Multimodal decoding of human liver regeneration.

The liver has a unique ability to regenerate1,2; however, in the setting of acute liver failure (ALF), this regenerative capacity is often overwhelmed, leaving emergency liver transplantation as the only curative option3-5. Here, to advance understanding of human liver regeneration, we use paired single-nucleus RNA sequencing combined with spatial profiling of healthy and ALF explant human livers to generate a single-cell, pan-lineage atlas of human liver regeneration. We uncover a novel ANXA2+ migratory hepatocyte subpopulation, which emerges during human liver regeneration, and a corollary subpopulation in a mouse model of acetaminophen (APAP)-induced liver regeneration. Interrogation of necrotic wound closure and hepatocyte proliferation across multiple timepoints following APAP-induced liver injury in mice demonstrates that wound closure precedes hepatocyte proliferation. Four-dimensional intravital imaging of APAP-induced mouse liver injury identifies motile hepatocytes at the edge of the necrotic area, enabling collective migration of the hepatocyte sheet to effect wound closure. Depletion of hepatocyte ANXA2 reduces hepatocyte growth factor-induced human and mouse hepatocyte migration in vitro, and abrogates necrotic wound closure following APAP-induced mouse liver injury. Together, our work dissects unanticipated aspects of liver regeneration, demonstrating an uncoupling of wound closure and hepatocyte proliferation and uncovering a novel migratory hepatocyte subpopulation that mediates wound closure following liver injury. Therapies designed to promote rapid reconstitution of normal hepatic microarchitecture and reparation of the gut-liver barrier may advance new areas of therapeutic discovery in regenerative medicine.

Resolving the fibrotic niche of human liver cirrhosis at single-cell level.

Liver cirrhosis is a major cause of death worldwide and is characterized by extensive fibrosis. There are currently no effective antifibrotic therapies available. To obtain a better understanding of the cellular and molecular mechanisms involved in disease pathogenesis and enable the discovery of therapeutic targets, here we profile the transcriptomes of more than 100,000 single human cells, yielding molecular definitions for non-parenchymal cell types that are found in healthy and cirrhotic human liver. We identify a scar-associated TREM2+CD9+ subpopulation of macrophages, which expands in liver fibrosis, differentiates from circulating monocytes and is pro-fibrogenic. We also define ACKR1+ and PLVAP+ endothelial cells that expand in cirrhosis, are topographically restricted to the fibrotic niche and enhance the transmigration of leucocytes. Multi-lineage modelling of ligand and receptor interactions between the scar-associated macrophages, endothelial cells and PDGFRα+ collagen-producing mesenchymal cells reveals intra-scar activity of several pro-fibrogenic pathways including TNFRSF12A, PDGFR and NOTCH signalling. Our work dissects unanticipated aspects of the cellular and molecular basis of human organ fibrosis at a single-cell level, and provides a conceptual framework for the discovery of rational therapeutic targets in liver cirrhosis.

αv integrins on mesenchymal cells regulate skeletal and cardiac muscle fibrosis.

Mesenchymal cells expressing platelet-derived growth factor receptor beta (PDGFRß) are known to be important in fibrosis of organs such as the liver and kidney. Here we show that PDGFRß+ cells contribute to skeletal muscle and cardiac fibrosis via a mechanism that depends on αv integrins. Mice in which αv integrin is depleted in PDGFRß+ cells are protected from cardiotoxin and laceration-induced skeletal muscle fibrosis and angiotensin II-induced cardiac fibrosis. In addition, a small-molecule inhibitor of αv integrins attenuates fibrosis, even when pre-established, in both skeletal and cardiac muscle, and improves skeletal muscle function. αv integrin blockade also reduces TGFß activation in primary human skeletal muscle and cardiac PDGFRß+ cells, suggesting that αv integrin inhibitors may be effective for the treatment and prevention of a broad range of muscle fibroses.

Growth and the Growth Hormone-Insulin Like Growth Factor 1 Axis in Children With Chronic Inflammation: Current Evidence, Gaps in Knowledge, and Future Directions.

Growth failure is frequently encountered in children with chronic inflammatory conditions like juvenile idiopathic arthritis, inflammatory bowel disease, and cystic fibrosis. Delayed puberty and attenuated pubertal growth spurt are often seen during adolescence. The underlying inflammatory state mediated by proinflammatory cytokines, prolonged use of glucocorticoid, and suboptimal nutrition contribute to growth failure and pubertal abnormalities. These factors can impair growth by their effects on the GH-IGF axis and also directly at the level of the growth plate via alterations in chondrogenesis and local growth factor signaling. Recent studies on the impact of cytokines and glucocorticoid on the growth plate further advanced our understanding of growth failure in chronic disease and provided a biological rationale of growth promotion. Targeting cytokines using biological therapy may lead to improvement of growth in some of these children, but approximately one-third continue to grow slowly. There is increasing evidence that the use of relatively high-dose recombinant human GH may lead to partial catch-up growth in chronic inflammatory conditions, although long-term follow-up data are currently limited. In this review, we comprehensively review the growth abnormalities in children with juvenile idiopathic arthritis, inflammatory bowel disease, and cystic fibrosis, systemic abnormalities of the GH-IGF axis, and growth plate perturbations. We also systematically reviewed all the current published studies of recombinant human GH in these conditions and discussed the role of recombinant human IGF-1.

Direct stimulation of bone mass by increased GH signalling in the osteoblasts of Socs2-/- mice.

The suppressor of cytokine signalling (Socs2(-/-))-knockout mouse is characterised by an overgrowth phenotype due to enhanced GH signalling. The objective of this study was to define the Socs2(-/-) bone phenotype and determine whether GH promotes bone mass via IGF1-dependent mechanisms. Despite no elevation in systemic IGF1 levels, increased body weight in 4-week-old Socs2(-/-) mice following GH treatment was associated with increased cortical bone area (Ct.Ar) (P<0.01). Furthermore, detailed bone analysis of male and female juvenile and adult Socs2(-/-) mice revealed an altered cortical and trabecular phenotype consistent with the known anabolic effects of GH. Indeed, male Socs2(-/-) mice had increased Ct.Ar (P<0.05) and thickness associated with increased strength. Despite this, there was no elevation in hepatic Igf1 expression, suggesting that the anabolic bone phenotype was the result of increased local GH action. Mechanistic studies showed that in osteoblasts and bone of Socs2(-/-) mice, STAT5 phosphorylation was significantly increased in response to GH. Conversely, overexpression of SOCS2 decreased GH-induced STAT5 signalling. Although an increase in Igf1 expression was observed in Socs2(-/-) osteoblasts following GH, it was not evident in vivo. Igf1 expression levels were not elevated in response to GH in 4-week-old mice and no alterations in expression was observed in bone samples of 6-week-old Socs2(-/-) mice. These studies emphasise the critical role of SOCS2 in controlling the local GH anabolic bone effects. We provide compelling evidence implicating SOCS2 in the regulation of GH osteoblast signalling and ultimately bone accrual, which maybe via mechanisms that are independent of IGF1 production in vivo.

Otologic injuries from airbag deployment.

Airbags became available as an optional passive restraint system in motor vehicles in 1973. The National Highway Traffic Safety Administration mandated placement of driver and right passenger airbags in all passenger vehicles and light trucks beginning in model year 1997. An estimated 2.1 million airbags have been deployed from the late 1980s until the present. There have been several case reports of hearing loss after exposure to airbag deployments in drivers and passengers since 1995. Members of the American Academy of Otolaryngology-Head and Neck Surgery submitted case reports on 71 patients with otologic symptoms after airbag deployment.

Efficacy of 3 commonly used hearing aid circuits: A crossover trial. NIDCD/VA Hearing Aid Clinical Trial Group.

CONTEXT: Numerous studies have demonstrated that hearing aids provide significant benefit for a wide range of sensorineural hearing loss, but no carefully controlled, multicenter clinical trials comparing hearing aid efficacy have been conducted. OBJECTIVE: To compare the benefits provided to patients with sensorineural hearing loss by 3 commonly used hearing aid circuits. DESIGN: Double-blind, 3-period, 3-treatment crossover trial conducted from May 1996 to February 1998. SETTING: Eight audiology laboratories at Department of Veterans Affairs medical centers across the United States. PATIENTS: A sample of 360 patients with bilateral sensorineural hearing loss (mean age, 67.2 years; 57% male; 78.6% white). INTERVENTION: Patients were randomly assigned to 1 of 6 sequences of linear peak clipper (PC), compression limiter (CL), and wide dynamic range compressor (WDRC) hearing aid circuits. All patients wore each of the 3 hearing aids, which were installed in identical casements, for 3 months. MAIN OUTCOME MEASURES: Results of tests of speech recognition, sound quality, and subjective hearing aid benefit, administered at baseline and after each 3-month intervention with and without a hearing aid. At the end of the experiment, patients ranked the 3 hearing aid circuits. RESULTS: Each circuit markedly improved speech recognition, with greater improvement observed for soft and conversationally loud speech (all 52-dB and 62-dB conditions, P

A review of randomized clinical trials in tinnitus.

OBJECTIVES: Review reports of randomized clinical trials (RCTs) in tinnitus to identify well-established treatments, promising developments, and opportunities for improvement in this area of clinical research. STUDY DESIGN: Literature review of RCTs (1964-1998) identified by MEDLINE and OLD MEDLINE searches and personal files. METHODS: Studies were compared with the RCT criteria of Guyatt et al. for quality of design, performance, and analysis; "positive" results were critically examined for potential clinical relevance. RESULTS: Sixty-nine RCTs evaluated tocainide and related drugs, carbamazepine, benzodiazepines, tricyclic antidepressants, 16 miscellaneous drugs, psychotherapy, electrical/magnetic stimulation, acupuncture, masking, biofeedback, hypnosis, and miscellaneous other nondrug treatments. No treatment can yet be considered well established in terms of providing replicable long-term reduction of tinnitus impact, in excess of placebo effects. CONCLUSIONS: Nonspecific support and counseling are probably helpful, as are tricyclic antidepressants in severe cases. Benzodiazepines, newer antidepressants, and electrical stimulation deserve further study. Future tinnitus therapeutic research should emphasize adequate sample size, open trials before RCTs, careful choice of outcome measures, and long-term follow-up.

Low-level steady-state auditory evoked potentials: effects of rate and sedation on detectability.

Steady-state auditory evoked potentials (SSAEPs) in alert adults are most detectable at stimulus or modulation rates of about 40 Hz. Sedation reduces the detectability of 40-Hz SSAEPs and increases it for higher rate SSAEPs. This study examined whether rates higher than 40 Hz would be preferable for detecting responses to low-intensity tones in sedated adults. Fourteen normal adults listened to 640-Hz tones at modulation rates (and toneburst rates) of 20-160 Hz, in 10-Hz steps, at levels of 38 and 58 dB peak equivalent sound-pressure level (peSPL) (20 and 40 dB normal hearing level (nHL) for amplitude-modulated (AM) tones), both alert and sedated (1-2 g chloral hydrate). Sedation reduced both signal (SSAEP) power and noise power at all rates, but noise power reduction was greater for higher rates. Detectability in the alert condition was always greatest at 40 Hz. Under sedation, a second detectability peak was present at 90 Hz for 58-dB peSPL tones, approximately equal to that seen at 40 Hz. At 38 dB peSPL (sedated), peak detectability moved from 40 to 50 Hz. These results suggest that presentation/modulation rates around 40 Hz may be optimal for SSAEP detectability at low levels in adults, whether alert or sedated.

Evaluation of posturography in the detection of malingering subjects.

OBJECTIVE: This study aimed to test the performance of proposed methods for detecting malingering subjects on computerized dynamic posturography using one subject group in three situations (normal, malingering, vestibular weakness). STUDY DESIGN: The study design was a prospective, blinded study. SETTING: The study was conducted at a university hospital. PATIENTS: Volunteer subjects aged 20-59 years of age participated. INTERVENTIONS: Computerized dynamic posturography was performed under three situations: best effort, faking vestibular weakness, and transient induced vestibular weakness with bilateral simultaneous caloric irrigation. MAIN OUTCOME MEASURES: Measured was identification of situation (normal, malingering, induced vestibular weakness) by each of three detection methods: blinded clinical scoring, a set of formulae, and a set of variables (the latter two methods proposed previously by other investigators). RESULTS: Each method performed well. In three-way discrimination, the formulae and clinical scoring each correctly identified approximately 75% of trials. In two-way discrimination (malingering vs. induced vestibular weakness), the best combination of variables slightly outperformed clinical scoring (0.93 vs. 0.88 ROC [receiver operating characteristic] curve area). CONCLUSIONS: Computerized dynamic posturography can distinguish malingering in normal subjects from trials performed with best effort or after binaural simultaneous caloric irrigation. The accuracy of blinded clinical scoring was comparable to that of two objective detection methods.

Impact of a laryngectomy on quality of life: perspective of the patient versus that of the health care provider.

This study retrospectively assesses the impact of laryngectomy on the quality of life of 46 patients as compared to the perception of the impact of laryngectomy of 13 health care providers (HCPs). Employing the "time trade-off" methodology, we assessed patient and HCP preferences and calculated estimated utilities. We found that 20% of patients would be willing to compromise anticipated life expectancy to preserve voice or preoperative quality of life. By comparison, 46% of the HCPs perceived that their patients would be willing to accept a reduced life span in order to preserve their larynx and quality of life. In conclusion, the percentage of HCPs who believed their patients would compromise survival was substantially higher than the percentage of actual patients who expressed this preference. This perception may influence physicians' attitudes toward recommending laryngeal preservation therapy for their patients. For most laryngectomy patients, treatments attempting laryngeal preservation, particularly if associated with compromised survival, may not be warranted.

A comparison of t test, F test, and coherence methods of detecting steady-state auditory-evoked potentials, distortion-product otoacoustic emissions, or other sinusoids.

Sinusoids in background noise can conveniently be detected using unsegmented power spectra, comparing power at the signal frequency to average power at several neighbor frequencies. In this case, the F test is preferable to t tests based on rms or dB values, because of the skewed distributions of rms and dB when signal-to-noise ratio (SNR) = 0. F-test performance improves as the number of frequencies increases, to about 15, but can be degraded if the background noise is not white, with a slope exceeding about 10 dB for the range of frequencies sampled. Segment analysis, using magnitude-squared coherence (MSC) or related statistics, has equivalent statistical power; MSC and F each yield unbiased SNR estimates that have identical distributions when SNR = 0. Selection of F or MSC for detection of sinusoids will usually be a matter of convenience.

Compensation for hearing loss.

Monetary compensation for occupational hearing loss in the U.S.A. is governed by at least 57 different state and federal systems. Costs of compensation are difficult to estimate. Most U.S. jurisdictions use the 1979 AMA Method, based on pure-tone thresholds, to determine the amount of compensation. Clinical data and epidemiological models can provide useful estimates of the relative contributions of occupational noise exposure, aging, and other causes.

Coherence analysis of envelope-following responses (EFRs) and frequency-following responses (FFRs) in infants and adults.

The frequency-following response (FFR) and the envelope-following response (EFR) were recorded in 1-month-old infants and in adults to examine the development of temporal coding. The stimuli were amplitude-modulated (AM) tones. A modulation frequency of 80 Hz was used in infants; modulation frequencies of 40 and 80 Hz were used in adults. The effects of intensity, carrier frequency, and modulation frequency on these responses were studied. Responses were analyzed using magnitude-squared coherence. The effect of intensity on the growth of FFR- and EFR-coherence were similar in infants and adults. In addition, the growth functions were not affected by the carrier frequency or the modulation frequency of the stimulus. FFR thresholds did not differ across age groups. 'Best frequency' (i.e., infant 80 Hz and adult 40 Hz) EFR thresholds were the same for infants and adults at 500 and 1000 Hz, but infant EFR thresholds were poorer than adult thresholds at 2000 Hz. Thus, although FFRs and EFRs are primarily adult-like at 1 month of age, there are some age differences in the EFR that deserve further study.