Changes in fecal microbiota with CFTR modulator therapy: A pilot study.

Studies have demonstrated that people with CF with pancreatic insufficiency (PI) have fecal dysbioses. Evidence suggests the causes of these dysbioses are multifactorial, and that important drivers include antibiotic exposure, dietary intake, and CF gastrointestinal tract dysfunction, including nutrient malabsorption. In this pilot study, we tested whether initiation of the CFTR modulator treatments ivacaftor (in a cohort of pancreatic sufficient (PS) people with CF and an R117H CFTR variant) or lumacaftor/ivacaftor (in a cohort of PI people with CF and an F508del variant) changed fecal measures of malabsorption or fecal microbiomes. While we identified no statistically significant fecal changes with either treatment, we detected trends in the PI cohort when initiating lumacaftor/ivacaftor towards decreased fecal fat content and towards fecal microbiomes that more closely resembled the fecal microbiota of people without PI. While these findings support a model in which nutrient malabsorption resulting from CF-induced PI drives fecal dysbiosis, they must be validated in future, larger studies of fecal microbiome and malabsorption outcomes with highly effective CFTR modulator therapies.

Targeting the PI3K/Akt/mTOR signalling pathway in Cystic Fibrosis.

Deletion of phenylalanine 508 of the cystic fibrosis transmembrane conductance regulator (ΔF508 CFTR) is a major cause of cystic fibrosis (CF), one of the most common inherited childhood diseases. ΔF508 CFTR is a trafficking mutant that is retained in the endoplasmic reticulum (ER) and unable to reach the plasma membrane. Efforts to enhance exit of ΔF508 CFTR from the ER and improve its trafficking are of utmost importance for the development of treatment strategies. Using protein interaction profiling and global bioinformatics analysis we revealed mammalian target of rapamycin (mTOR) signalling components to be associated with ∆F508 CFTR. Our results demonstrated upregulated mTOR activity in ΔF508 CF bronchial epithelial (CFBE41o-) cells. Inhibition of the Phosphatidylinositol 3-kinase/Akt/Mammalian Target of Rapamycin (PI3K/Akt/mTOR) pathway with 6 different inhibitors demonstrated an increase in CFTR stability and expression. Mechanistically, we discovered the most effective inhibitor, MK-2206 exerted a rescue effect by restoring autophagy in ΔF508 CFBE41o- cells. We identified Bcl-2-associated athanogene 3 (BAG3), a regulator of autophagy and aggresome clearance to be a potential mechanistic target of MK-2206. These data further link the CFTR defect to autophagy deficiency and demonstrate the potential of the PI3K/Akt/mTOR pathway for therapeutic targeting in CF.

Ivacaftor as salvage therapy in a patient with cystic fibrosis genotype F508del/R117H/IVS8-5T.

Ivacaftor is a novel CFTR potentiator that increases CFTR activity and improves clinical outcomes in cystic fibrosis (CF) patients with at least one copy of CFTR-G551D. Clinical trials have shown an improvement in lung function, weight and CF pulmonary exacerbation in adults with CFTR-G551D leading to the approval of ivacaftor as a novel CF therapy [1]. In vitro studies of ivacaftor have also shown significant improvements in CFTR chloride channel opening time in other non-G551D CFTR mutations suggesting that ivacaftor may be of benefit to patients with mutations other than gating mutations [2]. R117H-CFTR is a relatively common CFTR mutation that demonstrates an in-vitro response to ivacaftor [2,3]. A clinical trial has suggested that there may be a role for ivacaftor in older patients with R117H-CFTR although this trial did not include patients with very severe CF lung disease [4]. In 2014, ivacaftor was approved in the United States as a treatment for CF subjects aged greater than 6 years old with a copy of R117H-CFTR. We present a case demonstrating a substantial therapeutic effect of ivacaftor in a CF patient with genotype F508del/R117H and advanced lung disease.

Lemierre's syndrome.

Lemierre's syndrome is a rare disease that results in an oropharyngeal infection, which precipitates an internal jugular vein thrombosis and metastatic infection. Fusobacterium necrophorum is an anaerobic Gram-negative bacillus and has been identified as the causative agent. We describe the case of a young girl whose presentation and diagnosis were confounded by a history of valvular heart disease. Infection of heart valves can produce many of the signs and symptoms associated with Lemierre's syndrome. We describe the diagnosis, investigation and optimal management of this rare disorder.

Experience using centralized spirometry in the phase 2 randomized, placebo-controlled, double-blind trial of denufosol in patients with mild to moderate cystic fibrosis.

BACKGROUND: Centralized spirometry may significantly improve quality of spirometry and reduce variability of this outcome measure in clinical trials in cystic fibrosis (CF). METHODS: Spirometry was performed during the phase 2 randomized, placebo-controlled, double-blind clinical trial of denufosol in patients with mild to moderate CF using American Thoracic Society guidelines. Uniform spirometers were used with electronic data transmission of all the data to a reading center. Spirometry was evaluated for quality by a central reader based on start of test, cough during the test, and evidence of a plateau. RESULTS: A total of 1418 spirometry values were assessed in 89 subjects during the trial. In only 5 instances did the central reading center need to give feedback to sites regarding the quality of spirometry. The study site data matched the central reading center's data for all but 78 (6%) spirometry values in 33 patients. Many of these differences were small with only 35 (3%) values differing by more than 50 mL in 26 patients. CONCLUSION: Spirometry in this clinical trial was of high quality with low rate of significant centralized over-read.

The role of supplemental oxygen during submaximal exercise in patients with cystic fibrosis.

Repeated bouts of submaximal exercise are an important part of most pulmonary rehabilitation programmes. Patients with moderate-to-severe cystic fibrosis (CF) often demonstrate oxygen desaturation during submaximal exercise, which may limit their ability to participate in these programmes. This study examines whether arterial desaturation contributes to submaximal exercise limitation by testing whether supplemental O2 improves submaximal exercise capacity. Eight patients with CF (mean forced expiratory volume in one second 41% predicted) each underwent two submaximal exercise tests on a bicycle ergometer at 80% of maximal workload. The two tests were identical except for the addition of supplemental O2 (inspiratory O2 fraction 39%) during one of the tests. Exercise duration was significantly longer in the supplemental O2 study versus control (673+/-63 s versus 835+/-99 s). Arterial O2 saturation was also higher in the supplemental O2 study than the control exercise test (96+/-0.3% versus 86+/-1.5%). There was no statistical difference at end exercise between O2 consumption, minute ventilation and heart rate. There was a significant relationship between improvement in exercise capacity and the amount of desaturation during the control exercise test. Results indicate that supplemental oxygen improves submaximal exercise capacity in patients with moderate-to-severe cystic fibrosis. Oxygen therapy may be an important intervention to improve participation and maximise the benefits of pulmonary exercise rehabilitation programmes.

Categorical perception of face identity in noise isolates configural processing.

Neuropsychological evidence suggests that face recognition based on configural (holistic) information can occur in isolation from recognition based on local feature cues. The present study shows that configural processing can be isolated experimentally in normal subjects. A phenomenon is reported that exists only for upright whole faces, namely categorical perception (CP) of face identity in noise. Three discrimination tasks (ABX, better likeness, and similarity ratings) were used to test for perceptual distortion across the category boundary predicted from binary classification of face morphs. Noise was added such that any single local region provided unreliable cues to identity. Under these conditions, CP was found for upright faces but not for inverted faces or single features, even with more than 10,000 trials. The CP-in-noise signature phenomenon was then used to show that configural processing survives image plane rotations of 45 degrees-90 degrees.

In what sense is implicit memory "episodic"? The effect of reinstating environmental context.

We consider three aspects of the term episodic. Previous literature shows implicit memory does not make conscious autobiographical reference but does code an item's intrinsic context (e.g., perceptual detail). Here, we consider extrinsic context--namely, that not directly processed as part of item identification and not overtly relevant to the task. Study-test mismatch in environmental context (outdoors vs. indoors) reduced memory in an explicit stem-cued recall task but had no effect on repetition priming in an implicit stem completion task. This was true even for very low frequency words. We support the view that implicit memory reflects traces within perceptual (or semantic) knowledge-based systems that are instance specific but do not code the full spatiotemporal context information necessary to support conscious recollection. We also interpret our results as consistent with differences in environmental context specificity between free recall and recognition.

Short-term implicit memory: visual, auditory, and cross-modality priming.

Short-term implicit memory was examined for mixed auditory (A) and visual (V) stimuli. In lexical decision, words and nonwords were repeated at lags of 0, 1, 3, and 6 intervening trials, in four prime-target combinations (VV, VA, AV, AA). Same-modality repetition priming showed a lag x lexicality interaction for visual stimuli (nonwords decayed faster), but not for auditory stimuli (longer lasting smooth decay for both words and nonwords). These modality differences suggest that short-term priming has a perceptual locus, with the phonological lexicon maintaining stimuli active longer than the orthographic lexicon and treating pseudowords as potential words. We interpret these differences in terms of the different memory needs of speech recognition and text reading. Weak cross-modality short-term priming was present for words and nonwords, indicating recoding between perceptual forms.

Orientation invariance in naming rotated objects: individual differences and repetition priming.

In naming drawings of complex common objects, unpracticed naming times increase with rotation away from the upright, but this orientation effect is attenuated with practice. In principle, attenuation could result from learning to extract orientation-invariant information or from learning view-specific representations at the trained orientations. We contrasted these approaches by examining repetition priming for prime-target pairs presented on successive trials in either the same orientation (horse at 51 degrees primes horse at 51 degrees) or a different orientation (horse at 154 degrees primes horse at 51 degrees), for two subgroups of subjects. One subgroup showed no orientation effect, even when unpracticed, and a correspondingly high generalization of priming across different views. The other subgroup initially showed high sensitivity to misorientation and little priming across orientations but, with sufficient practice, came to show no orientation effect and complete generalization of priming. Thus, some subjects always used orientation-invariant procedures, whereas others learned to do so.

Acquisition of novel traces in short-term implicit memory: priming for nonwords and new associations.

McKone (1995) reported a short-lived repetition priming effect (up to 8 sec and three intervening items), superimposed on long-term priming. In lexical decision and naming, decay of this short-term implicit memory was faster for pseudowords than for words, suggesting an explanation in terms of transient activation of preexisting lexical representations. Here, we present two cases where, in contrast, preexperimental familiarity did not affect short-term priming, indicating acquisition of novel traces. Experiment 1 determined repetition priming in same-different judgments to lowercase-uppercase pairs for words, and for nonwords with three levels of wordlikeness. Across lags of 0, 1, and 6 intervening items (2-14 sec), short-term priming was the same for all stimuli, even random letter strings. Experiments 2 and 3 assessed priming in a double lexical decision task for old associations (orange-apple) and new associations (cigar-errand). Short-term priming for the association was equal in both cases.

Reproducibility of maximal exercise ergometer testing in patients with cystic fibrosis.

OBJECTIVES: Exercise testing in patients with cystic fibrosis (CF) has become an important tool in assessing disease severity and predicting overall outcome. The reproducibility of maximal exercise testing was examined in adult subjects with stable CF. METHODS: Nine subjects with CF underwent a total of three maximal exercise tests carried out under identical circumstances over a 28-day period. Oxygen uptake (VO2), minute ventilation (VE), respiratory frequency (f), heart rate (HR), and arterial oxygen saturation (SaO2) were measured at rest, at end exercise, and at 40% and 70% of maximum workload. RESULTS: There were no significant differences in these measurements among the three tests. Reproducibility of exercise performance was assessed using the coefficient of variation. The mean within-subject coefficient of variation for test variables at end exercise are as follows: VO2, 6.9%; VE, 6.2%; f, 5.8%; IIR, 3.0%; and SaO2, 1.1%. The mean within-subject coefficient of variation for test variables at 40% and 70% of maximal work rates are as follows: VO2, 5.2% and 4.6%; SaO2, 0.3% and 0.9%; HR, 4.0% and 3%; VE, 5.7% and 6.5%; and f, 5.8% and 7.2%, respectively. CONCLUSIONS: Variables measured during clinical cycle ergometer exercise testing in adult patients with stable CF are reproducible. No learning effect was found on repeated testing.

The decay of short-term implicit memory: unpacking lag.

McKone (1995) reported a short-lived repetition priming effect, superimposed on long-lived priming. This short-term implicit memory survived a few intervening items and several seconds for words but decayed precipitously for nonwords, producing a lag x lexicality interaction. Here, mechanisms of decay are studied by disconfounding the time delay and interference components of lag. In Experiment 1, time delay was varied while number of intervening items was held constant, and vice versa. In Experiment 2, priming was plotted as a function of time delay, with and without intervening items. Using a lexical decision task, both experiments found independent contributions of time and interference to the decay of short-term priming. Further, Experiment 2 attributed the lag x lexicality interaction to a particular sensitivity of nonword traces to interference. An illustration of how these effects might arise in the word recognition system is provided.

Environmental policy analysis: evaluating toxic impact assessment methods: what works best.

EDGAR G. HERTWICH Energy and Resources Group University of California Berkeley, CA 94720-3050 WILLIAM S. PEASE Environmental Defense Fund Oakland, CA 95616 THOMAS E. MCKONE Environmental Health Science University of California Berkeley, CA 94720-7360.

Explicit contamination in "implicit" memory for new associations.

In one view of implicit memory, priming arises from modification of preexisting representations; however, the role of such representations is currently in doubt following findings of implicit memory for newly formed associations. Closer consideration of studies reporting this effect, and of others that have failed to obtain it, suggests that such priming might results from the employment of explicit memory strategies. With measures designed to permit exclusion of such strategies, three experiments using lexical decision and stem-completion tasks found no evidence of truly implicit memory for unrelated pairs. Instead, priming was found only in those subjects (50% of the total in one experiment) who reported using explicit memory in stem completion. Contrary to previous conclusions, the results indicate a role for established representations in explaining implicit memory.