Newborn screening (NBS) for Krabbe disease, a rare neurodegenerative disorder caused by deficient galactocerebrosidase (GALC) enzyme activity, has recently been implemented in a number of US states. ...However, the spectrum of phenotypic manifestations associated with deficient GALC activity complicates the management of screen-positive newborns and underscores the need to identify clinically relevant biomarkers. Earlier studies with a small number of patients identified psychosine, a substrate of the GALC enzyme, as a potential biomarker for Krabbe disease. In this study, we provide, for the first time, longitudinal data on dried blood spot (DBS) psychosine concentrations in different Krabbe disease phenotypes for both untreated patients and those treated with hematopoietic stem cell transplantation (HSCT). Our cohort included patients previously identified by NBS to be at high risk to develop Krabbe disease. Substantially elevated DBS psychosine concentration during the newborn period was found to be a highly specific marker for infantile Krabbe disease. This finding supports the use of DBS psychosine concentration as a second-tier NBS test to aid in the identification of patients who require urgent evaluation for HSCT. In addition, longitudinal assessments showed that both natural disease progression and treatment with HSCT were associated with decreases in DBS psychosine concentrations. Based on these findings we provide recommendations for the interpretation of psychosine concentrations in DBS specimens collected during the first year of life. Future studies should aim to better delineate the relationship between DBS psychosine concentration and disease onset in patients with later-onset forms of Krabbe disease.
•DBS psychosine concentrations were evaluated in a large cohort of KD patients.•Elevated DBS psychosine at birth showed high specificity as a marker for KD.•Disease progression was associated with longitudinal decreases in DBS psychosine.•DBS psychosine typically declined following treatment with HSCT.•Measuring DBS psychosine may serve as a useful second-tier newborn screening test.
It is uncertain whether the administration of benzodiazepines by paramedics is an effective and safe treatment for out-of-hospital status epilepticus.
We conducted a randomized, double-blind trial to ...evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus. Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg), lorazepam (2 mg), or placebo. An identical second injection was given if needed.
Of the 205 patients enrolled, 66 received lorazepam, 68 received diazepam, and 71 received placebo. Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (59.1 percent) or diazepam (42.6 percent) than patients given placebo (21.1 percent) (P=0.001). After adjustment for covariates, the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 4.8 (95 percent confidence interval, 1.9 to 13.0). The odds ratio was 1.9 (95 percent confidence interval, 0.8 to 4.4) in the lorazepam group as compared with the diazepam group and 2.3 (95 percent confidence interval, 1.0 to 5.9) in the diazepam group as compared with the placebo group. The rates of respiratory or circulatory complications (indicated by bag valve-mask ventilation or an attempt at intubation, hypotension, or cardiac dysrhythmia) after the study treatment was administered were 10.6 percent for the lorazepam group, 10.3 percent for the diazepam group, and 22.5 percent for the placebo group (P=0.08).
Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults. Lorazepam is likely to be a better therapy than diazepam.
We describe an approach for the accurate quantification and concurrent sequence identification of the individual proteins within complex mixtures. The method is based on a class of new chemical ...reagents termed isotope-coded affinity tags (ICATs) and tandem mass spectrometry. Using this strategy, we compared protein expression in the yeast Saccharomyces cerevisiae, using either ethanol or galactose as a carbon source. The measured differences in protein expression correlated with known yeast metabolic function under glucose-repressed conditions. The method is redundant if multiple cysteinyl residues are present, and the relative quantification is highly accurate because it is based on stable isotope dilution techniques. The ICAT approach should provide a widely applicable means to compare quantitatively global protein expression in cells and tissues.
Cite this as: T. S. Hallstrand, Y. Lai, Z. Ni, R. C. Oslund, W. R. Henderson Jr, M. H. Gelb and S. E. Wenzel, Clinical & Experimental Allergy, 2011 (41) 801–810.
Summary
Background
Secreted ...phospholipase A2 (sPLA2) may be important mediators of asthma, but the specific sPLA2s involved in asthma are not known.
Objective
To evaluate sPLA2 group IIA, V, and X proteins (sPLA2‐IIA, sPLA2‐V, and sPLA2‐X) in bronchoalveolar lavage (BAL) fluid, BAL cells, and airway epithelial cells of subjects with and without asthma, and examine the relationship between the levels of specific sPLA2 enzymes and airway inflammation, asthma severity, and lung function.
Methods
The expression of sPLA2‐IIA, sPLA2‐V, and sPLA2‐X in BAL cells and epithelial brushings was assessed by qPCR. The levels of these sPLA2 proteins and sPLA2 activity with and without group II and group X‐specific inhibitors were measured in BAL fluid from 18 controls and 39 asthmatics.
Results
The airway epithelium expressed sPLA2‐X at higher levels than either sPLA2‐IIA or sPLA2‐V, whereas BAL cells expressed sPLA2‐IIA and sPLA2‐X at similar levels. The majority of sPLA2 activity in BAL fluid was attributed to either sPLA2‐IIA or sPLA2‐X. After 10‐fold concentration of BAL fluid, the levels of sPLA2‐X normalized to total protein were increased in asthma and were associated with lung function, the concentration of induced sputum neutrophils, and prostaglandin E2. The levels of sPLA2‐IIA were elevated in asthma when normalized to total protein, but were not related to lung function, markers of airway inflammation or eicosanoid formation.
Conclusions and Clinical Relevance
These data indicate that sPLA2‐IIA and sPLA2‐X are the major sPLA2s in human airways, and suggest a link between the levels of sPLA2‐X in the airways and several features of asthma.
We present the result of the search for the rare B meson decay of B+ → ℓ+νℓγ with ℓ = e,μ. For the search the full data set recorded by the Belle experiment of 711 fb−1 integrated luminosity near the ...Υ (4S) resonance is used. Signal candidates are reconstructed for photon energies Eγ larger than 1 GeV using a novel multivariate tagging algorithm. The novel algorithm fully reconstructs the second B meson produced in the collision using hadronic modes and was specifically trained to recognize the signal signature in combination with hadronic tag-side B meson decays. This approach greatly enhances the performance. Background processes that can mimic this signature, mainly charmless semileptonic decays and continuum processes, are suppressed using multivariate methods. The number of signal candidates is determined by analyzing the missing mass squared distribution as inferred from the signal side particles and the kinematic properties of the tag-side B meson. No significant excess over the background-only hypothesis is observed and upper limits on the partial branching fraction Δ B with Eγ > 1 GeV individually for electron and muon final states as well as for the average branching fraction of both lepton final states are reported. We find a Bayesian upper limit of Δ B (B+ → ℓ+νℓγ) < 3.0 × 10−6 at 90% CL and also report an upper limit on the first inverse moment of the light-cone distribution amplitude of the B meson of λB > 0.24 GeV at 90% CL.
False alarms in active sonar systems arising from physical objects in the ocean (e.g., rocks, fish, or seaweed) are often called clutter. A variety of statistical models have been proposed for ...representing the sonar probability of false alarm (P fa ) in the presence of clutter, including the log-normal, generalized-Pareto, Weibull, and K distributions. However, owing to the potential sparseness of the clutter echoes within the analysis window, a mixture distribution comprising one of the clutter distributions and a Rayleigh-distributed envelope (i.e., an exponentially distributed intensity) to represent diffuse background scattering and noise is proposed. Parameter-estimation techniques based on the expectation-maximization (EM) algorithm are developed for mixtures containing the aforementioned clutter distributions. While the standard EM algorithm handles the mixture containing log-normal clutter, the EM-gradient algorithm, which combines the EM algorithm with a one-step Newton optimization, is necessary for the generalized-Pareto and Weibull cases. The mixture containing K -distributed clutter requires development of a variant of the EM algorithm exploiting method-of-moments parameter estimation. Evaluation of three midfrequency active-sonar data examples, spanning mildly to very heavy-tailed P fa , illustrates that the mixture models provide a better fit than single-component models. As might be expected, inference on clutter-source scattering based on the shape parameter of the clutter distribution is shown to be less biased using the mixture model compared with a single-component distribution when the data contain both clutter echoes and diffuse background scattering or noise.
Introduction
The objective of this study was to evaluate real-world effectiveness of latanoprostene bunod (LBN) ophthalmic solution 0.024% in treatment-naïve patients newly diagnosed with open-angle ...glaucoma (OAG) or ocular hypertension.
Methods
This multicenter retrospective chart review included patients aged ≥ 18 years, with no history of medical, laser, or surgical intraocular pressure (IOP)-lowering intervention and at least two follow-up visits (spanning ≥ 2 months) following initiation of LBN treatment. Extracted data included age, sex, race, cup-to-disk ratio, central corneal thickness, IOP, visual acuity (VA), concomitant medications, and adverse events. In patients treated bilaterally, the eye with the higher baseline IOP was the study eye.
Results
Medical charts for 65 patients (mean SD age, 59 14 years; 53.8% female) encompassing 125 eyes treated with LBN were reviewed across nine clinical sites. Mean (SD) IOP at baseline was 21.7 (5.9) mmHg. Mean days to first and second follow-up visit were 43 and 141, respectively. LBN use resulted in a mean (SD) reduction from baseline of 7.1 (4.7) and 7.3 (5.1) mmHg at the first and second follow-up visits, respectively (
P
< 0.0001 for both). Reductions among patients with IOP > 21 mmHg (
n
= 30) at baseline were 10.0 (4.5) and 11.1 (4.6) mmHg at the first and second follow-up visits (
P
< 0.0001 for both). There were no meaningful changes in VA. Adverse events appeared infrequent, with only one report of ocular redness.
Conclusion
In this real-world, retrospective chart review, LBN 0.024% use resulted in robust IOP lowering in newly diagnosed OAG patients new to treatment, and appeared well tolerated.
PDF
