Corticosterone has independent effects on tissue maturation and growth in the suckling rat

Glucocorticoids are associated with reduced weight gain when used to improve pulmonary function in premature infants. However, tissue maturation is stimulated during normal development by an increase in serum glucocorticoids. We evaluated the effects of glucocorticoid treatment on tissue weight gain and the activity of specific enzymes in the suckling rat, with the hypothesis that these processes are independently regulated. Before the ontogenic surge in corticosterone, 6-d-old rat pups were implanted with a pellet to release corticosterone continuously at 0 (placebo), 48, 120, 240, or 360 micro g/d. We killed the pups at 7, 9, or 12 d of age and measured tissue weights and activities of sucrase and glutamine synthetase. Serum corticosterone concentrations were elevated with dose. Tissue weight gain was proportional to ln(e) serum corticosterone at all ages. In contrast, enzyme indices of tissue maturation did not respond to corticosterone until d9. Also, intestinal tissue was more sensitive than muscle to the effects of corticosterone on weight but less sensitive to its effects on maturation. We conclude that the immediate response, in terms of weight versus the delayed response of the enzymes and their reciprocal sensitivity in muscle and gut, indicates that these processes are independently regulated.     

Relationship among hormonal treatments, suppression of spermatogenesis, and testicular protection from chemotherapy-induced damage

To further elucidate the mechanism by which hormonal pretreatment protects the rat testis from damage by procarbazine, we investigated the relationship between the suppression of hormone levels and spermatogenesis and the recovery of spermatogenesis from stem spermatogonia. LBNF1 rats were implanted with capsules containing testosterone or testosterone plus estradiol. After hormone treatment, rats were injected with procarbazine, and recovery of spermatogenesis was assessed. Testosterone (2 cm) plus estradiol (0.5-cm) reduced serum LH levels causing intratesticular testosterone (ITT) to fall to 3% of control levels within 2 weeks, but testis weights and sperm head counts were not appreciably suppressed until 4 weeks. Two weeks' hormone pretreatment, only slightly enhanced spermatogenesis recovery, but 4 weeks markedly increased it. Testosterone (2 cm) alone produced slower suppression of spermatogenesis and less protection from procarbazine than did testosterone plus estradiol implants, despite equivalent suppression of LH and ITT. Long testosterone implants (24-cm) partially maintained ITT at 14% of control despite undetectable LH levels, prevented any decline in sperm counts, and nearly completely abrogated the protective effect of the hormone treatment. Protection appeared to be best correlated with the testis weight reduction by hormone treatment. Thus, recovery of spermatogenesis after chemotherapy is dependent on the degree of suppression of spermatogenesis caused by the reduction of ITT levels at the time of chemotherapy and likely involves cells, such as the Sertoli cells, that are both androgen-responsive and affected by the numbers of germ cells present.     

Spontaneous in vivo reversion to normal of an inherited mutation in a patient with adenosine deaminase deficiency

Somatic mosaicism in genetic disease generally results from a de novo deleterious mutation during embryogenesis. We now describe a somatic mosaicism due to the unusual mechanism of in vivo reversion to normal of an inherited mutation. The propositus was an adenosine deaminase-deficient (ADA-) child with progressive clinical improvement and unexpectedly mild biochemical and immunologic abnormalities. Mosaicism due to reversion was evidenced by absence of a maternally transmitted deleterious mutation in 13/15 authenticated B cell lines and in 17% of single alleles cloned from blood DNA, despite retention of a maternal 'private' ADA polymorphism linked to the mutation. Establishment of significant somatic mosaicism following reversion to normal could modify any disorder in which revertant cells have a selective advantage.     

Peripheral V gamma 9/V delta 2 T cell deletion and anergy to nonpeptidic mycobacterial antigens in asymptomatic HIV-1-infected persons

Gamma delta T cells represent a minor population of human peripheral lymphocytes, the majority of them expressing the V delta 2/V gamma 9 TCR. Their accumulation in infectious disease lesions and their reactivity toward mycobacterial Ags suggest that V gamma 9/V delta 2 T cells play a role during infectious diseases. We have shown previously a significant expansion of the V delta 1 subset parallel to a dramatic decrease of the V delta 2 subset in PBMC from HIV-infected persons. To understand the mechanisms involved in the deletion of V delta 2 T cells, we analyzed their ability to respond in vitro to several V gamma 9/V delta 2 t cell-specific ligands. We observed that in 60% of asymptomatic HIV-infected persons, V delta 2 T cells exhibited a functional anergy to Daudi and to Mycobacterium tuberculosis stimulations. These observations were supported by the defective expansion of this subset to the recently described nonpeptidic phosphorylated Ag, TUBAg-1. Since V delta 2 responsiveness to mycobacterial Ags was shown to be normally dependent on IL-2 secretion by Th1-type CD4 T cells, the ability of IL-2 to restore V delta 2 T cells' responsiveness to TUBAg-1 was tested. V delta 2 T cell anergy persisted in spite of the presence of IL-2, and was frequently correlated with a defect in CD25 expression on stimulated V delta 2 T cells. Since V delta 2 anergy was associated with an in vivo depletion of this subset, we studied whether programmed cell death could be involved in this process, particularly because of their activated phenotype. Although peripheral V delta 2 T cells from some HIV-infected persons showed an increased susceptibility to spontaneous and activation-induced apoptosis, statistical comparison between HIV+ and HIV- donors indicated that there was no difference between both groups in the rate of V delta 2 apoptosis. Finally, V delta 2 complementarity-determining region 3 TCR analysis indicated that, in vivo, the remaining V delta 2 T cells were still polyclonal. All together these results suggest that the qualitative and quantitative alterations of the V delta 2 subset in the course of HIV infection are the consequence of a chronic antigenic stimulation, and raise the question of the contribution of a cellular ligand induced or modified by chronic HIV infection.     

Celahinine A, a new sesquiterpene pyridine alkaloid from Celastrus hindsii

A new sesquiterpene pyridine alkaloid, celahinine A [1], and the related known polyester celahin A, as well as the known cytotoxic sesquiterpene pyridine alkaloid emarginatine A [2], were isolated from Celastrus hindsii. The structure of 1 was determined by 2D nmr techniques and was also confirmed by spectral comparison with the related 2.     

In situ comparison of 665 nm and 633 nm wavelength light penetration in the human prostate gland

The depth of treatment in photodynamic therapy (PDT) of tumors varies with the wavelength of light activating the photosensitizer. New generation photosensitizers that are excited at longer wavelengths have the potential for increasing treatment depths. Tin ethyl etiopurpurin (SnET2), a promising second-generation photosensitizer is maximally activated at 665 nm, which may be significantly more penetrating than 633 nm light currently used with porphyrins in PDT. The penetration of 665 nm and 633 nm wavelength red light in the prostate gland was compared in 11 patients undergoing prostatic biopsies for suspected prostatic cancer. Interstitial optical fibers determined the light attenuation within the prostate gland. Of the 11 patients, 7 had dual wavelength and 4 had single wavelength studies. The mean attenuation coefficients, mueff, for 665 nm and 633 nm wavelength light were 0.32 +/- 0.05 mm-1 and 0.39 +/- 0.05 mm-1, respectively, showing a statistically significant difference (P = 0.0003). This represented a 22% increase in the mean penetration depth and at 10 mm from the delivery fiber there was 1.8 times as much 665 nm light fluence than 633 nm. The mean mueff at 665 nm for benign and malignant prostate tissue were similar (P = 0.42), however, there was significant interpatient variation (mueff ranging from 0.24 to 0.42 mm-1) reflecting biological differences of therapeutic importance. The enhanced light fluence and penetration depth with 665 nm light should allow significantly larger volumes of prostatic tissue to be treated with SnET2-mediated PDT.