Background. Candida albicans has been the most common cause of fungal bloodstream infections (BSIs) in intensive care units (ICUs); however, infections due to non-albicans Candida species have been ...increasing in prevalence. We examined factors associated with BSIs due to non-albicans Candida species, compared with C. albicans BSIs, in an ICU patient population. Methods. For our case-comparator study, we identified consecutive adult ICU patients with BSIs due to non-albicans Candida species or C. albicans at 2 tertiary care hospitals during the period 1995–2005. Data collected included demographic characteristics, comorbidities, exposure to antibiotics and antifungals, and ICU-related factors, such as total parenteral nutrition, blood product transfusions, invasive procedures, central venous catheter use, hemodialysis, and mechanical ventilation. We built a multivariable logistic regression model that identified variables that differentiate BSIs due to non-albicans Candida species from BSIs due to C. albicans. Results. There were 67 patients with BSIs due to non-albicans Candida species and 79 patients with C. albicans BSIs. Variables were adjusted for time at risk. In multivariable models, factors associated with an increased risk of BSIs due to non-albicans Candida species, compared with C. albicans BSIs, included fluconazole exposure (odds ratio, 11.6; 95% confidence interval, 2.28–58.8), central venous catheter exposure (odds ratio, 1.95; 95% confidence interval, 1.10–3.47), and mean number of antibiotics per day (odds ratio, 2.31; 95% confidence interval, 0.71–7.54). Total parenteral nutrition exposure was associated with a decreased risk (odds ratio, 0.16; 95% confidence interval, 0.05–0.47) of BSIs due to non-albicans Candida species, compared with C. albicans BSIs. Duration of stay in the ICU was not significantly different between the 2 groups. Specific antibiotics, such as vancomycin and piperacillin-tazobactam, were not independently associated with BSI due to non-albicans Candida species. Conclusions. Receipt of fluconazole and central venous catheter exposure were associated with an increased risk of BSI due to non-albicans Candida species, and total parenteral nutrition was associated with a decreased risk of BSI due to non-albicans Candida species, compared with BSI due to C. albicans. Patients without characteristics of infection due to non-albicans Candida species might benefit from empirical antifungal therapy with fluconazole.
As both allergic contact dermatitis and atopic dermatitis (AD) have similar clinical presentations and are characterized by spongiotic dermatitis on skin biopsy, many children with AD are not ...referred for patch testing and allergic contact dermatitis is underdiagnosed.
To provide updated prevalence data of common contact allergens in children with and without AD.
This is a retrospective case-control study using the Pediatric Allergic Contact Dermatitis Registry from 2018 to 2022.
A total of 912 children were included (615 with AD and 297 without AD). Children with AD were more likely to have a longer history of dermatitis (4.1 vs 1.6 years, P < .0001), have seen more providers (2.3 vs 2.1, P = .003), have greater than 1 positive patch test (PPT) result (P = .005), have a greater number of PPT results overall (2.3 vs 1.9, P = .012), and have a more generalized distribution of dermatitis (P = .001). PPT to bacitracin (P = .030), carba mix (P = .025), and cocamidopropyl betaine (P = .0007) were significantly increased in children with AD compared to those without AD.
Technical variation between providers and potential for misclassification, selection, and recall biases.
Children with AD are significantly more likely to have PPT reactions and should be referred for evaluation of allergic contact dermatitis and obtain patch testing.
OBJECTIVE:To determine risk factors for bloodstream infections (BSI) with Candida non-albicans (C-NA) species and Candida albicans (CA) among critically ill patients.
DESIGN:Case-control study.
...SETTING:Adult medical and surgical intensive care units (ICUs) at two university hospitals.
PATIENTS:Consecutive patients with C-NA and CA BSIs from 1995–2005 formed the two case groups. Controls were patients without candidemia who were randomly selected in a ratio of 5:1 and matched by study hospital, ICU type (medical vs. surgical) and by ICU admission date within a 3-month period.
INTERVENTIONS:Data collected included demographics, comorbidities, exposure to antibiotics and antifungals, and ICU factors such as total parenteral nutrition (TPN), blood product transfusions, invasive procedures, central venous catheters, hemodialysis, and mechanical ventilation. We built multivariable logistic regression models, which identified risk factors for C-NA or CA BSIs compared with controls. Variables were adjusted for time-at-risk.
MEASUREMENTS AND MAIN RESULTS:There were 67 patients with C-NA BSIs, 79 patients with CA BSIs, and 780 controls. In multivariable models, factors associated with an increased risk of C-NA compared with controls included major pre-ICU operations odds ratio; (95% confidence interval) 2.12; (1.14–3.97), gastrointestinal procedures 2.24; (1.49–3.38), enteric bacteremia 3.43; (1.39–8.48), number of hemodialysis days 6.20; (2.67–14.4), TPN duration 2.87; (1.40–5.90), and mean number of red blood cell transfusions 2.72; (1.33–5.58). Factors associated with an increased risk of CA BSIs compared to controls were very similar and included major ICU operations 1.26; (1.14–3.97), enteric bacteremia 3.45; (1.38–8.63), number of hemodialysis days 3.84; (1.75–8.40), TPN duration 11.0; (5.52–21.7) and mean number of red blood cell transfusions 1.97; (0.98–3.99).
CONCLUSIONS:We found multiple common risk factors for both non-C. albicans and C. albicans BSIs, however we could not differentiate between these two groups based on clinical characteristics alone.
Background Candidaemia is often treated with fluconazole in the absence of susceptibility testing. We examined factors associated with candidaemia caused by Candida isolates with reduced ...susceptibility to fluconazole. Methods We identified consecutive episodes of candidaemia at two hospitals from 2001 to 2007. Species identification followed CLSI methodology and fluconazole susceptibility was determined by Etest or broth microdilution. Susceptibility to fluconazole was defined as: full susceptibility (MIC ≤ 8 mg/L); and reduced susceptibility (MIC ≥ 32 mg/L). Complete resistance was defined as an MIC > 32 mg/L. Results Of 243 episodes of candidaemia, 190 (78%) were fully susceptible to fluconazole and 45 (19%) had reduced susceptibility (of which 27 were fully resistant). Of Candida krusei and Candida glabrata isolates, 100% and 51%, respectively, had reduced susceptibility. Despite the small proportion of Candida albicans (8%), Candida tropicalis (4%) and Candida parapsilosis (4%) with reduced fluconazole susceptibility, these species composed 36% of the reduced-susceptibility group and 48% of the fully resistant group. In multivariate analysis, independent factors associated with reduced fluconazole susceptibility included male sex odds ratio (OR) 3.2, P < 0.01, chronic lung disease (OR 2.7, P = 0.01), the presence of a central vascular catheter (OR 4.0, P < 0.01) and prior exposure to antifungal agents (OR 2.2, P = 0.04). Conclusions A significant proportion of candidaemia with reduced fluconazole susceptibility may be caused by C. albicans, C. tropicalis and C. parapsilosis, species usually considered fully susceptible to fluconazole. Thus, identification of these species may not be predictive of fluconazole susceptibility. Other factors that are associated with reduced fluconazole susceptibility may help clinicians choose adequate empirical anti-Candida therapy.
KCNQ2 and KCNQ3 potassium-channel subunits can form both homomeric and heteromeric channels; the latter are thought to constitute native ganglionic M channels. We have tried to deduce the ...stoichiometric contributions of KCNQ2 and KCNQ3 subunits to currents generated by the coexpression of KCNQ2 and KCNQ3 cDNA plasmids in Chinese hamster ovary (CHO) cells, and to native M currents in dissociated rat superior cervical ganglion (SCG) neurons, by comparing the block of these currents produced by tetraethylammonium (TEA) with the block of currents generated by a tandem KCNQ3/2 construct. TEA concentration-inhibition curves against coexpressed KCNQ2 plus KCNQ3 currents, and against native M currents in SCG neurons from 6-week-old postnatal day 45 (P45) rats, were indistinguishable from those for the expressed tandem construct, and fully accorded with a 1:1 stoichiometry. Inhibition curves in neurons from younger (P17) rats could be better fitted assuming an additional small proportion of current carried by KCNQ2 homomultimers. Single-cell PCR yielded signals for KCNQ2, KCNQ3, and KCNQ5 mRNAs in all SCG neurons tested from both P17 and P45 rats. Quantitative PCR of whole-ganglion mRNA revealed stable levels of KCNQ2 and KCNQ5 mRNA between P7 and P45, but excess and incrementing levels of KCNQ3 mRNA. Increasing levels of KCNQ3 protein between P17 and P45 were confirmed by immunocytochemistry. We conclude that coexpressed KCNQ2 plus KCNQ3 cDNAs generate channels with 1:1 (KCNQ2:KCNQ3) stoichiometry in CHO cells and that native M channels in SCG neurons adopt the same conformation during development, assisted by the increased expression of KCNQ3 mRNA and protein.
The isolation of the peptide inhibitor of M-type K+ current, BeKm-1, from the venom of the Central Asian scorpion Buthus eupeus has been described previously (Fillipov A. K., Kozlov, S. A., ...Pluzhnikov, K. A., Grishin, E. V., and Brown, D. A. (1996) FEBS Lett. 384, 277–280). Here we report the cloning, expression, and selectivity of BeKm-1. A full-length cDNA of 365 nucleotides encoding the precursor of BeKm-1 was isolated using the rapid amplification of cDNA ends polymerase chain reaction technique from mRNA obtained from scorpion telsons. Sequence analysis of the cDNA revealed that the precursor contains a signal peptide of 21 amino acid residues. The mature toxin consists of 36 amino acid residues. BeKm-1 belongs to the family of scorpion venom potassium channel blockers and represents a new subgroup of these toxins. The recombinant BeKm-1 was produced as a Protein A fusion product in the periplasm of Escherichia coli. After cleavage and high performance liquid chromatography purification, recombinant BeKm-1 displayed the same properties as the native toxin. Three BeKm-1 mutants (R27K, F32K, and R27K/F32K) were generated, purified, and characterized. Recombinant wild-type BeKm-1 and the three mutants partly inhibited the native M-like current in NG108-15 at 100 nm. The effect of the recombinant BeKm-1 on different K+ channels was also studied. BeKm-1 inhibited hERG1 channels with an IC50 of 3.3 nm, but had no effect at 100 nm on hEAG, hSK1, rSK2, hIK, hBK, KCNQ1/KCNE1, KCNQ2/KCNQ3, KCNQ4 channels, and minimal effect on rELK1. Thus, BeKm-1 was shown to be a novel specific blocker of hERG1 potassium channels.
AF276623
The region of alternative splicing in the KCNQ2 potassium channel gene was determined by RNase protection analysis of KCNQ2 mRNA transcripts.
Systematic analysis of KCNQ2 alternative splice variant ...expression in rat superior cervical ganglia revealed multiple variant isoforms.
One class of KCNQ2 splice variants, those that contained exon 15a, was found to have significantly different kinetics to those of the other
isoforms. These transcripts encoded channel subunits that, when co-expressed with the KCNQ3 subunit, activated and deactivated
approximately 2.5 times more slowly than other isoforms. Deletion of exon 15a in these isoforms produced a reversion to the
faster kinetics.
Comparison of the kinetic properties of the cloned channel splice variants with those of the native M-current suggests that
alternative splicing of the KCNQ2 gene may contribute to the variation in M-current kinetics seen in vivo.
ABSTRACT
Objectives:
Nonalcoholic fatty liver disease (NAFLD) is common; however, no information is available on how pediatric gastroenterologists in the United States manage NAFLD. Therefore, study ...objectives were to understand how pediatric gastroenterologists in the US approach the management of NAFLD, and to identify barriers to care for children with NAFLD.
Methods:
We performed structured one‐on‐one interviews to ascertain each individual pediatric gastroenterologist's approach to the management of NAFLD in children. Responses were recorded from open‐ended questions regarding screening for comorbidities, recommendations regarding nutrition, physical activity, medications, and perceived barriers to care.
Results:
Response rate was 72.0% (486/675). Mean number of patients examined per week was 3 (standard deviation SD 3.5). Dietary intervention was recommended by 98.4% of pediatric gastroenterologists. Notably, 18 different dietary recommendations were reported. A majority of physicians provided targets for exercise frequency (72.6%, mean 5.6 days/wk, SD 1.6) and duration (69.9%, mean 40.2 minutes/session, SD 16.4). Medications were prescribed by 50.6%. Almost one‐half of physicians (47.5%) screened for type 2 diabetes, dyslipidemia, and hypertension. Providers who spent more than 25 minutes at the initial visit were more likely to screen for comorbidities (P = 0.003). Barriers to care were reported by 92.8% with 29.0% reporting ≥3 barriers.
Conclusions:
The majority of US pediatric gastroenterologists regularly encounter children with NAFLD. Varied recommendations regarding diet and exercise highlight the need for prospective clinical trials. NAFLD requires a multidimensional approach with adequate resources in the home, community, and clinical setting.
Abstract
Background
Distinguishing the cellular origins of childhood brain tumors is key for understanding tumor initiation and identifying lineage-restricted, tumor-specific therapeutic targets. ...Previous strategies to map the cell-of-origin typically involved comparing human tumors to murine embryonal tissues, which is potentially limited due to species-specific differences. The aim of this study was to unravel the cellular origins of the 3 most common pediatric brain tumors, ependymoma, pilocytic astrocytoma, and medulloblastoma, using a developing human cerebellar atlas.
Methods
We used a single-nucleus atlas of the normal developing human cerebellum consisting of 176 645 cells as a reference for an in-depth comparison to 4416 bulk and single-cell transcriptome tumor datasets, using gene set variation analysis, correlation, and single-cell matching techniques.
Results
We find that the astroglial cerebellar lineage is potentially the origin for posterior fossa ependymomas. We propose that infratentorial pilocytic astrocytomas originate from the oligodendrocyte lineage and MHC II genes are specifically enriched in these tumors. We confirm that SHH and Group 3/4 medulloblastomas originate from the granule cell and unipolar brush cell lineages. Radiation-induced gliomas stem from cerebellar glial lineages and demonstrate distinct origins from the primary medulloblastoma. We identify tumor genes that are expressed in the cerebellar lineage of origin, and genes that are tumor specific; both gene sets represent promising therapeutic targets for future study.
Conclusion
Based on our results, individual cells within a tumor may resemble different cell types along a restricted developmental lineage. Therefore, we suggest that tumors can arise from multiple cellular states along the cerebellar “lineage of origin.”
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