A system of surgery : theoretical and practical /

Imprint varies: v. 2-3 published by Parker, son, and Bourn; v. 4 by Longman, Green, Longman, Roberts, and Green.

Prolonged Duration of Sciatic Nerve Blockade in the Elderly after Foot and Ankle Surgery

1.1 Background and Objectives: Perioperative morbidity related to anesthesia renders elderly patients vulnerable because age related factors affect medication effects, clearance and metabolism. Regional anesthesia within a multimodal regimen reduces opioid adverse effects in the elderly and improves immediate analgesia but not long term recovery and prolonged nerve blockade has been reported. The purpose of this study was to assess analgesic effects of sciatic nerve blockade in the elderly. 1.2 Methods: Postoperative sciatic nerve blockade was administered for foot and ankle surgery to patients over age 18 years. Preoperative, post-anesthesia unit and 24 hour postoperative pain scores and opioid doses for these same intervals were recorded. 1.3 Results: 47 patients enrolled and 12 (25.5%) were over age 70. Preoperative, immediate and 24 post-operative pain scores and total intraoperative and immediate postoperative opioid doses were lower in the elderly. The total 24 hour postoperative opioid doses in the elderly were lower compared to the younger group. 1.4 Conclusions: Total 24 hour postoperative cumulative opioid doses after sciatic nerve blockade in patients over 70 are lower than in younger patients. Further observations in greater numbers of patients and improved ultrasound to assess sciatic nerve structure in the elderly are warranted to study this effect.

Urea based osmoregulation and endocrine control in elasmobranch fish with special reference to euryhalinity

Since the landmark contributions of Homer Smith and co-workers in the 1930s there has been a considerable advance in our knowledge regarding the osmoregulatory strategy of elasmobranch fish. Smith recognised that urea was retained in the body fluids as part of the 'osmoregulatory ballast' of elasmobranch fish so that body fluid osmolality is raised to a level that is iso- or slightly hyper-osmotic to that of the surrounding medium. From studies at that time he also postulated that many marine dwelling elasmobranchs were not capable of adaptation to dilute environments. However, more recent investigations have demonstrated that, at least in some species, this may not be the case. Gradual acclimation of marine dwelling elasmobranchs to varying environmental salinities under laboratory conditions has demonstrated that these fish do have the capacity to acclimate to changes in salinity through independent regulation of Na+, Cl- and urea levels. This suggests that many of the presumed stenohaline marine elasmobranchs could in fact be described as partially euryhaline. The contributions of Thomas Thorson in the 1970s demonstrated the osmoregulatory strategy of a fully euryhaline elasmobranch, the bull shark, Carcharhinus leucas, and more recent investigations have examined the mechanisms behind this strategy in the euryhaline elasmobranch, Dasyatis sabina. Both partially euryhaline and fully euryhaline species utilise the same physiological processes to control urea, Na+ and Cl- levels within the body fluids. The role of the gills, kidney, liver, rectal gland and drinking process is discussed in relation to the endocrine control of urea, Na+ and Cl- levels as elasmobranchs acclimate to different environmental salinities. (C) 2003 Elsevier Inc. All rights reserved.

Variation in Coral Photosynthesis, Respiration and Growth Characteristics in Contrasting Light Microhabitats: An Analogue to Plants in Forest Gaps and Understoreys?

1. The often complex architecture of coral reefs forms a diversity of light microhabitats. Analogous to patterns in forest plants, light variation may drive strategies for efficient light utilization and metabolism in corals. 2. We investigated the spatial distribution of light regimes in a spur-and-groove reef environment and examine the photophysiology of the coral Montipora monasteriata (Forskal 1775), a species with a wide habitat distribution. Specifically, we examined the variation in tissue and skeletal thickness, and photosynthetic and metabolic responses among contrasting light microhabitats. 3. Daily irradiances reaching corals in caves and under overhangs were 1-5 and 30-40% of those in open habitats at similar depth (3-5 m), respectively. Daily rates of net photosynthesis of corals in cave habitats approximated zero, suggesting more than two orders of magnitude variation in scope for growth across habitats. 4. Three mechanisms of photoadaptation or acclimation were observed in cave and overhang habitats: (1) a 20-50% thinner tissue layer and 40-60% thinner skeletal plates, maximizing light interception per unit mass; (2) a two- to threefold higher photosynthetic efficiency per unit biomass; and (3) low rates of dark respiration. 5. Specimens from open and cave habitats displayed a high capacity to acclimate to downshifts or upshifts in irradiance, respectively. However, specimens in caves displayed limited acclimation to further irradiance reduction, indicating that these live near their irradiance limit. 6. Analogous to patterns for some plant species in forest gaps, the morphological plasticity and physiological flexibility of M. monasteriata enable it to occupy light habitats that vary by more than two orders of magnitude.

Conditional inactivation of the Men1 gene leads to pancreatic and pituitary tumorigenesis but does not affect normal development of these tissues

Mutations of the MEN1 gene, encoding the tumor suppressor menin, predispose individuals to the cancer syndrome multiple endocrine neoplasia type 1, characterized by the development of tumors of the endocrine pancreas and anterior pituitary and parathyroid glands. We have targeted the murine Men1 gene by using Cre recombinase-loxP technology to develop both total and tissue-specific knockouts of the gene. Conditional homozygous inactivation of the Men1 gene in the pituitary gland and endocrine pancreas bypasses the embryonic lethality associated with a constitutional Men1(-/-) genotype and leads to beta-cell hyperplasia in less than 4 months and insulinomas and prolactinomas starting at 9 months. The pituitary gland and pancreas develop normally in the conditional absence of menin, but loss of this transcriptional cofactor is sufficient to cause beta-cell hyperplasia in some islets; however, such loss is not sufficient to initiate pituitary gland tumorigenesis, suggesting that additional genetic events are necessary for the latter.

Ion-trapping, microsomal binding, and unbound drug distribution in the hepatic retention of basic drugs

This study investigated the relative contribution of ion-trapping, microsomal binding, and distribution of unbound drug as determinants in the hepatic retention of basic drugs in the isolated perfused rat liver. The ionophore monensin was used to abolish the vesicular proton gradient and thus allow an estimation of ion-trapping by acidic hepatic vesicles of cationic drugs. In vitro microsomal studies were used to independently estimate microsomal binding and metabolism. Hepatic vesicular ion-trapping, intrinsic elimination clearance, permeability-surface area product, and intracellular binding were derived using a physiologically based pharmacokinetic model. Modeling showed that the ion-trapping was significantly lower after monensin treatment for atenolol and propranolol, but not for antipyrine. However, no changes induced by monensin treatment were observed in intrinsic clearance, permeability, or binding for the three model drugs. Monensin did not affect binding or metabolic activity in vitro for the drugs. The observed ion-trapping was similar to theoretical values estimated using the pHs and fractional volumes of the acidic vesicles and the pK(a) values of drugs. Lipophilicity and pK(a) determined hepatic drug retention: a drug with low pK(a) and low lipophilicity (e.g., antipyrine) distributes as unbound drug, a drug with high pK(a) and low lipophilicity (e.g., atenolol) by ion-trapping, and a drug with a high pK(a) and high lipophilicity (e.g., propranolol) is retained by ion-trapping and intracellular binding. In conclusion, monensin inhibits the ion-trapping of high pK(a) basic drugs, leading to a reduction in hepatic retention but with no effect on hepatic drug extraction.

Hepatic urea biosynthesis in the euryhaline elasmobranch Carcharhinus leucas

Plasma urea levels and hepatic urea production in the euryhaline bull shark, Carcharhinus leucas, acclimated to freshwater and seawater environments were measured. It was found that plasma urea concentration increased with salinity and that this increase was, in part, the result of a significant increase in hepatic production of urea. This study provides direct evidence that hepatic production of urea plays an important role in the osmoregulatory strategy of C. leucas.

Antisense-mediated inhibition of the plasma membrane Calcium-ATPase suppresses proliferation of MCF-7 cells

Alterations in Ca2+ signaling may contribute to tumorigenesis and the mechanism of action of some anticancer drugs. The plasma membrane calcium-ATPase (PMCA) is a crucial controller of intracellular Ca2+ signaling. Altered PMCA expression occurs in the mammary gland during lactation and in breast cancer cell lines. Despite this, the consequences of PMCA inhibition in breast cancer cell lines have not been investigated. In this work, we used Tet-off PMCA antisense-expressing MCF-7 cells to assess the effects of PMCA inhibition in a human breast cancer cell line. At a level of PMCA inhibition that did not completely prevent PMCA-mediated Ca2+ efflux and did not induce cell death, a dramatic inhibition of cellular proliferation was observed. Fluorescence-activated cell sorting analysis indicated that PMCA antisense involves changes in cell cycle kinetics but not cell cycle arrest. We concluded that modulation of PMCA has important effects in regulating the proliferation of human breast cancer MCF-7 cells.

An immunomodulator used to protect young in the pouch of the Tammar wallaby, Macropus eugenii

Eugenin [pGluGlnAspTyr(SO3)ValPheMetHisProPhe-NH2] has been isolated from the pouches of female Tammar wallabies (Macropus eugenii) carrying young in the early lactation period. The sequence of eugenin has been determined using a combination of positive and negative ion electrospray mass spectrometry. This compound bears some structural resemblance to the mammalian neuropeptide cholecystokinin 8 [AspTyr(SO3)MetGlyTrpMetAspPhe-NH2] and to the amphibian caerulein peptides [caerulein: pGluGlnAspTyr(SO3)ThrGlyTrpMetAspPhe-NH2]. Eugenin has been synthesized by a route which causes only minor hydrolysis of the sulfate group when the peptide is removed from the resin support. Biological activity tests with eugenin indicate that it contracts smooth muscle at a concentration of 10(-9) m, and enhances the proliferation of splenocytes at 10(-7) M, probably via activation of CCK2 receptors. The activity of eugenin on splenocytes suggests that it is an immunomodulator peptide which plays a role in the protection of pouch young.

In vivo analysis of growth hormone receptor signaling domains and their associated transcripts

The growth hormone receptor (GHR) is a critical regulator of postnatal growth and metabolism. However, the GHR signaling domains and pathways that regulate these processes in vivo are not defined. We report the first knock-in mouse models with deletions of specific domains of the receptor that are required for its in vivo actions. Mice expressing truncations at residue m569 (plus Y539/545-F) and at residue m391 displayed a progressive impairment of postnatal growth with receptor truncation. Moreover, after 4 months of age, marked male obesity was observed in both mutant 569 and mutant 391 and was associated with hyperglycemia. Both mutants activated hepatic JAK2 and ERK2, whereas STAT5 phosphorylation was substantially decreased for mutant 569 and absent from mutant 391, correlating with loss of IGF-1 expression and reduction in growth. Microarray analysis of these and GHR(-/-) mice demonstrated that particular signaling domains are responsible for the regulation of different target genes and revealed novel actions of growth hormone. These mice represent the first step in delineating the domains of the GHR regulating body growth and composition and the transcripts associated with these domains.

Promoter-, cell-, and ligand-specific transactivation responses of the VDRB1 isoform

The vitamin D receptor (VDR) mediates the effects of 1,25(OH)(2)D-3, the active form of vitamin D. The human VDRB1 isoform differs from the originally described VDR by an N-terminal extension of 50 amino acids. Here we investigate cell-, promoter-, and ligand-specific transactivation by the VDRB1 isoform. Transactivation by these isoforms of the cytochrome P450 CYP24 promoter was compared in kidney (HEK293 and COS1), tumor-derived colon (Caco-2, LS174T, and HCT15), and mammary (HS578T and MCF7) cell lines. VDRB1 transactivation in response to 1,25(OH)(2)D-3 was greater in Cost and HCT15 cells (145%), lower in HEK293 and Caco-2 cells (70-85%) and similar in other cell lines tested. By contrast, on the cytochrome P450 CYP3A4 promoter, 1,25(OH)(2)D-3-induced VDRB1 transactivation was significantly lower than VDRA in Caco-2 (68%), but comparable to VDRA in HEK293 and COS1 cells. Ligand-dependence of VDRB1 differential transactivation was investigated using the secondary bile acid lithocholic acid (LCA). On the CYP24 promoter LCA-induced transactivation was similar for both isoforms in COS1, whereas in Caco-2 and HEK293 cells VDRB1 was less active. On the CYP3A4 promoter, LCA activation of VDRB1 was comparable to VDRA in all the cell lines tested. Mutational analysis indicated that both the 1,25(OH)(2)D-3 and LCA-regulated activities of both VDR isoforms required a functional ligand-dependent activation function (AF-2) domain. In gel shift assays VDR:DNA complex formation was stronger in the presence of 1,25(OH)(2)D-3 than with LCA. These results indicate that regulation of VDRB1 transactivation activity is dependent on cellular context, promoter, and the nature of the ligand. (c) 2005 Elsevier Inc. All rights reserved.

Myoepithelial calls: Pathology, cell separation and markers of myoepithelial differentiation

Until recently the myoepithelial cell has been studied relatively little in terms of its role in breast cancer. A number of malignancies showing myoepithelial differentiation have been reported in the literature, although they are still thought to be relatively rare and only limited studies are published. As a result of recent expression profiling experiments, one type of tumor with myoepithelial features, the so-called 'basal' breast cancer, has received a renewed interest, although it has been known to pathologists for more than two decades. These tumors, which express markers of both luminal and myoepithelial cells, are now being studied using antibodies against some new molecules that have emerged from studies of sorted normal luminal and myoepithelial cells. These immunohistochemical data, combined with genomic studies, may lead to better identification and management of patients with 'basal' tumors.

Gene expression profiles in murine hematopoietic stem cells revisited: Analysis of cDNA libraries reveals high levels of translational and metabolic activities

Gene expression studies from hematopoietic stem cell (HSC) populations purified to variable degrees have defined a set of sternness genes. Unexpectedly, results also hinted toward a HSC chromatin poised in a wide-open state. With the aim of providing a robust tool for further studies into the molecular biology of HSCs, the studies herein describe the construction and comparative molecular analysis of A-phage cDNA libraries from highly purified HSCs that retained their long-term repopulating activities (long-term HSCs [LT-HSCs]) and from short-term repopulating HSCs that were largely depleted of these activities. Microarray analysis of the libraries confirmed the previous results but also revealed an unforeseen preferential expression of translation- and metabolism-associated genes in the LT-HSCs. Therefore, these data indicate that HSCs are quiescent only in regard of proliferative activities but are in a state of readiness to provide the metabolic and translational activities required after induction of proliferation and exit from the HSC pool.

Endocrinology: the next 60 years - the helix and the chip

In the 60 years since C H Li reported the isolation of bovine growth hormone (GH), endocrinologists have seen the widespread use of human GH for statural disorders, the measurement of plasma GH as a diagnostic test, the full development of the somatomedin hypothesis and the molecular details of the function of the GH receptor responsible for regulating somatic growth and metabolism. In diabetes, we have passed from administration of animal insulin to formulations with different release rates, insulin pumps and inhalers, insulin sensitizers and a greater understanding of insulin signalling and insulin resistance through genetically engineered murine models. What might we expect over the next few decades?