Human growth hormone presented by K14hGH-transgenic skin grafts induces a strong immune response but no graft rejection

Although immune responses leading to rejection of transplantable tumours have been well studied, requirements for epithelial tumour rejection are unclear. Here, we use human growth hormone (hGH) expressed in epithelial cells (skin keratinocytes) as a model neo-self antigen to investigate the consequences of antigen presentation from epithelial cells. Mice transgenic for hGH driven from the keratin 14 promoter express hGH in skin keratinocytes. This hGH-transgenic skin is not rejected by syngeneic non-transgenic recipients, although an antibody response to hGH develops in grafted animals. Systemic immunization of graft recipients with hGH peptides, or local administration of stimulatory anti-CD40 antibody, induces temporary macroscopic graft inflammation, and an obvious dermal infiltrate of inflammatory cells, but not graft rejection. These results suggest that a neo-self antigen expressed in somatic cells in skin can induce an immune response that can be enhanced further by induction of specific immunity systemically or non-specific immunity locally. However, immune responses do not always lead to rejection, despite induction of local inflammatory changes. Therefore, in vitro immune responses and in vivo delayed type hypersensitivity are not surrogate markers for immune responses effective against epithelial cells expressing neoantigens.

Blunted growth hormone response to clonidine in post-traumatic stress disorder

Hyperactivity of the sympathetic and noradrenergic systems is thought to be a feature of post-traumatic stress disorder (PTSD). Assessment of noradrenergic receptor function can be undertaken by measuring the growth hormone (GH) response to the alpha(2)-agonist clonidine. The aim of this study was to examine whether subjects with combat-related PTSD (with or without co-morbid depression) have a blunted growth hormone response to clonidine, compared to a combat-exposed control group. Twenty-three Vietnam veterans suffering from PTSD alone, 27 suffering from PTSD and co-morbid depression, and 32 veteran controls with no psychiatric illness were administered 1.5 mug/kg clonidine i.v. Plasma growth hormone was measured every 20 min for 120 min. The growth hormone response to clonidine was significantly blunted in the non-depressed PTSD group compared to both the depressed PTSD group and the control group as measured by peak growth hormone, delta growth hormone and AUC growth hormone. Subjects with PTSD and no co-morbid depressive illness show a blunted growth hormone response to clonidine. This suggests that post-synaptic alpha(2)-receptors are subsensitive. This finding is consistent with other studies showing increased noradrenergic activity in PTSD. (C) 2003 Elsevier Ltd. All rights reserved.

Effect of training on the response of plasma vascular endothelial growth factor to exercise in patients with peripheral arterial disease

Expansion of the capillary network, or angiogenesis, occurs following endurance training. This process, which is reliant on the presence of VEGF (vascular endothelial growth factor), is an adaptation to a chronic mismatch between oxygen demand and supply. Patients with IC (intermittent claudication) experience pain during exercise associated with an inadequate oxygen delivery to the muscles. Therefore the aims of the present study were to examine the plasma VEGF response to acute exercise, and to establish whether exercise training alters this response in patients with IC. In Part A, blood was collected from patients with IC (n = 18) before and after (+ 20 and + 60 min post-exercise) a maximal walking test to determine the plasma VEGF response to acute exercise. VEGF was present in the plasma of patients (45.11 +/- 29.96 pg/ml) and was unchanged in response to acute exercise. Part B was a training study to determine whether exercise training altered the VEGF response to acute exercise. Patients were randomly assigned to a treatment group (TMT; n = 7) that completed 6 weeks of high-intensity treadmill training, or to a control group (CON; n = 6). All patients completed a maximal walking test before and after the intervention, with blood samples drawn as for Part A. Training had no effect on plasma VEGF at rest or in response to acute exercise, despite a significant increase in maximal walking time in the TMT group (915 + 533 to 1206 + 500 s; P = 0.009) following the intervention. The absence of a change in plasma VEGF may reflect altered VEGF binding at the endothelium, although this cannot be confirmed by the present data.

Inhibition of transforming growth factor-beta 1 signaling attenuates ataxia telanglectasia mutated activity in response to genotoxic stress

Ionizing radiation causes DNA damage that elicits a cellular program of damage control coordinated by the kinase activity of ataxia telangiectasia mutated protein (ATM). Transforming growth factor beta (TGF beta)-1, which is activated by radiation, is a potent and pleiotropic mediator of physiologic and pathologic processes. Here we show that TGF beta inhibition impedes the canonical cellular DNA damage stress response. Irradiated Tgf beta 1 nail murine epithelial cells or human epithelial cells treated with a small-molecule inhibitor of TGF beta type I receptor kinase exhibit decreased phosphorylation of Chk2, Rad17, and p53; reduced gamma H2AX radiation-induced foci; and increased radiosensitivity compared with TGF beta competent cells. We determined that loss of TGF beta signaling in epithelial cells truncated ATM autophosphorylation and significantly reduced its kinase activity, without affecting protein abundance. Addition of TGF beta restored functional ATM and downstream DNA damage responses. These data reveal a heretofore undetected critical link between the microenvironment and ATM, which directs epithelial cell stress responses, cell fate, and tissue integrity. Thus, Tgf beta 1, in addition to its role in homoeostatic growth control, plays a complex role in regulating responses to genotoxic stress, the failure of which would contribute to the development of cancer; conversely, inhibiting TGF beta may be used to advantage in cancer therapy.

Genetic parameters and predicted response to selection for lean growth in an Australian commercial nucleus pig herd

Genetic parameters for performance traits in a pig population were estimated using a multi-trait derivative-free REML algorithm. The 2590 total data included 922 restrictively fed male and 1668 ad libitum fed female records. Estimates of heritability (standard error in parentheses) were 0.25 (0.03), 0.15 (0.03), and 0.30 (0.05) for lifetime daily gain, test daily gain, and P2-fat depth in males, respectively; and 0.27 (0.04) and 0.38 (0.05) for average daily gain and P2-fat depth in females, respectively. The genetic correlation between P2-fat depth and test daily gain in males was -0.17 (0.06) and between P2-fat and lifetime average daily gain in females 0.44 (0.09). Genetic correlations between sexes were 0.71 (0.11) for average daily gain and -0.30 (0.10) for P2-fat depth. Genetic response per standard deviation of selection on an index combining all traits was predicted at $AU120 per sow per year. Responses in daily gain and backfat were expected to be higher when using only male selection than when using only female selection. Selection for growth rate in males will improve growth rate and carcass leanness simultaneously.

A polymorphism in the growth hormone (GH)-releasing hormone (GHRH) receptor gene is associated with elevated response to GHRH by human pituitary somatotrophinomas in vitro

A previous study has suggested that a G to A base change at position 169 of the GHRH-receptor gene in human somatotrophinomas is a mutation and confers hypersensitivity to GHRH. The alternative base converts codon 57 from GCG to AGC, resulting in replacement of alanine (Ala) with threonine (Thr). In the present study, two of five human GH-secreting somatotrophinomas were found to possess the codon 57 AGC sequence. The GCG allele was also detected, indicating heterozygosity. However, the patients' normal blood-derived DNA also yielded the same sequence pattern, indicating that the Ala=> Thr amino acid change is a normal polymorphism, and not a somatic mutation. Nevertheless, in vitro, the tumors possessing the Ala=> Thr amino acid change responded very strongly to GHRH in terms of cAMP formation, being increased 40- and 200-fold, in comparison to the 2-fold increases by tumors without the alternative GHRH-receptor sequence. Likewise, the in vitro response of GH secretion to GHRH was elevated. One of the two tumors with the alternative Thr residue, and the highest responder to GHRH, possessed a gsp muration, despite the fact that these defects are thought to reduce responsiveness to GHRH. These results fail to confirm that the GCG => AGC at codon 57 of the GHRH-receptor gene is a mutation, but do support the concept that the alternative form with Thr confers increased sensitivity to GHRH. (C) 2000 Academic Press.

The response of lichen growth to additions of distilled water, rainwater and water from a rock surface

Three lichen species were wetted in the field with distilled water, rainwater or water which had run off a rock surafce, during July 1974 to February 1975. The radial growth rate of Parmelia glabratula ssp. fuliginosa was not influenced by the wetting treatments. The radial growth rate of P. conspersa with the distilled water was greater than the control, rainwater and runoff treatments. The radial growth rate of Physcia orbicularis was lower with rainwater and runoff treatmentss than the control and distilled water treatment. These results may be explained by the effect of wetting on the carbon balance of the lichens and by the influence of water chemistry.

The effect of garlic extract on growth, haematology and cell-mediated immune response of newborn goat kids

The present study was carried out to evaluate the effect of different levels of garlic extract supplemented in milk on growth rate, haematology and cell–mediated immune response of Markhoz newborn goat kids. Twenty four newborn goat kids (aged 7+/-3days) were randomly assigned to four groups. The groups consisted of control (received milk without garlic extract), T1, T2 and T3 which received milk supplemented with 62.5, 125 and 250 mg aqueous garlic extract per kg live weight per day for 42 days, respectively. Body weights were measured weekly throughout the experimental period. At day 42, about 10 ml blood samples were collected from each kid via the jugular vein for haematological study. Cell–mediated immune response was evaluated through double skin thickness after intradermal injection of phyto-hematogglutinin (PHA) at day 21 and 42. Total gain was significantly higher for kids in T3 (P<0.05) compared with the control group. Average daily gain (ADG) in T3 group in week 4–5 was higher (P<0.05). Significant differences in globulin (P<0.01), hemoglobin (Hb; P<0.001), hematocrit (PCV; P<0.001), erythrocyte (RBC; P<0.001), neutrophil (P<0.001), lymphocyte (P<0.001) and leukocyte (WBC; P<0.001) were observed among groups. Hb, PCV, RBC, lymphocytes and WBC were higher in kids given garlic extract supplementation. There was a significant difference of double skin thickness among the groups at day 42 (P<0.01). In conclusion, this study indicated that milk supplemented with aqueous garlic extract improved growth rate and immunity of newborn goat kids.