Cutting edge: precursor frequency affects the helper dependence of cytotoxic T cells.

Generation of CTL immunity often depends on the availability of CD4 T cell help. In this report, we show that CTL responses induced by cross-priming can be converted from CD4-dependent to CD4-independent by increasing the frequency of CTL precursors. In the absence of CD4 T cells, high numbers of CTL precursors were able to expand in number and become effector CTL. The ability of high frequencies of CD8 T cells to override help was not due to their ability to signal CD40 via expression of CD154. These findings suggest that when precursor frequencies are high, priming of CD8 T cell responses may not require CD4 T cell help.     

Altered morphogenesis of the immature hamster uterus following neonatal exposure to diethylstilbestrol

Abstract. In previous studies, we found that a single neonatal exposure to diethylstilbestrol (DES) resulted in severe hyperplasia and a high incidence of endometrial adenocarcinoma in the uterus of adult hamsters. These observations prompted us to investigate the consequences of DES exposure on earlier stages of uterine morphogenesis. After neonates were treated within 6 h of birth (day 1) with 100 μg of DES or oil vehicle, uterine tissue morphometry plus cell labelling indices following in vivo pulse labeling with [³H]thymidine were determined on days 3–21 of life. The sequential findings were: (1) a precocious (day 3) burst of cellular proliferation throughout the uterus, (2) an early period (days 3–9) of hypertrophy and increased cell density in the luminal epithelium, (3) an extreme acceleration of uterine growth resulting in a persistent increase in total uterine mass (threefold enhancement on days 5–21), (4) precocious development of endometrial glands (day 9) that were sites of intense but transient proliferative activity, (5) a middle period (days 9–15) when the percentage of stromal cells engaged in proliferative activity was reduced, (6) a second wave (days 15–21) of enhanced proliferative activity in the luminal epithelium, and (7) later development (day 21) of reduced cell density in the uterine stroma, apparently due to increased intercellular collagen accumulation. These results support our working hypothesis that the acute uterotropic response to neonatal DES treatment initiates a change in the developing hamster uterus, and later estrogenic stimulation promotes neoplastic progression in the DES-altered adult organ, perhaps due to disruption of stromal-epithelial interactions.     

Analysis of Immune Response Markers in Jorge Lobo's Disease Lesions Suggests the Occurrence of Mixed T Helper Responses with the Dominance of Regulatory T Cell Activity

Jorge Lobo’s disease (JLD) is a chronic infection that affects the skin and subcutaneous tissues. Its etiologic agent is the fungus Lacazia loboi. Lesions are classified as localized, multifocal, or disseminated, depending on their location. Early diagnosis and the surgical removal of lesions are the best therapeutic options currently available for JLD. The few studies that evaluate the immunological response of JLD patients show a predominance of Th2 response, as well as a high frequency of TGF-β and IL-10 positive cells in the lesions; however, the overall immunological status of the lesions in terms of their T cell phenotype has yet to be determined. Therefore, the objective of this study was to evaluate the pattern of Th1, Th2, Th17 and regulatory T cell (Treg) markers mRNA in JLD patients by means of real-time PCR. Biopsies of JLD lesions (N = 102) were classified according to their clinical and histopathological features and then analyzed using real-time PCR in order to determine the expression levels of TGF-β1, FoxP3, CTLA4, IKZF2, IL-10, T-bet, IFN-γ, GATA3, IL-4, IL-5, IL-13, IL-33, RORC, IL-17A, IL-17F, and IL-22 and to compare these levels to those of healthy control skin (N = 12). The results showed an increased expression of FoxP3, CTLA4, TGF-β1, IL-10, T-bet, IL-17F, and IL-17A in lesions, while GATA3 and IL-4 levels were found to be lower in diseased skin than in the control group. When the clinical forms were compared, TGF-β1 was found to be highly expressed in patients with a single localized lesion while IL-5 and IL-17A levels were higher in patients with multiple/disseminated lesions. These results demonstrate the occurrence of mixed T helper responses and suggest the dominance of regulatory T cell activity, which could inhibit Th-dependent protective responses to intracellular fungi such as L. loboi. Therefore, Tregs may play a key role in JLD pathogenesis.     

Do Doctors Undertreat Pain?

Routinely, physicians discount patients' pain reports and provide too little analgesia too late. Critics call them callous, sadistic, and Puritanical, but the causes of these clinical practices are different — namely, a psychological need to distance themselves from the pain they encounter and inflict, and more subtly, a peculiar concept of pain acquired in medical training.
Physicians learn to think of pain as a symptom to observe and explore in diagnosing and monitoring disease — not as a complaint to relieve quickly or fully. Moreover, pain-relief is regarded as subordinate to, and competing with efforts to cure or maintain the life of a patient. This training, I suggest, gives physicians a new, clinical concept of pain at odds with their prior, lay concept of pain whose manifestations standardly call for sympathetic efforts at relief.
The conceptual nature of this difference is obscured by thinking of pain as a solely private sensation, rather than as a sensation with public and social aspects (a la Wittgenstein). Although suppressed in certain clinical circumstances, these standard public and social aspects are shown in the very tests used in clinical pain research.
This clinical pain concept is rooted in Medicine conceived as preeminently curative and life-prolonging. Physicians are, however, themselves undermining this professional self-definition (by treating AIDS and Alzheimer's patients; by no longer pressing their patients to 'fight to the end'; by collaborating with non-medical healers). Accordingly, pain-relief may gain greater therapeutic status, and, so too, the ordinary concept of pain that medical training has suppressed.     

Behavioral laterality in captive bonobos (Pan paniscus): Replication and extension

We report observational data on behavioral laterality in 10 captive bonobos (Pan paniscus)at the San Diego Zoo. The unimanual measures include carrying, leading limb in locomotion, self-touching, face-touching, reaching, and gestures. We also recorded bimanual feeding in these subjects. A significant population level left-hand bias exists for carrying. Right-hand biases occur for leading limb in locomotion and gestures. During bimanual feeding, the bonobos hold food items with the left hand while feeding with the right hand. Overall, bonobos exhibit behavioral asymmetries that are similar to previous findings in other pongid ape species. The asymmetries in gestures and bimanual feeding represent novel findings with theoretical implications for the origins of tool use and language.