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Author(s): P. Ramachandran [sup.1] , R. Dobie [sup.1] , J. R. Wilson-Kanamori [sup.1] , E. F. Dora [sup.1] , B. E. P. Henderson [sup.1] , N. T. Luu [sup.2] [sup.3] [...], 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.sup.+CD9.sup.+ subpopulation of macrophages, which expands in liver fibrosis, differentiates from circulating monocytes and is pro-fibrogenic. We also define ACKR1.sup.+ and PLVAP.sup.+ 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 PDGFR[alpha].sup.+ 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. Single-cell RNA sequencing is used to characterize and compare the functional diversity of cells from liver biopsies of human scarred and normal liver, and identifies markers for scar-associated macrophages and endothelial cells.

The comparative energy intensity positions of the world's major energy consuming regions and the carbon dioxide levels that they contribute are examined in view of the Kyoto Climate Change accord. It is suggested that policymakers must firstly think of solutions to problem on the environment if wind power is made use of before starting on any major deployment programme.

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 Igfl 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 Igfl expression was observed in Socs2-/- osteoblasts following GH, it was not evident in vivo. Igfl 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. [ABSTRACT FROM AUTHOR]

Otologists may be reluctant to perform labyrinthectomy in unilateral Menière's disease, fearing the later development of bilateral disease and severe hearing loss in the previously normal ear. To illuminate this issue, we reviewed audiologic records for 85 patients diagnosed as having bilateral Menière's disease at the University of Washington Hospital from 1969 to 1986. The progression of hearing loss in each ear was noted, as well as interaural relationships. Nine patients experienced a significant reversal, in which the initially better ear surpassed the other ear in hearing deficit, but only one of these patients could at any time have been considered a labyrinthectomy candidate, according to hypothetically liberal audiometric criteria. [ABSTRACT FROM AUTHOR]

Forty-six patients in an emergency room (ER) setting and 159 people suspected of driving while intoxicated (DWI) had their blood alcohol concentrations estimated by the angle of onset of horizontal gaze nystagmus and confirmed by blood alcohol analysis or breath-alcohol analysis (BAA) tests. In the ER group, 25/26 (96%) of legally intoxicated patients (blood alcohol concentration greater than or equal to .10% w/v) had an estimation consistent with intoxication. There were no cases in which the blood alcohol concentration (BAC) was incorrectly estimated to be greater than .10% w/v in the absence of other drugs. In DWI suspects there was a correlation of .878 between estimated BAC and BAA results. Three subjects were incorrectly classified as intoxicated. No subjects with estimated BAC less than .10% w/v were legally intoxicated by BAA testing. Alcohol gaze nystagmus is presented as an effective tool for estimating the BAC in pure alcoholic intoxication. [ABSTRACT FROM AUTHOR]

The Hearing Conservation Amendment published by the Occupational Safety and Health Administration (OSHA) in 1983 requires hearing conservation programs to be provided for over 5 million workers whose daily noise exposures exceed 85 dBA time-weighted average. The permissible exposure level is 90 dBA, above which the use of hearing protectors is mandatory. Current policies rely heavily on periodic audiometry to detect early threshold shifts due to inadequate use of hearing protection or to individual variation in susceptibility to noise induced hearing loss (NIHL). Studies including over 1,000 noise exposed workers have shown that audiometry in the industrial setting is less reliable than clinical audiometry. Pure tone averaging markedly reduces test-retest variability and should be incorporated into rules for decision-making based on industrial audiometry. However, at least half of observed shifts are spurious. In addition, aging is an important confounding variable; in our data, about half of the population mean threshold shift seen was attributable to aging. Thus, only a minority of threshold shifts seen in industrial audiometry are due to NIHL. The large number of "false positive" shifts will inevitably eventually have the effect of a de facto lowering of the permissible exposure level to 85 dBA. Otologic referral and major administrative action should be reserved for large or repeated threshold shifts. OSHA does not specify rules for otologic referral, but the criteria recommended by the American Academy of Otolaryngology-Head and Neck Surgery are reasonable and should be supported. The necessity for otologic evaluation in the differential diagnosis of NIHL from other entities (particularly baseline audiometric abnormalities) is not universally appreciated; otolaryngologists need to educate their medical and nonmedical colleagues about this. [ABSTRACT FROM AUTHOR]

A retrospective study of 61 consecutive patients with floor of mouth carcinoma and a clinically negative neck was done to determine the value of elective treatment to the neck. Subsequent histologically proven nodal disease was analyzed according to initial treatment modality (23 surgical, 38 irradiation), stage (29--T1,27--T2,5--T3), hemi-neck at risk (midline lesions placed both hemi-necks at risk), and primary control for a minimum of 2 years (50 patients, 78 hemi-necks at risk). Neck failures were classified by T stage, extent of neck treatment (upper neck or complete) and by primary control at the time of manifest neck metastasis. Of the hemi-necks at risk with the primary controlled, 10% (17% of patients) developed nodal disease without complete neck treatment; 86% (6/7) of these patients were salvaged. The occult positive node incidence, conservatively calculated by elimination of all patients treated with elective partial or total neck irradiation, was 10% for patients with T1 and T2 lesions (7% for hemi-necks at risk). Based on the clinical course of patients with primary control, only 1 patient (2%) might have benefited from initial complete elective neck treatment. These results suggest that elective neck treatment in early (T1 and T2, N0) floor of mouth carcinoma is of doubtful value. Supraomohyoid , rather than suprahyoid dissection, is recommended if surgical treatment of the neck is undertaken. [ABSTRACT FROM AUTHOR]

Hearing conservation in industry relies heavily on monitoring audiometry to detect early noise-induced hearing loss in workers who are exposed to potentially damaging noise, with or without hearing protectors. The "real-world" reliability and validity of these measurements, as well as otoscopic observations in industry, have not been extensively investigated. In addition, there is considerable controversy over the selection of a definition of "significant threshold shift" in industrial audiometry. These and related issues were considered in a series of three studies utilizing data from an active hearing conservation program. Test-retest variability in industry is much higher than has been reported for clinical settings; this variability is reduced by pure-tone averaging. Workers referred for otologic evaluation were found to have hearing levels which were, on the average, about 5 dB better than indicated by plant audiometry, even without excluding 4% of referred workers who had unilateral deafness and showed "shadow curves" on the plant audiograms. Otoscopic data obtained by the plant audiometrists were uncorrelated with the results of otoscopy by consultant otologists. Techniques borrowed from decision theory and signal detection theory were used to evaluate possible criteria for significant threshold shift. Criteria based on pure-tone averaging were superior to those based on a certain amount of threshold shift for any frequency tested. It is proposed that a significant threshold shift be defined as a 10 dB or greater change for the worse for either the 0.5, 1, 2 kHz pure-tone average or the 3, 4, 6 kHz pure-tone average, in either ear, and that such shifts be validated by prompt retesting. Even with this criterion, a substantial number of shifts (most shifts, in some situations) will be either spurious or attributable to disorders other than noise-induced hearing loss, such as presbycusis. Otologic referral in cases of large or repeated shifts may prevent unjustified administrative actions, to the advantage of both workers and management. A practical consequence of the use of monitoring audiometry may be a de facto lowering of the permissible exposure level to 85 dBA TWA. [ABSTRACT FROM AUTHOR]

Critical assessment of head and neck cancer with respect to staging has, on occasion, been disappointingly ineffective. We have attempted to correlate the incidence of measureable uptake of cobalt 57 tagged bleomycin by primary squamous cell carcinoma and metastatic cervical lymph nodes. Forty-six cases have been evaluated with respect to histopathological confirmation of the suspected metastatic disease. We have found that this diagnostic measure increases our acumen in staging of head and neck cancer. The relevance of the Co-Bleo scans as a diagnostic aid is reported in 46 cases. Malignant tumors greater than 2 cm in size appear to demonstrate active uptake of the imaging agent. Small tumor size and excess background radioactivity contribute to the false-negatives (17%). Inflammatory conditions or benign tumors of the salivary apparatus may result in minimal uptake, thus, a false-positive result (10%). An increase in the radioactivity of the Co-Bleo may enhance the benefits of this procedure in the search for an undiagnosed primary, as well as undiagnosed local or distant metastases. [ABSTRACT FROM AUTHOR]