Sequencing identifies a distinct signature of circulating microRNAs in early radiographic knee osteoarthritis.

OBJECTIVE: MicroRNAs act locally and systemically to impact osteoarthritis (OA) pathophysiology, but comprehensive profiling of the circulating miRNome in early vs late stages of OA has yet to be conducted. Sequencing has emerged as the preferred method for microRNA profiling since it offers high sensitivity and specificity. Our objective was to sequence the miRNome in plasma from 91 patients with early [Kellgren-Lawrence (KL) grade 0 or 1 (n = 41)] or late [KL grade 3 or 4 (n = 50)] symptomatic radiographic knee OA to identify unique microRNA signatures in each disease state. DESIGN: MicroRNA libraries were prepared using the QIAseq miRNA Library Kit and sequenced on the Illumina NextSeq 550. Counts were produced for microRNAs captured in miRBase and for novel microRNAs. Statistical, bioinformatics, and computational biology approaches were used to refine and interpret the final list of microRNAs. RESULTS: From 215 differentially expressed microRNAs (FDR < 0.01), 97 microRNAs showed an increase or decrease in expression in ≥85% of samples in the early OA group as compared to the median expression in the late OA group. Increasing this threshold to ≥95%, seven microRNAs were identified: hsa-miR-335-3p, hsa-miR-199a-5p, hsa-miR-671-3p, hsa-miR-1260b, hsa-miR-191-3p, hsa-miR-335-5p, and hsa-miR-543. Four novel microRNAs were present in ≥50% of early OA samples and had 27 predicted gene targets in common with the prioritized set of predicted gene targets from the 97 microRNAs, suggesting common underlying mechanisms. CONCLUSION: Sequencing of well-characterized patient cohorts produced unbiased profiling of the circulating miRNome and identified a unique panel of 11 microRNAs in early radiographic knee OA.

Microglial SK3 and SK4 currents and activation state are modulated by the neuroprotective drug, riluzole.

Microglia monitor the CNS for 'danger' signals after acute injury, such as stroke and trauma, and then undergo complex activation processes. Classical activation of microglia can produce neurotoxic levels of glutamate and immune mediators (e.g., pro-inflammatory cytokines, reactive oxygen and nitrogen species), while alternative activation up-regulates anti-inflammatory molecules and is thought to resolve inflammation and protect the brain. Thus, pharmacological strategies to decrease classical- and/or promote alternative activation are of interest. Here, we assessed actions of the neuroprotective drug, riluzole, on two Ca(2+)- activated K channels in microglia - SK3 (KCa2.3, KCNN3) and SK4 (KCa3.1, KCNN4) - and on classical versus alternative microglial activation. Riluzole is used to treat amyotrophic lateral sclerosis, and is in clinical trials for several other CNS disorders, where it has been presumed to target neurons and reduce glutamate-mediated toxicity. We show that simply elevating intracellular Ca(2+) to micromolar levels in whole-cell recordings does not activate SK channels in a cell line derived from primary rat microglia (MLS-9). In intact cells, riluzole raised cytoplasmic Ca(2+), but it was marginal (~200 nM) and transient (2 min). Surprisingly then, in whole cell recordings, riluzole rapidly activated SK3 and SK4 channels for as long as it was present, and did not require elevated intracellular Ca(2+). We then used primary rat microglia to analyze expression of several activation markers and inflammatory mediators. Riluzole decreased classical LPS-induced activation, and increased some aspects of IL-4-induced alternative activation. These actions on microglia suggest an additional mechanism underlying the neuroprotective actions of riluzole.

Well siblings living with schizophrenia. Impact of associated behaviors.

As a result of the ongoing hallucinations and delusions, life at home became "anxious and chaotic" with "lots of stress." Because there was no on-site crisis intervention by professionals, well siblings were sometimes called upon to control the violent behavior and were vigilant and fearful regarding the potential for abuse. Negative symptoms were the most disturbing to well siblings. Siblings need help to understand that social isolation and lack of motivation are symptoms of the illness--not due to "laziness."

On prototypes and phonetic categories: a critical assessment of the perceptual magnet effect in speech perception.

According to P. K. Kuhl (1991), a perceptual magnet effect occurs when discrimination accuracy is lower among better instances of a phonetic category than among poorer instances. Three experiments examined the perceptual magnet effect for the vowel /i/. In Experiment 1, participants rated some examples of /i/ as better instances of the category than others. In Experiment 2, no perceptual magnet effect was observed with materials based on Kuhl's tokens of /i/ or with items normed for each participant. In Experiment 3, participants labeled the vowels developed from Kuhl's test set. Many of the vowels in the nonprototype /i/ condition were not categorized as /i/s. This finding suggests that the comparisons obtained in Kuhl's original study spanned different phonetic categories.

Sibling perception of schizophrenia: impact on relationships, roles, and health.

This descriptive field study examined the impact of schizophrenia on 30 adult siblings of patients with schizophrenia. Sibling perceptions of impact on roles, relationships, and health were investigated. Findings revealed that schizophrenia brings about changes in all relationships, but the relationship most affected was that with the ill sibling. Participants experienced grief over loss of the sibling and had difficulty maintaining the relationship. Leisure activities were influenced, as were school and work performance. A significant relationship between health and impact was found. The results of this study provide a basis for developing sibling-specific interventions.

Training Japanese listeners to identify English /r/ and /l/. III. Long-term retention of new phonetic categories.

Monolingual speakers of Japanese were trained to identify English /r/ and /l/ using Logan et al.'s [J. Acoust. Soc. Am. 89, 874-886 (1991)] high-variability training procedure. Subjects' performance improved from the pretest to the post-test and during the 3 weeks of training. Performance during training varied as a function of talker and phonetic environment. Generalization accuracy to new words depended on the voice of the talker producing the /r/-/l/ contrast: Subjects were significantly more accurate when new words were produced by a familiar talker than when new words were produced by an unfamiliar talker. This difference could not be attributed to differences in intelligibility of the stimuli. Three and six months after the conclusion of training, subjects returned to the laboratory and were given the post-test and tests of generalization again. Performance was surprisingly good on each test after 3 months without any further training: Accuracy decreased only 2% from the post-test given at the end of training to the post-test given 3 months later. Similarly, no significant decrease in accuracy was observed for the tests of generalization. After 6 months without training, subjects' accuracy was still 4.5% above pretest levels. Performance on the tests of generalization did not decrease and significant differences were still observed between talkers. The present results suggest that the high-variability training paradigm encourages a long-term modification of listeners' phonetic perception. Changes in perception are brought about by shifts in selective attention to the acoustic cues that signal phonetic contrasts. These modifications in attention appear to be retrained over time, despite the fact that listeners are not exposed to the /r/-/l/ contrast in their native language environment.

Explanatory models of diabetes: patient practitioner variation.

Most cases of diabetes, a complex disorder that requires many lifestyle changes, can be controlled if persons adhere to their prescribed regimen. However, compliance is difficult to attain. Differences in explanatory models between client and practitioner have been suggested as one reason for non-compliance in several disorders. In this ethnographic investigation, individual explanatory models were elicited from persons with diabetes and from health professionals working with these patients. Professionals described models of diabetes in general and their model of a particular patient's diabetes. A composite professional model was constructed and compared with each of the patients' models. The models were most congruent regarding treatment. Etiology, pathophysiology, and severity had less congruence, and time and mode of symptom onset were least congruent. The Spearman correlation coefficient showed a positive but non-significant association of explanatory model congruence between professionals and patients with normal glycosylated hemoglobin levels. Patients and professionals seem to emphasize different domains; patients emphasized difficulties in the social domain and the impact of diabetes on their lives while staff saw diabetes primarily as a pathophysiological problem with impact on patients' physical bodies. This study's importance rests on its clear articulation of significant differences between patients' and staffs' models even when they are similar in demographic characteristics.

Training Japanese listeners to identify English /r/ and /l/. II: The role of phonetic environment and talker variability in learning new perceptual categories.

Two experiments were carried out to extend Logan et al.'s recent study [J. S. Logan, S. E. Lively, and D. B. Pisoni, J. Acoust. Soc. Am. 89, 874-886 (1991)] on training Japanese listeners to identify English /r/ and /l/. Subjects in experiment 1 were trained in an identification task with multiple talkers who produced English words containing the /r/-/l/ contrast in initial singleton, initial consonant clusters, and intervocalic positions. Moderate, but significant, increases in accuracy and decreases in response latency were observed between pretest and posttest and during training sessions. Subjects also generalized to new words produced by a familiar talker and novel words produced by an unfamiliar talker. In experiment 2, a new group of subjects was trained with tokens from a single talker who produced words containing the /r/-/l/ contrast in five phonetic environments. Although subjects improved during training and showed increases in pretest-posttest performance, they failed to generalize to tokens produced by a new talker. The results of the present experiments suggest that variability plays an important role in perceptual learning and robust category formation. During training, listeners develop talker-specific, context-dependent representations for new phonetic categories by selectively shifting attention toward the contrastive dimensions of the non-native phonetic categories. Phonotactic constraints in the native language, similarity of the new contrast to distinctions in the native language, and the distinctiveness of contrastive cues all appear to mediate category acquisition.

Effects of age on serial recall of natural and synthetic speech.

The present study addressed the effects of aging on auditory serial-recall performance for natural and synthetic words. Word difficulty, measured in terms of frequency of occurrence and phonological similarity, and rate of presentation were also manipulated in an effort to determine which processes underlying serial-recall performance, if any, were affected by aging. Results indicated that age per se had little effect on short-term (working) memory as measured by the serial recall of monosyllabic words. Rate of presentation had little effect on recall for either subject group. Word difficulty, on the other hand, affected recall for both groups, with easy words being more readily recalled than hard words.

Effects of cognitive workload on speech production: acoustic analyses and perceptual consequences.

The present investigation examined the effects of cognitive workload on speech production. Workload was manipulated by having talkers perform a compensatory visual tracking task while speaking test sentences of the form "Say hVd again." Acoustic measurements were made to compare utterances produced under workload with the same utterances produced in a control condition. In the workload condition, some talkers produced utterances with increased amplitude and amplitude variability, decreased spectral tilt and F0 variability and increased speaking rate. No changes in F1, F2, or F3 were observed across conditions for any of the talkers. These findings indicate both laryngeal and sublaryngeal adjustments in articulation, as well as modifications in the absolute timing of articulatory gestures. The results of a perceptual identification experiment paralleled the acoustic measurements. Small but significant advantages in intelligibility were observed for utterances produced under workload for talkers who showed robust changes in speech production. Changes in amplitude and amplitude variability for utterances produced under workload appeared to be the major factor controlling intelligibility. The results of the present investigation support the assumptions of Lindblom's ["Explaining phonetic variation: A sketch of the H&H theory," in Speech Production and Speech Modeling (Klewer Academic, The Netherlands, 1990)] H&H model: Talkers adapt their speech to suit the demands of the environment and these modifications are designed to maximize intelligibility.

Comprehension of synthetic speech produced by rule: word monitoring and sentence-by-sentence listening times.

Previous comprehension studies using postperceptual memory tests have often reported negligible differences in performance between natural speech and several kinds of synthetic speech produced by rule, despite large differences in segmental intelligibility. The present experiments investigated the comprehension of natural and synthetic speech using two different on-line tasks: word monitoring and sentence-by-sentence listening. On-line task performance was slower and less accurate for passages of synthetic speech than for passages of natural speech. Recognition memory performance in both experiments was less accurate following passages of synthetic speech than of natural speech. Monitoring performance, sentence listening times, and recognition memory accuracy all showed moderate correlations with intelligibility scores obtained using the Modified Rhyme Test. The results suggest that poorer comprehension of passages of synthetic speech is attributable in part to the greater encoding demands of synthetic speech. In contrast to earlier studies, the present results demonstrate that on-line tasks can be used to measure differences in comprehension performance between natural and synthetic speech.

Training Japanese listeners to identify English /r/ and /l/: a first report.

Native speakers of Japanese learning English generally have difficulty differentiating the phonemes /r/ and /l/, even after years of experience with English. Previous research that attempted to train Japanese listeners to distinguish this contrast using synthetic stimuli reported little success, especially when transfer to natural tokens containing /r/ and /l/ was tested. In the present study, a different training procedure that emphasized variability among stimulus tokens was used. Japanese subjects were trained in a minimal pair identification paradigm using multiple natural exemplars contrasting /r/ and /l/ from a variety of phonetic environments as stimuli. A pretest-posttest design containing natural tokens was used to assess the effects of training. Results from six subjects showed that the new procedure was more robust than earlier training techniques. Small but reliable differences in performance were obtained between pretest and posttest scores. The results demonstrate the importance of stimulus variability and task-related factors in training nonnative speakers to perceive novel phonetic contrasts that are not distinctive in their native language.

Teaching communication skills in an integrated curriculum.

During the seven weeks students showed growth in empathic responding. In addition, many students were able to move beyond beginning empathy to identifying underlying feelings experienced by the patient. Progress in concreteness was noted as irrelevant questioning decreased and selective, open-ended questioning increased. There seemed to be a positive correlation between self-awareness and growth in communication skills. Initially, use of behaviorally specific feedback helped the students identify strengths and weaknesses. As the sessions progressed, students became more independent in critiquing their own interpersonal style. For example, one student identified her abrasive manner in a taped interaction and recognized her need to maintain control. She modified her approach and became more caring and empathic. Initially, Stage II skills were difficult for the students. Some students who expected to see change occur quickly, became impatient with relationship building, and used challenging skills prematurely. Other students had difficulty taking the risk to challenge the patient to focus on problem exploration. Role playing in the training sessions and faculty feedback in the clinical settings helped the students begin to use skills more appropriately. Observing the positive effects on patient behavior reinforced continued use. Students and faculty were enthusiastic about the workshop format and outcome. Student reactions reinforced the value of the systematic approach. Through verbal and written evaluations they identified the small group practice and clinical audiotaping as the most valuable activities. Many liked being able to practice and receive immediate feedback from their peers and instructors. Faculty found that the four components-description, demonstration, practice and application-provided direction for teaching.(ABSTRACT TRUNCATED AT 250 WORDS)