INTERVENTIONS: Internal thoracic impedance (ITI) was monitored by the RS-205. The RS-205 is approximately three times more sensitive than the Kubicek monitor, and it eliminates the effect of the drift of skin-to-electrode impedance. This is achieved by eliminating skin electrode impedance by a special algorithm, thus allowing measurement of ITI rather than total transthoracic impedance. Measuring ITI, the main component of which is lung impedance, is a noninvasive and safe method. CPE was diagnosed in accordance with well-accepted clinical and roentgenological criteria. MEASUREMENTS AND MAIN RESULTS: The controls' initial ITI was 68.3 +/- 12.38 ohms. During 6 hrs of monitoring, the ITI attained a minimum average value of -1.3 +/- 2.08% and a maximum average value of 4.6 +/- 3.56% relative to baseline. In all patients entering CPE, ITI decreased by 14.4 +/- 5.42% on the average (p <.001) 1 hr before the appearance of clinical symptoms. In patients with evolving CPE, ITI decreased significantly compared with controls (22.25 +/- 9.82%, p <.001). In patients at the peak of pulmonary edema, ITI was 2.1 times lower than in the control group (33.1 +/- 10.90 ohms, p <.001). In the last hour before the resolution of CPE, ITI increased in all patients by 17.7 +/- 19.74% compared with the peak of disease (p <.05). After the resolution of pulmonary edema, ITI increased in all patients by 44.14 +/- 26.90% compared with the peak of disease (p <.001). Importantly, the trend in ITI in all patients changed in accordance with the dynamics of CPE. A mixed general linear model shows that ITI values correlated well with the degree of crepitation, a direct characteristics of CPE. CONCLUSIONS: The RS-205 is suitable for monitoring patients at high risk of CPE development. It enables detection of CPE and the monitoring of patients at all stages of CPE.