Increased response to antigen and histamine release in smaller sensitized canine bronchi

Presynaptic alpha 2-autoreceptors in mouse atria were characterized in terms of the alpha 2A, alpha 2B, alpha 2C and alpha 2D subtypes. Segments of the atria were preincubated with 3H-noradrenaline and then superfused and stimulated electrically. The affinity of up to 16 antagonists for the autoreceptors was assessed as (1) pEC30% values. i.e. concentrations that increased previously autoinhibited release of 3H-noradrenaline (120 pulses, 3 Hz) by 30%, and (2) pKd values against the release-inhibiting effect of 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14,304) under conditions of no or little autoinhibition (2 trains of 20 pulses, 50 Hz, train interval 120 s). The pKd values correlated well with the pEC30% values (r = 0.98; P < 0.001; slope of regression line 0.93), indicating that UK 14,304 and released noradrenaline modulated the release of noradrenaline through pharmacologically identical receptors. Comparison with antagonist affinities for (1) prototypic native alpha 2 radioligand binding sites, (2) radioligand binding sites in COS cells transfected with alpha 2 subtype genes, and (3) previously classified presynaptic alpha 2-autoreceptors-all taken from the literature-indicated that the mouse atrial autoreceptors corresponded to the alpha 2D subtype. For example, the pKd values at mouse atrial auto-receptors correlated closely with pKd values at native alpha 2D binding sites in the bovine pineal gland (r = 0.96; P < 0.001); with pKd values at alpha 2D binding sites in COS cells transfected with the rat alpha 2D gene (r = 0.85; P < 0.01); and with pKd values at guinea-pig cerebral and atrial and mouse cerebral alpha 2D-autoreceptors (r = 0.96-0.98; P < 0.001). The antagonist pKd values at mouse atrial autoreceptors correlated less with pKd values at alpha 2A, alpha 2B and alpha 2C sites. It is concluded that the presynaptic alpha 2-autoreceptors in mouse atria are alpha 2D. This identification supports the hypothesis that at least the majority of alpha 2-autoreceptors belong to the alpha 2A/D pair of orthologous alpha 2-adrenoceptors.     

Characterization of a human papillomavirus type 16 variant-dependent neutralizing epitope

We have determined that three type-specific and conformationally dependent monoclonal antibodies, H16.E70, H16.U4, and H16.V5, neutralize pseudotype human papillomavirus type 16 (HPV16) virions in vitro. H16.U4 and H16.V5 neutralized pseudotype virions derived from the German HPV16 variant 114K and the Zairian variant Z-1194 with equal efficiency. In contrast, neutralization of Z-1194 pseudotype virions by H16.E70 was two orders of magnitude weaker than neutralization of 114K pseudotype virions. This difference correlated with enzyme-linked immunosorbent assay reactivity of H16.E70 to L1 virus-like particles of the two variants. A substitution at residue 282 of L1 was responsible for this differential reactivity, suggesting that this residue constitutes part of the H16.E70 epitope.     

TGF-beta: a balancing act

Regulation of developmental processes as well as host defense and repair mechanisms requires the maintenance of a delicate balance of positive and negative regulatory signals. TGF-beta, a molecule known for its many diverse activities, can promote or inhibit cell growth and function. Disruption of the balance between these opposing activities can contribute to aberrant development, malignancy, or pathogenic immune and inflammatory responses. TGF-beta transgenic mouse studies highlight the essential function(s) of TGF-beta and its receptors and provide insight to potential therapeutic approaches to manipulate TGF-beta expression.     

Relationships of PPARgamma and PPARgamma2 mRNA levels to obesity, diabetes and hyperinsulinaemia in rhesus monkeys

OBJECTIVE: To examine the expression of peroxisome proliferator-activated receptor gamma (PPARgamma) together with CCAAT/enhancer binding protein alpha (C/EBPalpha), lipoprotein lipase (LPL) and glucose transporter (GLUT4) mRNA in adipose tissue of rhesus monkeys in relation to obesity. DESIGN: Cloning of the PPARgamma1 and gamma2 cDNAs and analysis of PPARgamma, C/EBPalpha, LPL and GLUT4 mRNA levels in the adipose tissue of lean and obese monkeys. SUBJECTS: 28 rhesus monkeys (Macaca mulatta) with a wide range of body weights (9.2-22.6 kg) and with or without type 2 diabetes. MEASUREMENTS: Sequence of PPARgamma1 and gamma2. Tissue distribution of PPARgamma1 and gamma2. The mRNA levels of PPARgamma, C/EBPalpha, LPL and GLUT4 in adipose tissue. The ratio of PPARgamma2 mRNA to total PPARgamma mRNA. RESULTS: The monkey PPARgamma2 protein showed 99% identity with the human protein. PPARgamma1 mRNA was shown to be expressed in various tissues and most abundantly in adipose tissue. PPARgamma2 existed mainly in adipose tissue. A significant correlation between the ratio of PPARgamma2 mRNA to total PPARgamma mRNA and obesity was observed, whereas total PPARgamma mRNA levels showed no significant relationships to obesity. There was also a significant relationship between the ratio of PPARgamma2 mRNA to total PPARgamma mRNA and fasting plasma insulin concentration. The mRNA levels of C/EBPalpha, LPL and GLUT4 were highly correlated to that of total PPARgamma mRNA. They were also significantly correlated to the mRNA levels of PPARgamma1 and PPARgamma2. CONCLUSIONS: The ratio of PPARgamma2 mRNA to total PPARgamma mRNA is related to obesity in the rhesus monkey and mRNA expression of PPARgamma1, PPARgamma2, C/EBPalpha, LPL and GLUT4 appear to be coordinated in vivo.     

Occupational injuries among older workers with visual, auditory, and other impairments. A validation study

This study aims to validate a previously defined model of the risk of occupational injuries among older workers with visual, auditory, or other impairments. That model was based upon the Health and Retirement Study (HRS). The previous logistic regression model was recalculated using data from the 1994 National Health Interview Survey (NHIS). The parameter estimates for impaired hearing (.181 in NHIS, 1.55 in HRS), impaired vision (2.42 in NHIS, 1.48 in HRS), and self-employment (0.22 in NHIS, 0.49 in HRS) were in same direction and of roughly the same magnitude. The previously defined model was confirmed using NHIS data. The data suggest that as the workforce ages, more attention must be paid to the accommodation of disabilities in the workplace, especially sensory impairments-poor vision and hearing.     

Two-dimensional echocardiography with a wide angle (60 degrees) sector scanner

A wide angle (60 degrees) sector scanner producing a real-time two-dimensional echocardiogram has been used to examine healthy infants, children, and adults. Its method of use is described and findings from longitudinal and transverse scans are presented. The points of difference between the various types of electronic and mechanical two-dimensional scanning systems are discussed. This equipment minimises problems of chest contact and rib and lung interference and, by providing echocardiograms of high line density from a wide angle, is a suitable real-time two-dimensional scanning system for examining patients of all ages.     

Protease inhibitors induce specific changes in protein tyrosine phosphorylation that correlate with inhibition of apoptosis in myeloid cells

To investigate early signaling events responsible for regulation of programmed cell death or apoptosis, we studied campothecin (a topoisomerase I inhibitor)-mediated apoptosis in the human promyelocytic leukemia cell line HL60. We demonstrate a tight correlation between protection of HL60 cells from apoptosis-associated internucleosomal DNA fragmentation by specific protease inhibitors or protein phosphatase inhibitors, with early tyrosine phosphorylation of a single protein substrate with a molecular weight of approximately 42,000. Exposure to protease inhibitors that did not protect HL60 cells from DNA fragmentation did not result in phosphorylation of this substrate. Likewise, a protein tyrosine kinase inhibitor that did not interfere with specific phosphorylation did not prevent DNA fragmentation. Taken together, these results suggest that phosphorylation of a Mr 42,000 substrate constitutes an important signaling event that may participate in regulation of the apoptotic response.     

Ocular chrysiasis correlated with gold concentrations in the crystalline lens during chrysotherapy

The eyes of 11 patients with rheumatoid arthritis (RA) who received extended chrysotherapy (mean cumulative dose greater than 7 grams during a mean 6-year period) were examined biomicroscopically. Minute reddish-purple particles were seen in the cornea (corneal chrysiasis) in 5 and in the lens (lens chrysiasis) in 4 patients. Particulate deposits were absent in 11 other RA patients who had not received gold treatment. Seven crystalline lenses from 5 gold-treated patients were removed surgically because of incidental cataract formation and analyzed for gold content using neutron activation analysis. Although the mean lens gold concentration was higher in these patients than in non-gold-treated controls without RA (0.0073 microgram/grams versus 0.001 microgram/grams), the absolute gold level was markedly lower than that found in 25 diverse tissue analyzed previously. This finding is compatible with the absence of clinical gold-related lens disease or visual impairment.