The majority of mutations which lead to clinical cystic fibrosis are located within the two predicted nucleotide binding domains
of the cystic fibrosis gene product. We have used a prokaryotic ...expression system to synthesize and purify the first nucleotide
binding domain (NBD-1, amino acids 426-588) with and without the most common mutation associated with the disease (the deletion
of phenylalanine at position 508, delta F508). Both wild type and delta F508 NBD-1 bind ATP-agarose in a quantitatively comparable
manner; this binding was inhibited by excess Na2ATP, trinitrophenol-ATP, or 8-azido-ATP. Irreversible NBD-1 labeling by an
ATP analog was demonstrated using 32P8-azido-ATP. This covalent labeling was inhibited by preincubation with Na2ATP, with
half-maximal inhibition for Na2ATP occurring at approximately 5 mM for both the wild type and delta F508 nucleotide binding
domain. These experiments are among the first to confirm the expectation that the cystic fibrosis transmembrane conductance
regulator NBD-1 binds nucleotide. Since, under the conditions used in our study, NBD-1 without phenylalanine 508 displays
very similar nucleotide binding characteristics to the wild type protein, our results support previous structural models which
predict that the delta F508 mutation should not cause an alteration in ATP binding.
To determine the effect of COVID-19 convalescent plasma on mortality, we aggregated patient outcome data from 10 randomized clinical trials, 20 matched control studies, 2 dose-response studies, and ...96 case reports or case series. Studies published between January 1, 2020, and January 16, 2021, were identified through a systematic search of online PubMed and MEDLINE databases. Random effects analyses of randomized clinical trials and matched control data demonstrated that patients with COVID-19 transfused with convalescent plasma exhibited a lower mortality rate compared with patients receiving standard treatments. Additional analyses showed that early transfusion (within 3 days of hospital admission) of higher titer plasma is associated with lower patient mortality. These data provide evidence favoring the efficacy of human convalescent plasma as a therapeutic agent in hospitalized patients with COVID-19.
To investigate the prognostic value of quantitative computed tomographic (CT) scoring for the extent of fibrosis or emphysema in the context of a clinical model that includes the gender, age, and ...physiology ( GAP gender, age, and physiology model) of the patient.
Study cohorts were approved by local institutional review boards, and all patients provided written consent. This was a retrospective cohort study that included 348 patients (246 men, 102 women; mean age, 69 years ± 9) with idiopathic pulmonary fibrosis from two institutions. Fibrosis and emphysema visual scores were independently determined by two radiologists. Models were based on competing risks regression for death and were evaluated by using the C index and reclassification improvement.
The CT- GAP gender, age, and physiology model (a modification of the original GAP gender, age, and physiology model that replaces diffusion capacity of carbon monoxide with CT fibrosis score) had accuracy comparable to that of the original GAP gender, age, and physiology model, with a C index of 70.3 (95% confidence interval: 66.4, 74.0); difference in C index compared with the GAP gender, age, and physiology model of -0.4 (95% confidence interval: -2.2, 3.4). The performance of the original GAP gender, age, and physiology model did not change significantly with the simple addition of fibrosis score, with a change in C index of 0.0 (95% confidence interval: -1.8, 0.5) or of emphysema score, with a change in C index of 0.0 95% confidence interval: -1.3, 0.4).
CT fibrosis score can replace diffusion capacity of carbon monoxide test results in a modified GAP gender, age, and physiology model (the CT- GAP gender, age, and physiology model) with comparable performance. This may be a useful alternative model in situations where CT scoring is more reliable and available than diffusion capacity of carbon monoxide.
To examine the time course (immediate, 10, 20, and 30 min) for the acute effects of 2, 4, and 8 min of passive stretching (PS) on isometric peak torque (PT), percent voluntary activation (%VA), EMG ...amplitude, peak twitch torque (PTT), rate of twitch torque development (RTD), and range of motion (ROM) of the plantarflexors.
Thirteen volunteers (mean +/- SD age, 22 +/- 3 yr) participated in four randomly ordered experimental trials: control (CON) with no stretching, 2 min (PS2), 4 min (PS4), and 8 min (PS8) of PS. Testing was conducted before (pre), immediately after (post), and at 10, 20, and 30 min poststretching. The PS trials involved varied repetitions of 30-s passive stretches, whereas the CON trial included 15 min of resting. PT, %VA, EMG amplitude, PTT, and RTD were assessed during the twitch interpolation technique, whereas ROM was quantified as the maximum tolerable angle of passive dorsiflexion.
PT decreased (P < or = 0.05) immediately after all conditions CON (4%), PS2 (2%), PS4 (4%), and PS8 (6%) but returned to baseline at 10, 20, and 30 min poststretching. %VA and EMG amplitude were unaltered (P > 0.05) after all conditions. PTT and RTD decreased (P < or = 0.05) immediately after the PS4 (7%) and the PS8 (6%) conditions only; however, these changes were not sufficient to alter voluntary force production. There were also increases (P < or = 0.05) in ROM after the PS2 (8%), the PS4 (14%), and the PS8 (13%) conditions that returned to baseline after 10 min.
Practical durations of stretching (2, 4, or 8 min) of the plantarflexors did not decrease isometric PT compared with the CON but caused temporary improvements in the ROM, thereby questioning the overall detrimental influence of PS on performance.
The first nucleotide binding fold (NBF-1) from the cystic fibrosis transmembrane regulator (CFTR) has been expressed in bacteria and found to bind ATP and to express anion channel activity when ...reconstituted onto a planar lipid bilayer. This evidence suggests that the NBF forms the anion-selective portion of the CFTR channel. We also found that the recombinant NBF-1 anion channel is blocked by ATP (1 mM), under which condition it appears to have a minimal conductance of ≈ 9 pS and an ohmic current-voltage relationship. We further found that the recombinant NBF-1 bearing the Δ F508 mutation has nearly identical anion channel activity to that of the wild-type protein but can be distinguished from wild type under bianionic conditions with chloride and gluconate. We conclude from these data that the anion channel activity of the recombinant NBF-1 could represent all or part of the anion conductance mechanism of CFTR and that the role of the ATP binding by the NBF could be to modulate this anion channel activity.
Summary
Objective
Infantile spasms (IS) represent a severe epileptic encephalopathy presenting in the first 2 years of life. Recommended first‐line therapies (hormonal therapy or vigabatrin) often ...fail. We evaluated response to second treatment for IS in children in whom the initial therapy failed to produce both clinical remission and electrographic resolution of hypsarhythmia and whether time to treatment was related to outcome.
Methods
The National Infantile Spasms Consortium established a multicenter, prospective database enrolling infants with new diagnosis of IS. Children were considered nonresponders to first treatment if there was no clinical remission or persistence of hypsarhythmia. Treatment was evaluated as hormonal therapy (adrenocorticotropic hormone ACTH or oral corticosteroids), vigabatrin, or “other.” Standard treatments (hormonal and vigabatrin) were compared to all other nonstandard treatments. We compared response rates using chi‐square tests and multivariable logistic regression models.
Results
One hundred eighteen infants were included from 19 centers. Overall response rate to a second treatment was 37% (n = 44). Children who received standard medications with differing mechanisms for first and second treatment had higher response rates than other sequences (27/49 55% vs. 17/69 25%, p < 0.001). Children receiving first treatment within 4 weeks of IS onset had a higher response rate to second treatment than those initially treated later (36/82 44% vs. 8/34 24%, p = 0.040).
Significance
Greater than one third of children with IS will respond to a second medication. Choosing a standard medication (ACTH, oral corticosteroids, or vigabatrin) that has a different mechanism of action appears to be more effective. Rapid initial treatment increases the likelihood of response to the second treatment.
To evaluate the performance of an internally developed and previously validated artificial intelligence (AI) algorithm for magnetic resonance (MR)–derived total kidney volume (TKV) in autosomal ...dominant polycystic kidney disease (ADPKD) when implemented in clinical practice.
The study included adult patients with ADPKD seen by a nephrologist at our institution between November 2019 and January 2021 and undergoing an MR imaging examination as part of standard clinical care. Thirty-three nephrologists ordered MR imaging, requesting AI-based TKV calculation for 170 cases in these 161 unique patients. We tracked implementation and performance of the algorithm over 1 year. A radiologist and a radiology technologist reviewed all cases (N=170) for quality and accuracy. Manual editing of algorithm output occurred at radiology or radiology technologist discretion. Performance was assessed by comparing AI-based and manually edited segmentations via measures of similarity and dissimilarity to ensure expected performance. We analyzed ADPKD severity class assignment of algorithm-derived vs manually edited TKV to assess impact.
Clinical implementation was successful. Artificial intelligence algorithm–based segmentation showed high levels of agreement and was noninferior to interobserver variability and other methods for determining TKV. Of manually edited cases (n=84), the AI-algorithm TKV output showed a small mean volume difference of –3.3%. Agreement for disease class between AI-based and manually edited segmentation was high (five cases differed).
Performance of an AI algorithm in real-life clinical practice can be preserved if there is careful development and validation and if the implementation environment closely matches the development conditions.
Fathead minnows, 'Pimephales promelas', have the ability to detect predators through visual, chemical and possibly mechanosensory cues. The predominant chemical cue used by minnows is alarm ...substance, a chemical released when the skin of a minnow is damaged. Previous research assumed that alarm substance was a pheromone designed to alert other members of the shoat of danger. If individuals sensed alarm substance, they were expected to react regardless of the context. Recent studies have created a controversy by demonstrating the response to alarm substance is dependent on the context (i.e., the level of risk) in which it is encountered. I propose that the response to alarm substance is not only determined by the level of risk, but also by the availability of information through the other senses. I developed a sensory compensation model that assumes the concentration of alarm substance necessary to generate an antipredator response decreases as the predation risk and the turbidity level increases. Two experiments were conducted to test the predictions of the model by manipulating the level of risk. The first experiment modified risk sensitivity with hunger levels and the second altered risk of predation through the availability of cover. (Abstract shortened by UMI.)
PDF
