Albumin synthesis and bone collagen formation in human immunodeficiency virus-positive subjects: differential effects of growth hormone administration

Loss of lean tissue often accompanies human immunodeficiency virus (HIV) infection. Exogenous human recombinant GH (hrGH) has been shown to be beneficial in reversing this wasting. However, catabolic effects of hrGH on muscle protein metabolism have also been reported. Therefore, the responsiveness of other GH-sensitive tissues, including bone formation and albumin synthesis, has been examined. Anabolic activity in bone, from serum levels of carboxy-terminal propeptide of type I collagen, was stimulated by 2 weeks of hrGH in controls (56 +/- 15%, P = 0.002), patients with asymptomatic HIV (24 +/- 10%, not significant), patients with AIDS (47 +/- 7%, P < 0.001), and patients with AIDS and > 10% weight loss (21 +/- 12%, P = 0.02). Albumin synthesis, determined from the incorporation of L-[2H5]phenylalanine, was increased in response to hrGH in controls (23 +/- 7%, P < 0.05), HIV+ subjects (39 +/- 16%, P < 0.05), and patients with AIDS (25 +/- 7%, P < 0.01). Patients with AIDS and weight loss, however, did not increase albumin synthesis (-0.6 +/- 12%) in response to hrGH. The results indicate variable anabolic responses to hrGH. Bone collagen synthesis remained sensitive to hrGH, whereas, the anabolic action of hrGH on the synthesis of albumin diminished with severity of disease. However unlike muscle protein synthesis, albumin synthesis was not depressed below basal levels by hrGH.     

Experimental Goodpasture's syndrome in Wistar-Kyoto rats immunized with alpha3 chain of type IV collagen

BACKGROUND: Glomerulonephritis and lung hemorrhage of autoimmune Goodpasture syndrome develop due to immune reactions against epitope(s) of the non-collagenous (NC1) domain of alpha3-chain of type IV collagen [alpha3(IV) NC1]. Whether thymic mechanisms have a role in the loss of tolerance to the Goodpasture epitope has not been established. We studied the renal and pulmonary effects of immunization with different forms (monomer, dimer, or hexamer) of alpha3(IV) NC1 collagen in Wistar-Kyoto (WKY) rats, and assessed whether the intrathymic inoculation of the antigen may protect against anti-GBM disease. METHODS: WKY rats were immunized with bovine alpha3(IV) monomer, dimer, or hexamer, or with alpha3(IV) NC1 synthetic peptide. Renal function, kidney and lung immunohistology, and circulating and tissue bound antibodies to type IV collagen chains were analyzed. Effects of intrathymic inoculation of antigen on subsequent disease induction were analyzed in WKY rats given alpha3(IV) NC1 dimer or GBM preparation intrathymically 48 hours before immunization. RESULTS: Proteinuria, linear IgG deposition in GBM, and crescentic glomerulonephritis developed in WKY rats immunized with alpha3(IV) NC1 dimer or hexamer. Lesions were dose-dependent upon injections of 10 to 100 microgram dimer. The alpha3(IV) NC1 monomer induced less severe proteinuria and no crescents. Pulmonary hemorrhage was detectable in 35% of rats immunized with 25 to 100 microgram alpha3(IV) NC1 dimer; alpha3(IV) synthetic peptide (36 carboxyl terminal) did not induce disease. Rats injected intrathymically with up to 100 microgram alpha3(IV) NC1 dimer or with GBM 48 hours before immunization were not protected against subsequent development of proteinuria and glomerulonephritis. CONCLUSIONS: These findings document that glomerulonephritis and lung hemorrhage can be elicited in WKY rats by immunization with alpha3(IV) NC1. Failure of the intrathymic inoculation of antigen to prevent disease suggests that immunological tolerance cannot be achieved by this intervention, in contrast to other autoimmune conditions, and may imply independent roles for cellular and humoral nephritogenic pathways in anti-GBM nephritis.     

Verb generation in patients with focal frontal lesions: a neuropsychological test of neuroimaging findings

What are the neural bases of semantic memory? Traditional beliefs that the temporal lobes subserve the retrieval of semantic knowledge, arising from lesion studies, have been recently called into question by functional neuroimaging studies finding correlations between semantic retrieval and activity in left prefrontal cortex. Has neuroimaging taught us something new about the neural bases of cognition that older methods could not reveal or has it merely identified brain activity that is correlated with but not causally related to the process of semantic retrieval? We examined the ability of patients with focal frontal lesions to perform a task commonly used in neuroimaging experiments, the generation of semantically appropriate action words for concrete nouns, and found evidence of the necessity of the left inferior frontal gyrus for certain components of the verb generation task. Notably, these components did not include semantic retrieval per se.     

Physical activity and incidence of hypertension in college alumni

In a study population of 14,998 Harvard male alumni, 681 hypertensives were first diagnosed during a 6-10-year follow-up beginning 16-50 years after college entrance. The study comprised 105,662 man-years of observation of these men who had entered college in 1916-1950, and who were followed from 1962 or 1966 to 1972. Presence or absence of a background of collegiate sports did not influence risk of hypertension in this study population, nor did stair-climbing, walking, or light sports play by alumni. But, alumni who did not engage in vigorous sports play were at 35% greater risk of hypertension than those who did, and this relationship held at all ages, 35-74 years. Higher levels of body mass index, weight gain since college, history of parental hypertension, and lack of strenuous exercise independently predicted increased risk of hypertension in alumni. Men 20% or more over ideal weight-for-height were at 78% greater risk than lighter men. Those who had gained 25+ lbs (c. 11.5+ kg) since entering college were at 60% greater risk than those who had gained less. Alumni with a hypertensive parent were at 83% higher risk than men without such parentage. Contemporary vigorous exercise was inversely related to hypertension risk, but chiefly among alumni overweight-for-height. In the clinical sense, attributable risk estimates ranged from 30% to nearly 50% for the alumni characteristics of overweight, weight gain, parental hypertension, and lack of vigorous exercise. In the community sense, attributable risk of these same characteristics ranged 13-26%. To sum up, vigorous exercise is associated with lower hypertension incidence, and, without necessarily altering body weight-for-height, avoids or reduces fat and promotes muscle; obesity, rather than excess weight-for-height, is associated with higher hypertension incidence; hence, vigorous exercise is appropriate for use as an intervention regimen in the prevention of hypertension.     

Enhanced signal transduction by a directly fused protein of interleukin-6 and its receptor

In order to develop a new type of agonist for the interleukin 6 (IL-6) signal, the gene encoding a directly fused protein (DFP) was constructed by joining the N-terminal portion of IL-6 and the C-terminal (soluble) portion of IL-6R (sIL-6R) without using a flexible polypeptide linker. The biological activity if DFP from a recombinant Pichia pastoris was examined by growth stimulation of IL-6-dependent BAF130 cells expressing human gp130, a membrane receptor. The recombinant DFP exhibited a much stronger growth stimulation (10 times) than the independent IL-6 and sIL-6R (IL-6/sIL-6R), mainly because association of the IL-6 and IL-6R could be maintained even at lower concentrations of DFP. Surface plasmon resonance (SPR) analysis showed that DFP bound to the extracellular portion of gp130 in the biphasic mode, and the dissociation constants of DFP for two phases were the same as those of IL-6/sIL-6R. In cells treated with DFP, stimulation of Stat3 phosphorylation was maintained for a longer period (150 min) than in cells treated with IL6/Il-6R, suggesting that the signal mediated by the DFP was more durable than that mediated by IL-6/sIL-6R, although the signal transduction mechanisms are almost the same for both DFP and IL-6/IL-6R. Therefore, the stronger activity of DFP was attributed to the maintained association of its subunits and/or prolonged phosphorylation of Stat3.