Acute hypothalamic-pituitary-adrenal responses to the stress of treadmill exercise. Physiologic adaptations to physical training

To study the effects of physical conditioning on the hypothalamic-pituitary-adrenal axis, we examined the plasma ACTH, cortisol, and lactate responses in sedentary subjects, moderately trained runners, and highly trained runners to graded levels of treadmill exercise (50, 70, and 90 percent of maximal oxygen uptake) and to intravenous ovine corticotropin-releasing hormone (1 microgram per kilogram of body weight). Basal evening concentrations of ACTH and cortisol, but not of lactate, were elevated in highly trained runners as compared with sedentary subjects and moderately trained runners. Exercise-stimulated ACTH, cortisol, and lactate responses were similar in all groups and were proportional to the exercise intensity employed. These responses, however, were attenuated in the trained subjects when plotted against applied absolute workload. Only the highly trained group had diminished responses of ACTH and cortisol to ovine corticotropin-releasing hormone, consistent with sustained hypercortisolism. We conclude that physical conditioning is associated with a reduction in pituitary-adrenal activation in response to a given workload. Alterations of the hypothalamic-pituitary-adrenal axis consistent with mild hypercortisolism and similar to findings in depression and anorexia nervosa were found only in highly trained runners. Whether these alterations represent an adaptive change to the daily stress of strenuous exercise or a marker of a specific personality profile in highly trained athletes is unknown.     

The phage T4 nrdB intron: a deletion mutant of a version found in the wild

Bacteriophage T4 possesses three self-splicing group I introns. Two of the three introns are mobile elements; the third, in the gene encoding a subunit of the phage nucleotide reductase (nrdB), is not mobile. Because intron mobility offers a reasonable explanation for the paradoxical occurrence of large intervening sequences in a space-efficient eubacterial phage, it is puzzling that the nrdB intron is not mobile like its compatriots. We have discovered a larger nrdB intron in a closely related phage, and we infer from comparative sequence data that the T4 intron is a deletion mutant derived from this larger intron. This larger nrdB intron encodes an open reading frame of 269 codons, which we have cloned and overexpressed. The overexpressed protein shows a dsDNA endonuclease activity specific for the intronless nrdB gene, typical of mobile introns. Thus, we believe that all three introns of T4 are or were mobile "infectious introns" and that they have entered into and been maintained in the phage population by virtue of this efficient mobility.     

Amphiphysin IIm, a novel amphiphysin II isoform, is required for macrophage phagocytosis

Phagocytosis of pathogens by macrophages initiates the innate immune response, which in turn orchestrates the adaptive immune response. Amphiphysin II participates in receptor-mediated endocytosis, in part, by recruiting the GTPase dynamin to the nascent endosome. We demonstrate here that a novel isoform of amphiphysin II associates with early phagosomes in macrophages. We have ablated the dynamin-binding site of this protein and shown that this mutant form of amphiphysin II inhibits phagocytosis at the stage of membrane extension around the bound particles. We define a signaling cascade in which PI3K is required to recruit amphiphysin II to the phagosome, and amphiphysin II in turn recruits dynamin. Thus, amphiphysin II facilitates a critical initial step in host response to infection.     

Hypothalamic obesity following knife cuts that minimize arterial damage

Parasagittal knife cuts that separate the medial hypothalamus from the lateral hypothalamus produce obesity. It has been assumed that the obesity results from the cutting of axons. However, these cuts also appear to sever arteries. The present study demonstrates that the severing of arteries is not necessary for the production of obesity. Knife cuts were placed at an angle so as to separate the medial hypothalamus from the lateral hypothalamus with minimal damage to arteries. These rats overate and became obese just as rapidly as rats with parasagittal cuts.     

A novel in vitro DNA packaging system demonstrating a direct role for the bacteriophage lambda FI gene product

A new in vitro bacteriophage lambda DNA packaging system is described in which all the proteins necessary for head morphogenesis are supplied by extracts of plasmid-transformed cells. This assay is used to demonstrate that the lambda FI gene product (gpFI) is necessary for maximal packaging efficiency when proheads and terminase are present in limiting amounts. A 100- to 200-fold decrease in packaging is seen when gpFI is omitted. gpFI is shown to act at and/or after the stage in packaging where proheads bind to the DNA:terminase complex.     

A new histologic approach to the differentiation of enchondroma and chondrosarcoma of the bones. A clinicopathologic analysis of 51 cases

Fifty-one cases of central, hyalin cartilage tumors of the long and flat bones were analyzed. Although Grade 2 and 3 chondrosarcomas could be diagnosed on the basis of cytologic features alone, low-grade chondrosarcoma could not be adequately differentiated from pure, benign enchondroma(s) by cytology alone. The tumors can be distinguished by a new histologic approach based on tissue patterns. The crucial enchondroma patterns consist of multiple nodules of hyalin cartilage separated by normal marrow in conjunction with partial to complete encompassing plates of lamellar bone that conform to the irregular shapes of the cartilage nodules. The chondrosarcomatous patterns consist of a single confluent mass of cartilage, which commonly permeates the marrow, "trapping" host lamellar bone on all sides, and which forms bands of fibrosis between the confluent peripheral cartilage lobules. Other less common patterns included cartilagenous infiltration of the Haversian systems or marrow fat and/or the development of a soft tissue mass. A central secondary chondrosarcoma is defined as one that shows the combination of both the enchondromatous and chondrosarcomatous patterns. All 18 of the pure enchondromas diagnosed by the methods proposed in this article behaved with strict benignity (i.e., without evidence of recurrence or metastasis with an average follow-up period of 7.2 years). The 33 primary and secondary chondrosarcomas diagnosed using the described patterns behaved with the predicted frequency of recurrence, metastasis, and patient demise.     

Number of cortisol time-points and dexamethasone suppression test sensitivity for major depression

Failure to suppress cortisol secretion after administration of dexamethasone has been reported to be a diagnostic marker for major depression and to have prognostic implications when repeated after antidepressant treatment. The pulsatile pattern of cortisol secretion suggested to us that increasing the number of post-dexamethasone cortisol determinations might significantly increase the sensitivity of the dexamethasone suppression test (DST) for major depression. With a conventional two-point DST (1600 h and midnight), 5% of 20 normal volunteers, 8% of 13 inpatients with non-major depressions, and 31% of 65 inpatients with primary major depression failed to suppress. With six post-dexamethasone points (0800 h, 1200 h, 1600 h, 2000 h, 2200 h, midnight), the respective percentages were 10, 15 and 44%. The additional points increased the sensitivity from 31 to 44%, mostly by identifying more major depressives with a "late escape" pattern. If a clinician is using the DST to establish a marker for major depression that can be repeated to monitor response to treatment and the likelihood of relapse, then perhaps the increased sensitivity of the six-point DST would be helpful, despite a modest decrease in specificity from 94 to 88%.     

"High-dose" calcitriol for control of renal osteodystrophy in children on CAPD

High doses of calcitriol were used prospectively for 11 to 29 months to raise serum calcium levels in an effort to control renal osteodystrophy in 16 children undergoing CAPD. Serum Ca, P, iPTH and alkaline phosphatase were measured monthly; hand radiographs were obtained every six months, and a semiquantitative score of bone abnormalities was evaluated by two independent observers. During the study, serum Ca increased from 9.9 +/- 0.9 to 11.0 +/- 0.6 mg/dl (P less than 0.001); serum iPTH decreased by 113 +/- 131 microliter Eq/ml (P less than 0.005); serum P was unchanged; and serum alkaline phosphatase fell by 33 +/- 46% (P less than 0.02), 530 +/- 397 to 204 +/- 551 IU/liter. The radiographic score fell from 4.8 +/- 4.6 to 0.9 +/- 1.2 (P less than 0.005). The average and maximal doses of calcitriol were 0.61 +/- 0.37 and 0.95 +/- 0.56 microgram/day or 28 +/- 18 and 46 +/- 28 ng/kg body wt/day, respectively. Transient and asymptomatic hypercalcemia occurred in nine patients and two patients had reversible conjunctivitis in association with the hypercalcemia. Thus, "high dose" calcitriol prevented or controlled progression of hyperparathyroid bone disease in most pediatric CAPD patients. The failure to suppress PTH or reverse secondary hyperparathyroidism until the serum Ca rose to 10.5 to 11.0 mg/dl could reflect an increase in the "set point" for PTH suppression by serum calcium in many uremic children.