Effects of ambient air temperature, humidity and rainfall on annual survival of adult little penguins Eudyptula minor in southeastern Australia.

Seabirds are subject to the influences of local climate variables during periods of land-based activities such as breeding and, for some species, moult; particularly if they undergo a catastrophic moult (complete simultaneous moult) as do penguins. We investigated potential relationships between adult penguin survival and land-based climate variables (ambient air temperature, humidity and rainfall) using 46 years of mark-recapture data of little penguins Eudyptula minor gathered at a breeding colony on Phillip Island in southeastern Australia. Our results showed that adult penguin survival had a stronger association with land-based climate variables during the moult period, when birds were unable to go to sea for up to 3 weeks, than during the breeding period, when birds could sacrifice breeding success in favour of survival. Annual adult survival probability was positively associated with humidity during moult and negatively associated with rainfall during moult. Prolonged heat during breeding and moult had a negative association with annual adult survival. Local climate projections suggest increasing days of high temperatures, fewer days of rainfall which will result in more droughts (and by implication, lower humidity) and more extreme rainfall events. All of these predicted climate changes are expected to have a negative impact on adult penguin survival.

Hemispheric asymmetry in ocean change and the productivity of ecosystem sentinels.

Climate change and other human activities are causing profound effects on marine ecosystem productivity. We show that the breeding success of seabirds is tracking hemispheric differences in ocean warming and human impacts, with the strongest effects on fish-eating, surface-foraging species in the north. Hemispheric asymmetry suggests the need for ocean management at hemispheric scales. For the north, tactical, climate-based recovery plans for forage fish resources are needed to recover seabird breeding productivity. In the south, lower-magnitude change in seabird productivity presents opportunities for strategic management approaches such as large marine protected areas to sustain food webs and maintain predator productivity. Global monitoring of seabird productivity enables the detection of ecosystem change in remote regions and contributes to our understanding of marine climate impacts on ecosystems.

Lesions in many different spindle components activate the spindle checkpoint in the budding yeast Saccharomyces cerevisiae.

The spindle checkpoint arrests cells in mitosis in response to defects in the assembly of the mitotic spindle or errors in chromosome alignment. We determined which spindle defects the checkpoint can detect by examining the interaction of mutations that compromise the checkpoint (mad1, mad2, and mad3) with those that damage various structural components of the spindle. Defects in microtubule polymerization, spindle pole body duplication, microtubule motors, and kinetochore components all activate the MAD-dependent checkpoint. In contrast, the cell cycle arrest caused by mutations that induce DNA damage (cdc13), inactivate the cyclin proteolysis machinery (cdc16 and cdc23), or arrest cells in anaphase (cdc15) is independent of the spindle checkpoint.

Characteristics of marine debris that entangle Australian fur seals (Arctocephalus pusillus doriferus) in southern Australia.

Marine debris is a global issue that can have devastating impacts on marine mammals. To understand the types of materials that result in entanglement and thus the potential impact of entangling items on marine wildlife, we analysed data collected from items in which Australian fur seals had been entangled in southern Victoria, Australia over a 15year period. From 1997 to 2012, 138 entangling items were removed from seals. The majority of these entanglements were plastic twine or rope, and seals were entangled in green items more than in any other colour. In general, younger seals were more likely to be entangled than adults. Understanding the effects of marine debris entanglement on the Australian fur seal population can lead to more effective management of the sources of debris and the wildlife that interact with it.

Progressive pancreatic islet hyperplasia in the islet-targeted, parathyroid hormone-related protein-overexpressing mouse.

PTH-related protein (PTHrP) is a paracrine/autocrine factor produced in most cell types in the body. Its functions include the regulation of cell cycle, of differentiation, of apoptosis, and of developmental events. One of the cells which produces PTHrP is the pancreatic beta cell. We have previously described a transgenic mouse model of targeted overexpression of PTHrP in the beta cell, the RIP-PTHrP mouse. These studies showed that PTHrP overexpression markedly increased islet mass and insulin secretion and resulted in hypoglycemia. Those studies were limited to RIP-PTHrP mice of 8-12 weeks of age. In the current report, we demonstrate that PTHrP overexpression induces a progressive increase in islet mass over the life of the RIP-PTHrP mouse, and that, in contrast to some other models of targeted PTHrP overexpression, the phenotype is not developmental, but occurs postnatally. The marked increase in islet mass is not associated with a measurable increase in beta cell replication rates. A further slowing in the normally low islet apoptosis rate could not be demonstrated in the RIP-PTHrP islet. Thus, the marked increase in islet mass in the RIP-PTHrP mouse is unexplained in mechanistic terms. Finally, RIP-PTHrP mice are resistant to the diabetogenic effects of streptozotocin. The mechanisms responsible for the increase in islet mass in the RIP-PTHrP mouse likely lie in either very subtle changes in islet turnover or in early steps in islet differentiation and development. The ability of PTHrP to increase islet mass and function, as well as its ability to attenuate the diabetogenic effects of streptozotocin, indicate that further study of PTHrP on islet development and function are important and may lead to therapeutic strategies in diabetes mellitus.

A high abundance midregion species of parathyroid hormone-related protein: immunological and chromatographic characterization in plasma.

The widespread expression of the gene for PTH-related protein (PTHrP) and the high interspecies conservation of the primary sequence of even the non-PTH-like portion of the protein argue for a vital role(s) for PTHrP in normal physiology. Emerging evidence suggests that PTHrP may be processed into smaller bioactive peptides, but the circulating forms of PTHrP are not well characterized. We have measured plasma concentrations in well defined patient groups using a RIA directed toward midregion PTHrP-(37-74), compared midregion concentrations to amino-terminal and carboxy-terminal PTHrP concentrations in the same patients, and further defined the components of midregion PTHrP immunoreactivity by high pressure liquid chromatography. Patients with humoral hypercalcemia of malignancy (HHM) had concentrations of PTHrP-(37-74) immunoreactivity of 90 +/- 10 pmol/L (mean +/- SEM), 9-fold higher than PTHrP-(1-74) immunoreactivity and about 3-fold higher than PTHrP-(109-138) immunoactivity. There was no consistent elevation of midregion PTHrP in patients with local osteolytic hypercalcemia, hyperparathyroidism, or renal failure, but discrimination of these groups from HHM was less complete using PTHrP-(37-74) than using PTHrP-(1-74) immunoactivity. By reverse phase high pressure liquid chromatography, plasma PTHrP-(37-74) immunoactivity in patients with HHM was resolved into three components: 1) a major peak coeluting with that found in medium conditioned by cells transfected with human PTHrP-(1-141), which we have previously sequenced and found to represent a midregion peptide beginning at residue 38; 2) a minor peak with both PTHrP-(37-74) and -(1-74) immunoreactivity; and 3) another minor peak with PTHrP-(37-74), but not PTHrP-(1-74), immunoactivity. In conclusion, the predominant circulating form of PTHrP in patients with HHM is a midregion species similar or identical to the peptide beginning at residue 38, which has been shown to be a secretory form of PTHrP.

Parathyroid hormone-related protein-(1-36) is biologically active when administered subcutaneously to humans.

PTH-related protein (PTHrP) is responsible for most cases of humoral hypercalcemia of malignancy (HHM). It mimics the actions of PTH as a result of its structural homology with PTH and its ability to bind to and signal via the PTH/PTHrP receptor in bone and kidney. PTHrP-(1-36) appears to be one of several secretory forms of PTHrP. This peptide has been administered iv to normal volunteers previously and has been shown to produce effects that are qualitatively and quantitatively the same as those produced by PTH-(1-34). To determine whether PTHrP-(1-36) could be used sc in humans as a diagnostic reagent for elucidating the differences between HHM and hyperparathyroidism, we performed a 12-h dose-finding study examining whether sc PTHrP-(1-36) could elicit effects on mineral homeostasis. PTHrP-(1-36) administered sc in three doses (0.82, 1.64, and 3.28 micrograms/kg) to 21 normal women produced increases in circulating PTHrP-(1-36), reductions in serum phosphorus and the renal phosphorus threshold, increments in fractional calcium excretion and nephrogenous cAMP excretion, and increases in plasma 1,25-dihydroxyvitamin D. These changes were highly significant in statistical terms and were observed at doses that had no effect on serum calcium or endogenous PTH. These studies demonstrate the feasibility of using PTHrP-(1-36) as a diagnostic probe for future studies aimed at elucidating the differing pathophysiologies of HHM and hyperparathyroidism.

Absence of functional type 1 parathyroid hormone (PTH)/PTH-related protein receptors in humans is associated with abnormal breast development and tooth impaction.

Recent studies in transgenic mice have demonstrated that PTH-related protein (PTHrP), signaling through the type 1 PTH/PTHrP receptor (PTHR1), regulates endochondral bone development and epithelial-mesenchymal interactions during the formation of the mammary glands and teeth. Recently, it has been shown that loss-of-function mutations in the PTHR1 gene result in a rare, lethal form of dwarfism known as Blomstrand chondrodysplasia. These patients suffer from severe defects in endochondral bone formation, but abnormalities in breast and tooth development have not been reported. To ascertain whether PTHrP signaling was important to human breast and tooth development, we studied two fetuses with Blomstrand chondrodysplasia. These fetuses lack nipples and breasts. Developing teeth were present, but they were severely impacted within the surrounding alveolar bone, leading to distortions in their architecture and orientation. Compatible with the involvement of PTHR1 and PTHrP in human breast and tooth morphogenesis, both were expressed within the developing breasts and teeth of normal human fetuses. Therefore, impairment of the PTHrP/PTHR1 signaling pathway in humans is associated with severe abnormalities in tooth and breast development. In addition to regulating human bone formation, this signaling pathway is also necessary for the normal development of the human breast and tooth.

Effect of acyclovir on genital infection with herpes simplex virus types 1 and 2 in the guinea pig.

The pathogenesis of genital infection with three different strains of herpes simplex virus type 1 (HSV-1) and three strains of herpes simplex virus type 2 (HSV-2) was compared in the guinea pig. Strain differences in severity of clinical disease and mortality were noted. HSV-1 strains generally produced milder disease than HSV-2. Both HSV-1 and HSV-2 infections resulted in acute and chronic changes in the cervix. Virus recovery during latent infection was more frequently obtained from the spinal cord in HSV-1-infected animals and from lumbosacral ganglia in HSV-2-infected animals. Systemic treatment with acyclovir, after the onset of clinical disease, had minimal, if any, effect on genital infection with HSV-1 (NYU-78), but similar treatment of HSV-2 (WT-186) infection resulted in decreased lesion scores, paralysis, and mortality during acute infection. A reduction in virus isolations from lumbosacral ganglia was noted during both acute and latent infection with HSV-2 (WT-186) in the acyclovir-treated groups.

Temporally regulated overexpression of parathyroid hormone-related protein in the mammary gland reveals distinct fetal and pubertal phenotypes.

We have previously demonstrated that overexpression of parathyroid hormone-related protein (PTHrP) in the mammary glands of transgenic mice results in defects in ductal elongation and branching during puberty and in lobuloalveolar development during pregnancy. In addition, we have shown that PTHrP is necessary for the formation of the initial ductal tree during embryonic mammary development. In order to examine the effect of varying the timing of PTHrP overexpression on mammary development, we created tetracycline-regulated, K14-tTA/Tet(O)-PTHrP double transgenic mice. In this report, we document that this 'tet-off' system directs transgene expression to the mammary gland and that it is fully repressed in the presence of tetracycline. Using these mice, we demonstrate that transient overexpression of PTHrP before birth causes defects in ductal branching during puberty and that overexpression of PTHrP during puberty decreases the rate of ductal elongation. Furthermore, we demonstrate that if PTHrP overexpression is initiated after ductal morphogenesis is completed, lobuloalveolar development is unaffected. Finally, we demonstrate that the impairment in ductal elongation caused by PTHrP is associated with an increase in the basal rate of epithelial cell apoptosis in terminal end buds and a failure to increase end bud cell proliferation and decrease apoptosis in response to estrogen and progesterone.

Clonal variation of p53 expression and proliferative phenotype in A253 squamous carcinoma cells.

Loss of normal p53 tumor-suppressor gene function is characteristic of the majority of squamous carcinomas. During the course of gene transfer studies in the human squamous carcinoma cell line, A253, which does not express p53 mRNA or protein, we incidentally observed increased levels of p53 expression in up to 20% of clonal cell lines derived from parental A253 cells. p 53-expressing A253 cells (A253-p53) were also isolated by dilutional cloning. Nuclear p53 protein was identified by immunohistochemistry in A253-p53 cells in a wild-type pattern, and p53 mRNA (2.5 kb) was demonstrated by northern blot. Mutational analysis of the p53 gene in A253-p53 cells revealed no evidence for mutations in exons 5-9. A253-p53 cells could be distinguished from native A253 cells by prolonged doubling times (2-5 fold) and by a marked reduction of [3H]-thymidine uptake. Whereas A253 cells were unresponsive to the growth-inhibitory effects of TGF-beta, EGF-stimulated A253-p53 cells responded to TGF-beta with markedly reduced DNA synthetic rates. A253-p53 cells cocultured with A253 demonstrated enhanced cell growth and DNA synthesis rates compared to control A253-p53 cells. Finally, A253-p53 cells show reduced expression of c-fos, fibronectin, thrombospondin and parathyroid hormone-related protein (PTHrP) mRNAs. PTHrP measured by RIA in conditioned medium was approximately 300 pM for A253 but undetectable for A253-p53. We conclude that the A253 cell line contains a subpopulation of cells which express high levels of "wild-type-like" p53 protein. This results in dramatic changes in gene expression and a slower-growing phenotype in vitro.

[MR-morphological changes of the metacarpophalangeal joints in patients with rheumatoid arthritis: Comparison of early and chronical stages]. / MR-morphologische Veränderungen der Metacarpophalangealgelenke bei Rheumatoider Arthritis: Vergleich früher und später Stadien.

UNLABELLED: MR-morphological changes of the metacarpophalangeal joints in patients with rheumatoid arthritis: Comparison of early and chronical stages. PURPOSE: Evaluation of MRI findings in the metacarpophalangeal (MCP) joints in patients with early (eRA) and chronical rheumatoid arthritis (cRA). MATERIAL AND METHODS: In 22 RA patients (9 with disease duration

Immunohistochemical detection of parathyroid hormone-related protein in a cutaneous squamous cell carcinoma causing humoral hypercalcemia of malignancy.

Humoral hypercalcemia of malignancy is a cancer-related hypercalcemia caused by production of humoral factors by malignant cells in patients without bone metastases. Squamous cell carcinomas are the tumors most frequently associated with humoral hypercalcemia of malignancy, and parathyroid hormone-related protein is the main humoral factor implicated. In spite of the fact that normal keratinocytes produce parathyroid hormone-related protein, it is highly unusual for patients with squamous cell carcinomas of the skin to present with humoral hypercalcemia of malignancy. We present a well-documented case of cutaneous squamous cell carcinoma complicated by hypercalcemia in a patient with high levels of plasma parathyroid hormone-related protein and immunohistochemical evidence of high parathyroid hormone-related protein production by the tumoral cells.

Resolving mixtures of strategies in spatial visualization tasks.

The models of standard test theory, having evolved under a trait-oriented psychology, do not reflect the knowledge structures and the problem-solving strategies now seen as central to understanding performance and learning. In some applications, however, key qualitative distinctions among persons as to structures and strategies can be expressed through mixtures of test theory models, drawing on substantive theory to delineate the components of the mixture. This approach is illustrated with response latencies to spatial visualization tasks that can be solved by mental rotation or by a non-rotational rule-based strategy. It is assumed that a subject employs the same strategy on all tasks, but the possibility of extending the approach to strategy-switching is discussed.

Glial nodule encephalitis in the guinea pig: serial observations following cytomegalovirus infection.

Cytomegalovirus (CMV) encephalitis, characterized by microglial nodules, is a major neurological complication in AIDS. There is a clear need for a well-characterized laboratory model of CMV encephalitis. We report here the sequential virological, histopathological, and antibody responses of young guinea pigs inoculated intracerebrally with guinea pig CMV. Virus was found to peak in the brain in the 1st week, to peak in the spleen in the 2nd week, and to be cleared from the brain with the development of serum neutralizing antibody 3 to 4 weeks post infection. Leptomeningitis peaked at the end of the 1st week, independent of the changes found in the parenchyma. Diffuse and focal infiltration of systemic cells was found in the cortex. Microglial nodules consisting of swirled and elongated cells, sometimes in association with intranuclear inclusion bearing cells, were prominent. The parenchymal changes, including scattered foci of ependymitis and ventriculitis, were most prominent in the 2nd week post infection. This model should facilitate studies of the host defense response in the brain and of the role of antiviral therapy in CMV encephalitis.

Effect of vasoactive agents on induction of Egr-1 in rat mesangial cells: correlation with mitogenicity.

The early growth response gene 1 (Egr-1) is a member of the family of immediate early response genes. Egr-1 encodes a nuclear phosphoprotein that binds a specific nonameric DNA sequence through three zinc-finger domains and functions as a transcriptional activator. We tested whether the vasoactive agents platelet-derived growth factor (PDGF), arginine vasopressin (AVP), serotonin (5-HT), and angiotensin II (ANG II) induced Egr-1 mRNA in cultured rat mesangial cells (MCs) and investigated the role of protein kinase C (PKC) in mediating the induction process. PDGF, AVP, and 5-HT induced Egr-1 mRNA within 15 min, reaching peak levels at 45-60 min. After PDGF and 5-HT stimulation, Egr-1 mRNA levels returned to baseline within 4 h, whereas AVP induced a sustained increase for up to 8 h. There was a very close correlation between doses required for Egr-1 induction and induction of MC proliferation. ANG II was a very weak MC mitogen and induced only a small increase in Egr-1 mRNA. Comparison of control cells with cells depleted of PKC by 48 h of PMA treatment revealed that induction of Egr-1 by PDGF and 5-HT is independent of PKC. In contrast, however, the Egr-1 response to AVP was diminished in PKC-depleted cells. AVP induced Egr-1 mRNA 10.9-fold in control cells, compared with 7.8-fold in PKC-depleted cells. Egr-1 mRNA after AVP stimulation remained elevated in control cells for up to 8 h but returned to baseline after 120 min in PKC-depleted cells. Similar results were obtained using the PKC-inhibitor H-7. Using immunocytochemistry, PDGF and AVP were found to induce Egr-1 protein within 30 min localized to the nucleus. We conclude that there is a strong correlation between induction of Egr-1 after stimulation with PDGF, AVP, 5-HT, and ANG II and the proliferative response elicited by these agents in MCs. AVP induces Egr-1 by both PKC-dependent and PKC-independent pathways, whereas the effects of PDGF and 5-HT are independent of PKC.

[Synovial membrane diagnostic assessment in rheumatoid arthritis]. / Synovialis-Diagnostik bei Rheumatoider Arthritis.

Rheumatoid arthritis (RA) is the most frequent inflammatory rheumatic disease. At the beginning of the disease, where, based on today's knowledge the therapeutic possibilities are largest, the diagnostic methods do not permit a differentiated estimation of the prognosis. Conventional x-rays are mostly normal and serum markers unspecific. So far--in contrast to other diseases--only little information had been drawn from the pathomorphologic substrate "synovialis" itself to assess the prognosis. Reasons therefor were found in difficulties in obtaining synovial tissue besides surgical interventions, particularly in patients with early arthritis. By minimalizing the diagnostic instruments and improvement of the technique, synovial tissue sampling in RA has become minimally invasive and it is even possible to perform on the smallest joints, such as finger joints. Hereby, synovial analysis is open for detecting pathways of inflammation and joint destruction, which might support the advancement of new therapeutic strategies, followed by a better prognosis and outcome of RA.

Mechanisms of injury to the central nervous system following experimental cytomegalovirus infection.

A guinea pig model was used to determine the mechanisms of injury to the central nervous system by cytomegalovirus. Focal, well-contained, histopathologic responses included the microglial nodule without residua, and the ependymitis with focal residual glial scarring. Higher virus dose infection in the brain resulted in inflammatory necrosis with an astrocytic response to injury. However, monocytes and microglia were the predominant responding cells of host defense. A vasogenic pathogenesis was suggested by the involvement of the vascular endothelium, and separately by central nervous system vasculitis, demonstrated here for the first time in this model. Hence, our studies suggest four potential mechanisms of injury to the central nervous system by cytomegalovirus: viral cytopathology, inflammatory mediators from cells of the monocyte series, two separate types of vascular impairment, and astroglial scarring.