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.

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.

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.

[Sensitivity and significance of nuclear magnetic tomography findings of finger joints in rheumatoid arthritis]. / Sensitivität und Bedeutung kernspintomographischer Befunde an den Fingergelenken der Rheumatoiden Arthritis.

Evaluation of the sensitivity and value of magnetic resonance imaging (MRI) findings and miniarthroscopic investigations (mini-/needle-arthroscopy = MA) of metacarpophalangeal (MCP) joints in patients with rheumatoid arthritis (RA). 30 patients with RA (21 female, 9 male), disease duration 2 months to 22 years and mean disease activity score (DAS) of 3.90 (range: 2.00-7.67) were examined by MRI of the hand (MCP region) and following MA of the MCP-II joints. MRI parameters for arthritis (synovial enhancement, synovial extension, cortical alterations, joint gap width) and corresponding macroscopic items (synovial extension, synovial hyperemia and vascularity, cortical alterations) by MA, scored semiquantitatively for synovitis (graduated from 0-III degree), were correlated. Additionally, normal radiographs of the hands were performed and compared with MRI findings concerning the detection of bony lesions. Evaluation of the 30 MRI and MA examination revealed highly significant correlations (p < 0.0001) for the parameters of synovial extension (MRI/MA), cortical alterations (MRI/MA) and synovial enhancement (MRI) compared to synovial hyperemia and vascularity (MA). We found significant correlations for parameters of activity and chronicity of RA pathology as assessed by MRI and MA. The detection rate of cortical lesions by MRI was two and a half times higher than by X-ray. MRI findings of MCP-II joints compared to those of MCP III-V showed that the MCP-II joint was more strongly involved.

[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.

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.

Magnetic resonance imaging and miniarthroscopy of metacarpophalangeal joints: sensitive detection of morphologic changes in rheumatoid arthritis.

OBJECTIVE: To evaluate and characterize magnetic resonance imaging (MRI) findings in the metacarpophalangeal (MCP) joints of rheumatoid arthritis (RA) patients macroscopically, using miniarthroscopy (MA; needle arthroscopy). METHODS: The second MCP joint of the dominant hand of 22 RA patients (13 with various RA activities/stages; 9 with early RA [< or = 1.5 years' duration]) was examined by MRI followed by MA. Findings were evaluated by standardized semiquantitative measures of synovial and bony pathologic changes of the MCP joint, and were compared with the clinical and conventional radiologic findings. RESULTS: Erosions and pre-erosions were detected in 17 of 22 patients by MRI; 2 of the other 5 patients (all early RA) displayed bony changes on MA. All 10 joints with pre-erosions on MRI (grade I bony alterations on MRI) exhibited significant cartilaginous and bony pathology on MA. Synovial membrane pathology was detected in all but 1 patient by MRI and in all patients by MA, although findings of plain radiography were normal in 6 of the 22 patients and another 9 patients had a Larsen score of 1. Semiquantitative analysis of synovial findings of MRI revealed gadolinium diethylenetriaminepentaacetic acid enhancement as a significant marker of macroscopically varied synovial vascularity and hyperemia, both of which strongly correlated with clinical activity (as measured by the Disease Activity Score). The extent of synovitis/synovial proliferation shown by MA and MRI were significantly correlated with each other, but not with any other activity or damage parameter analyzed. CONCLUSION: In RA, both MRI and MA findings support early detection and staging of synovial changes. Ongoing longitudinal studies are aimed at evaluating the value of synovial proliferation as visualized by both methods.

[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

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.

Parathyroid hormone-related protein maintains mammary epithelial fate and triggers nipple skin differentiation during embryonic breast development.

Prior reports have demonstrated that both parathyroid hormone-related protein (PTHrP) and the type I PTH/PTHrP receptor are necessary for the proper development of the embryonic mammary gland in mice. Using a combination of loss-of-function and gain-of-function models, we now report that PTHrP regulates a series of cell fate decisions that are central to the survival and morphogenesis of the mammary epithelium and the formation of the nipple. PTHrP is made in the epithelial cells of the mammary bud and, during embryonic mammary development, it interacts with the surrounding mesenchymal cells to induce the formation of the dense mammary mesenchyme. In response, these mammary-specific mesenchymal cells support the maintenance of mammary epithelial cell fate, trigger epithelial morphogenesis and induce the overlying epidermis to form the nipple. In the absence of PTHrP signaling, the mammary epithelial cells revert to an epidermal fate, no mammary ducts are formed and the nipple does not form. In the presence of diffuse epidermal PTHrP signaling, the ventral dermis is transformed into mammary mesenchyme and the entire ventral epidermis becomes nipple skin. These alterations in cell fate require that PTHrP be expressed during development and they require the presence of the PTH/PTHrP receptor. Finally, PTHrP signaling regulates the epidermal and mesenchymal expression of LEF1 and (&bgr;)-catenin, suggesting that these changes in cell fate involve an interaction between the PTHrP and Wnt signaling pathways.

Targeted expression of placental lactogen in the beta cells of transgenic mice results in beta cell proliferation, islet mass augmentation, and hypoglycemia.

The factors that regulate pancreatic beta cell proliferation are not well defined. In order to explore the role of murine placental lactogen (PL)-I (mPL-I) in islet mass regulation in vivo, we developed transgenic mice in which mPL-I is targeted to the beta cell using the rat insulin II promoter. Rat insulin II-mPL-I mice displayed both fasting and postprandial hypoglycemia (71 and 105 mg/dl, respectively) as compared with normal mice (92 and 129 mg/dl; p < 0.00005 for both). Plasma insulin concentrations were inappropriately elevated, and insulin content in the pancreas was increased 2-fold. Glucose-stimulated insulin secretion by perifused islets was indistinguishable from controls at 7.5, 15, and 20 mm glucose. Beta cell proliferation rates were twice normal (p = 0. 0005). This hyperplasia, together with a 20% increase in beta cell size, resulted in a 2-fold increase in islet mass (p = 0.0005) and a 1.45-fold increase in islet number (p = 0.0012). In mice, murine PL-I is a potent islet mitogen, is capable of increasing islet mass, and is associated with hypoglycemia over the long term. It can be targeted to the beta cell using standard gene targeting techniques. Potential exists for beta cell engineering using this strategy.

Miniarthroscopy of metacarpophalangeal joints in rheumatoid arthritis. Rating of diagnostic value in synovitis staging and efficiency of synovial biopsy.

OBJECTIVE: To evaluate miniarthroscopy (MA) (needle arthroscopy) of involved joints in rheumatoid arthritis (RA) in the early detection and staging of synovitis and its application in visual guided synovial biopsies. METHODS: 1.0 and 1.9 mm (0 degree/30 degrees) arthroscopes were used in a 2 portal technique. MA performance was developed and evaluated first on hand cadavers (n = 20) and then transferred to metacarpophalangeal (MCP) joints under local anesthesia conditions. Joints of 20 patients with RA with different disease activity and duration were scoped and rated according to scores adapted from arthroscopy of other joints. RESULTS: In 20/20 cases MA provided visualizing and magnification of intraarticular features of MCP joints in RA and allowed grading of synovial alterations, chondromalacia, and bony alterations. Synovial surface changes, thickness, and fibrosis were related to disease duration, as was damage to cartilage and bone. The degree of acute inflammatory reactions like vascularity and hyperemia varied independently of chronic changes; synovial proliferation was reflected to some extent by C-reactive protein. In 2 patients with early RA, synovitis criteria were found macroscopically and histologically. In 18/20 joints, biopsies were taken under visual control; in the other 2, progression of disease (Larsen score >3) limited arthroscopy to 1.0 scope imaging only. Sampling sizes were sufficient for histologic and molecular analysis. CONCLUSION: The developed standardized procedure of MCP arthroscopy is minimally invasive, practicable, and well tolerated by patients, and may allow synovitis monitoring, staging, and biopsy in patients with early as well as chronic arthritis.

Parathyroid hormone-related protein signaling is necessary for sexual dimorphism during embryonic mammary development.

Male mice lack mammary glands due to the interaction of circulating androgens with local epithelial-mesenchymal signaling in the developing mammary bud. Mammary epithelial cells induce androgen receptor (AR) within the mammary mesenchyme and, in response to androgens, the mesenchyme condenses around the epithelial bud, destroying it. We show that this process involves apoptosis and that, in the absence of parathyroid hormone-related protein (PTHrP) or its receptor, the PTH/PTHrP receptor (PPR1), it fails due to a lack of mesenchymal AR expression. In addition, the expression of tenascin C, another marker of the mammary mesenchyme, is also dependent on PTHrP. PTHrP expression is initiated on E11 and, within the ventral epidermis, is restricted to the forming mammary epithelial bud. In contrast, PPR1 expression is not limited to the mammary bud, but is found generally within the subepidermal mesenchyme. Finally, transgenic overexpression of PTHrP within the basal epidermis induces AR and tenasin C expression within the ventral dermis, suggesting that ectopic expression of PTHrP can induce the ventral mesenchyme to express mammary mesenchyme markers. We propose that PTHrP expression specifically within the developing epithelial bud acts as a dominant signal participating in cell fate decisions leading to a specialized mammary mesenchyme.

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.

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.

Expression and role of parathyroid hormone-related protein in human renal proximal tubule cells during recovery from ATP depletion.

Parathyroid hormone (PTH)-related protein (PTHrP) is widely expressed in normal fetal and adult tissues and regulates growth and differentiation in a number of organ systems. Although various renal cell types produce PTHrP, and PTHrP expression in rat proximal renal tubules is upregulated in response to ischemic injury in vivo, the role of PTHrP in the kidney is unknown. To study the effects of injury on PTHrP expression and its consequences in more detail, the immortalized human proximal tubule cell line HK-2 was used in an in vitro model of ATP depletion to mimic in vivo renal ischemic injury. These cells secrete PTHrP into conditioned medium and express the type I PTH/PTHrP receptor. Treatment of confluent HK-2 cells for 2 h with substrate-free, glucose-free medium containing the mitochondrial inhibitor antimycin A (1 microM) resulted in 75% depletion of cellular ATP. After an additional 2 h in glucose-containing medium, cellular ATP levels recovered to approximately 75% of baseline levels. PTHrP mRNA levels, as measured in RNase protection assays, peaked at 2 h into the recovery period (at four times baseline expression). The increase in PTHrP mRNA expression was correlated with an increase in PTHrP protein content in HK-2 cells at 2 to 6 h into the recovery period. Heat shock protein-70 mRNA expression was not detectable under baseline conditions but likewise peaked at 2 h into the recovery period. Treatment of HK-2 cells during the recovery period after injury with an anti-PTHrP(1-36) antibody (at a dilution of 1:250) resulted in significant reductions in cell number and uptake of [3H]thymidine, compared with nonimmune serum at the same titer. Similar results were observed in uninjured HK-2 cells. It is concluded that this in vitro model of ATP depletion in a human proximal tubule cell line reproduces the pattern of gene expression previously observed in vivo in rat kidney after ischemic injury and that PTHrP plays a mitogenic role in the proliferative response after energy depletion.

Parathyroid hormone-related protein in the pancreatic islet and the cardiovascular system.

Parathyroid hormone-related protein was discovered as the causative agent responsible for the common paraneoplastic syndrome, humoral hypercalcemia of malignancy. It is now clear that the PTHrP gene is expressed in virtually every cell and tissue in the body at some point in development or adult life and that the peptide is critical for normal life. Two of the tissues that produce PTHrP are the insulin-producing beta cells of the pancreatic islet and the vascular smooth muscle cells of the arterial wall. In this review, the physiologic roles of PTHrP in the islet and in the arterial wall are explored. PTHrP is a classical neuroendocrine prohormone that undergoes extensive post-translational processing to yield a family of daughter peptides that are the mature secretory forms of the peptide. In addition to its ability to act as a traditional endocrine, paracrine, or autocrine factor, PTHrP appears to be able to act as an "intracrine" factor as well, directly entering the nucleus after translation and stimulating proliferation, apoptosis, and perhaps other cellular responses as well. The cell biology underlying this phenomenon is also explored herein.

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.

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.

Opposing mitogenic and anti-mitogenic actions of parathyroid hormone-related protein in vascular smooth muscle cells: a critical role for nuclear targeting.

Parathyroid hormone-related protein (PTHrP) is a prohormone that is posttranslationally processed to a family of mature secretory forms, each of which has its own cognate receptor(s) on the cell surface that mediate the actions of PTHrP. In addition to being secreted via the classical secretory pathway and interacting with cell surface receptors in a paracrine/autocrine fashion, PTHrP appears to be able to enter the nucleus directly following translation and influence cellular events in an "intracrine" fashion. In this report, we demonstrate that PTHrP can be targeted to the nucleus in vascular smooth muscle cells, that this nuclear targeting is associated with a striking increase in mitogenesis, that this nuclear effect on proliferation is the diametric opposite of the effects of PTHrP resulting from interaction with cell surface receptors on vascular smooth muscle cells, and that the regions of the PTHrP sequence responsible for this nuclear targeting represent a classical bipartite nuclear localization signal. This report describes the activation of the cell cycle in association with nuclear localization of PTHrP in any cell type. These findings have important implications for the normal physiology of PTHrP in the many tissues which produce it, and suggest that gene delivery of PTHrP or modified variants may be useful in the management of atherosclerotic vascular disease.