In response to stress, bacteria upregulate specific groups of proteins which maintain the integri... more In response to stress, bacteria upregulate specific groups of proteins which maintain the integrity of the cell; one such protein is HtrA, a serine protease. HtrA production in different bacteria appears to be induced by distinct environmental stress conditions, eg. in Escherichia coli the htrA gene is essential for bacterial survival at high temperatures7, whereas a Salmonella typhimurium htrA mutant was temperature insensitive, but susceptible to oxidative stress5. A Bruceila abortus htrA mutant is both temperature and oxidative stress sensitive4. The HtrA family of stress-response proteins may also be important in bacterial pathogenicity as the S. typhimurium and B. abortus mutants are attenuated for mouse virulence4,5. The mutant’s susceptibility to oxidative stress suggests increased sensitivity to oxidative killing within macrophages.
Human peripheral mononuclear cells (MC) secrete 2 soluble activities that modulate the growth of ... more Human peripheral mononuclear cells (MC) secrete 2 soluble activities that modulate the growth of human synovial fibroblastic cells. A growth-suppressive, lectin-dependent activity is elaborated by the non-adherent population and its secretion begins before DNA synthesis is initiated in concanavalin-stimulated MC cultures. The elaboration of this activity is partially dependent on the presence of serum and it appears to be distinct from virus-induced human leukocyte interferon. The second activity is secreted spontaneously by the MC, under a variety of culture conditions including supplementation with homologous human plasma, and it enhances the growth of synovial fibroblasts. The rate of secretion of the growth-enhancing activity by the nonstimulated MC approximately parallels that of the inhibitory activity from the stimulated MC cultures. MC from patients with rheumatoid arthritis and from nonaffected individuals secrete similar concentrations of growth-stimulatory activity for the synovial fibroblasts.
Human, blood‐derived mononuclear cells (MC), stimulated with Concanavalin A (Con A), synthesized ... more Human, blood‐derived mononuclear cells (MC), stimulated with Concanavalin A (Con A), synthesized a chondroitin sulfate (CS) proteoglycan (PG), which was elaborated largely by T‐cells. Following Con A stimulation, the majority of MC adhered to the culture dish by day 2; but as incubation progressed to day 10 the proportion of non‐adherent (NAd) MC increased in a fashion which approximately paralleled the accumulation of PG in the medium. Cell kinetic studies suggest that, following Con A stimulation, there was an inverse relationship between the amount of newly synthesized cellular PG and adherence, which appears to be related to a reciprocal effect on PG synthesis of the declining adherent (Ad) cell density with time of culture. In the stimulated cultures, NAd cells contained much more newly synthesized CS/cell than Ad cells up to day 6 of incubation. Cell type analysis, using monoclonal antibodies against specific cell surface markers, suggested that the higher PG synthesis in the NAd population may, at least in part, be due to a greater proportion of T‐helper cells.
Human blood derived mononuclear cell (MC) cultures required concanavalin A (Con A) stimulation to... more Human blood derived mononuclear cell (MC) cultures required concanavalin A (Con A) stimulation to synthesize and secrete into the medium high levels of a protease-resistant proteoglycan (PG) containing predominantly chondroitin sulfate (CS), which was elaborated largely by T-cells in culture. PG and DNA synthesis were studied in MC cultures in the absence and presence of Con A as well as serum and some biologically active polypeptide factors. In the presence of Con A, stimulation of PG synthesis was substantially greater in T-cell enriched cultures than in B-cell enriched cultures. DNA synthesis was also stimulated in the presence of Con A. This stimulation was concentration-dependent, but required the presence of serum for additional responses. DNA and cell proliferation were stimulated by interleukin-2 (IL-2), but PG production was not stimulated by conditioned media, IL-1, IL-2, IL-3, or transforming growth factor-beta (TGF-beta). Our results indicate that the elaboration of PG from T-cells of human MC is independent of the effects of regulatory peptides on cell proliferation and DNA synthesis.
At the Royal Hallamshire Hospital in Sheffield, a trial group of patients suffering from Dupuytre... more At the Royal Hallamshire Hospital in Sheffield, a trial group of patients suffering from Dupuytren's contracture have undergone segmental aponeurectomy, a technique which the authors understand to be comparatively new to this country. The study is not yet complete but it was considered that a description of the technique and postoperative regime would be of Interest to those Involved in the treatment of hand problems.
Western and Southern Australia have many karst areas developed on soft sandy limestones (calcaren... more Western and Southern Australia have many karst areas developed on soft sandy limestones (calcarenites) which are quite different to the traditional "hard-rock" limestones found elsewhere. These are the syngenetic karsts of the youthful Quaternary dune limestones and related soft-rock karsts of the Tertiary limestones (which also show some syngenetic features). In syngenetic karst speleogenesis and lithogenesis are concurrent: caves and karst features are forming at the same time as the loose sediment is being cemented into a soft, porous rock. The distinctive features of syngenetic karst are: shallow horizontal cave systems; a general lack of directed conduits (low irregular chambers occur instead); clustering of caves at the margins of topographic highs or along the coast; paleosoil horizons; vertical solution pipes which locally form dense fields; extensive breakdown and subsidence to form collapse-dominated cave systems; a variety of surface and subsurface breccias and ...
Abstract We investigated the distinctive shallow sub-surface hydrology of the southwest Western A... more Abstract We investigated the distinctive shallow sub-surface hydrology of the southwest Western Australia (SWWA) dune calcarenite using observed rainfall and rainfall δ 18 O; soil moisture, cave drip rate and dripwater δ 18 O over a six-year period: August 2005–March 2012. A lumped parameter hydrological model is developed to describe water fluxes and drip δ 18 O. Comparison of observed data and model output allow us to assess the critical non-climatic karst hydrological processes that modify the precipitation δ 18 O signal and discuss the implications for speleothem paleoclimate records from this cave and those with a similar karst setting. Our findings include evidence of multiple reservoirs, characterised by distinct δ 18 O values and recharge responses (‘low’ and ‘high’ flow sites). Dripwaters exhibit δ 18 O variations in wet versus dry years at low-flow sites receiving diffuse seepage from the epikarst with an attenuated isotopic composition that approximates mean rainfall. Recharge from high-magnitude rain events is stored in a secondary reservoir which is associated with high-flow dripwater that is 1‰ lower than our monitored low-flow sites (δ 18 O). One drip site is characterised by mixed-flow behaviour and exhibits a non-linear threshold response after the cessation of drainage from a secondary reservoir following a record dry year (2006). Additionally, our results yield a better understanding of the vadose zone hydrology and dripwater characteristics in Quaternary age dune limestones. We show that flow to our monitored sites is dominated by diffuse flow with inferred transit times of less than one year. Diffuse flow appears to follow vertical preferential paths through the limestone reflecting differences in permeability and deep recharge into the host rock.
ABSTRACTThe parapoxvirus orf virus encodes a novel soluble protein inhibitor of ovine granulocyte... more ABSTRACTThe parapoxvirus orf virus encodes a novel soluble protein inhibitor of ovine granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2). The GM-CSF- and IL-2-inhibitory factor (GIF) gene was expressed as an intermediate-late viral gene in orf virus-infected cells. GIF formed homodimers and tetramers in solution, and it bound ovine GM-CSF with aKdof 369 pM and ovine IL-2 with aKdof 1.04 nM. GIF did not bind human GM-CSF or IL-2 in spite of the fact that orf virus is a human pathogen. GIF was detected in afferent lymph plasma draining the skin site of orf virus reinfection and was associated with reduced levels of lymph GM-CSF. GIF expression by orf virus indicates that GM-CSF and IL-2 are important in host antiviral immunity.
The oversight of research involving human participants is widely believed to be inadequate. The U... more The oversight of research involving human participants is widely believed to be inadequate. The U.S. Congress, national commissions, the Department of Health and Human Services, the Institute of Medicine, numerous professional societies, and others are proposing remedies based on the assumption that the main problems are researchers' conflict of interest, lack of institutional review board (IRB) resources, and the volume and complexity of clinical research. Developing appropriate reform proposals requires carefully delineating the problems of the current system to know what reforms are needed. To stimulate a more informed and meaningful debate, we delineate 15 current problems into 3 broad categories. First, structural problems encompass 8 specific problems related to the way the research oversight system is organized. Second, procedural problems constitute 5 specific problems related to the operations of IRB review. Finally, performance assessment problems include 2 problems related to absence of systematic assessment of the outcomes of the oversight system. We critically assess proposed reforms, such as accreditation and central IRBs, according to how well they address these 15 problems. None of the reforms addresses all 15 problems. Indeed, most focus on the procedural problems, failing to address either the structure or the performance assessment problems. Finally, on the basis of the delineation of problems, we outline components of a more effective reform proposal, including bringing all research under federal oversight, a permanent advisory committee to address recurrent ethical issues in clinical research, mandatory single-time review for multicenter research protocols, additional financial support for IRB functions, and a standardized system for collecting and disseminating data on both adverse events and the performance assessment of IRBs.
American Journal of Physical Medicine & Rehabilitation, 1949
Advertisement. Close Window. Close Window. Thank you for choosing to subscribe to the eTOC for Am... more Advertisement. Close Window. Close Window. Thank you for choosing to subscribe to the eTOC for American Journal of Physical Medicine & Rehabilitation. Enter your Email address: Wolters Kluwer Health may email you for journal ...
In response to stress, bacteria upregulate specific groups of proteins which maintain the integri... more In response to stress, bacteria upregulate specific groups of proteins which maintain the integrity of the cell; one such protein is HtrA, a serine protease. HtrA production in different bacteria appears to be induced by distinct environmental stress conditions, eg. in Escherichia coli the htrA gene is essential for bacterial survival at high temperatures7, whereas a Salmonella typhimurium htrA mutant was temperature insensitive, but susceptible to oxidative stress5. A Bruceila abortus htrA mutant is both temperature and oxidative stress sensitive4. The HtrA family of stress-response proteins may also be important in bacterial pathogenicity as the S. typhimurium and B. abortus mutants are attenuated for mouse virulence4,5. The mutant’s susceptibility to oxidative stress suggests increased sensitivity to oxidative killing within macrophages.
Human peripheral mononuclear cells (MC) secrete 2 soluble activities that modulate the growth of ... more Human peripheral mononuclear cells (MC) secrete 2 soluble activities that modulate the growth of human synovial fibroblastic cells. A growth-suppressive, lectin-dependent activity is elaborated by the non-adherent population and its secretion begins before DNA synthesis is initiated in concanavalin-stimulated MC cultures. The elaboration of this activity is partially dependent on the presence of serum and it appears to be distinct from virus-induced human leukocyte interferon. The second activity is secreted spontaneously by the MC, under a variety of culture conditions including supplementation with homologous human plasma, and it enhances the growth of synovial fibroblasts. The rate of secretion of the growth-enhancing activity by the nonstimulated MC approximately parallels that of the inhibitory activity from the stimulated MC cultures. MC from patients with rheumatoid arthritis and from nonaffected individuals secrete similar concentrations of growth-stimulatory activity for the synovial fibroblasts.
Human, blood‐derived mononuclear cells (MC), stimulated with Concanavalin A (Con A), synthesized ... more Human, blood‐derived mononuclear cells (MC), stimulated with Concanavalin A (Con A), synthesized a chondroitin sulfate (CS) proteoglycan (PG), which was elaborated largely by T‐cells. Following Con A stimulation, the majority of MC adhered to the culture dish by day 2; but as incubation progressed to day 10 the proportion of non‐adherent (NAd) MC increased in a fashion which approximately paralleled the accumulation of PG in the medium. Cell kinetic studies suggest that, following Con A stimulation, there was an inverse relationship between the amount of newly synthesized cellular PG and adherence, which appears to be related to a reciprocal effect on PG synthesis of the declining adherent (Ad) cell density with time of culture. In the stimulated cultures, NAd cells contained much more newly synthesized CS/cell than Ad cells up to day 6 of incubation. Cell type analysis, using monoclonal antibodies against specific cell surface markers, suggested that the higher PG synthesis in the NAd population may, at least in part, be due to a greater proportion of T‐helper cells.
Human blood derived mononuclear cell (MC) cultures required concanavalin A (Con A) stimulation to... more Human blood derived mononuclear cell (MC) cultures required concanavalin A (Con A) stimulation to synthesize and secrete into the medium high levels of a protease-resistant proteoglycan (PG) containing predominantly chondroitin sulfate (CS), which was elaborated largely by T-cells in culture. PG and DNA synthesis were studied in MC cultures in the absence and presence of Con A as well as serum and some biologically active polypeptide factors. In the presence of Con A, stimulation of PG synthesis was substantially greater in T-cell enriched cultures than in B-cell enriched cultures. DNA synthesis was also stimulated in the presence of Con A. This stimulation was concentration-dependent, but required the presence of serum for additional responses. DNA and cell proliferation were stimulated by interleukin-2 (IL-2), but PG production was not stimulated by conditioned media, IL-1, IL-2, IL-3, or transforming growth factor-beta (TGF-beta). Our results indicate that the elaboration of PG from T-cells of human MC is independent of the effects of regulatory peptides on cell proliferation and DNA synthesis.
At the Royal Hallamshire Hospital in Sheffield, a trial group of patients suffering from Dupuytre... more At the Royal Hallamshire Hospital in Sheffield, a trial group of patients suffering from Dupuytren's contracture have undergone segmental aponeurectomy, a technique which the authors understand to be comparatively new to this country. The study is not yet complete but it was considered that a description of the technique and postoperative regime would be of Interest to those Involved in the treatment of hand problems.
Western and Southern Australia have many karst areas developed on soft sandy limestones (calcaren... more Western and Southern Australia have many karst areas developed on soft sandy limestones (calcarenites) which are quite different to the traditional "hard-rock" limestones found elsewhere. These are the syngenetic karsts of the youthful Quaternary dune limestones and related soft-rock karsts of the Tertiary limestones (which also show some syngenetic features). In syngenetic karst speleogenesis and lithogenesis are concurrent: caves and karst features are forming at the same time as the loose sediment is being cemented into a soft, porous rock. The distinctive features of syngenetic karst are: shallow horizontal cave systems; a general lack of directed conduits (low irregular chambers occur instead); clustering of caves at the margins of topographic highs or along the coast; paleosoil horizons; vertical solution pipes which locally form dense fields; extensive breakdown and subsidence to form collapse-dominated cave systems; a variety of surface and subsurface breccias and ...
Abstract We investigated the distinctive shallow sub-surface hydrology of the southwest Western A... more Abstract We investigated the distinctive shallow sub-surface hydrology of the southwest Western Australia (SWWA) dune calcarenite using observed rainfall and rainfall δ 18 O; soil moisture, cave drip rate and dripwater δ 18 O over a six-year period: August 2005–March 2012. A lumped parameter hydrological model is developed to describe water fluxes and drip δ 18 O. Comparison of observed data and model output allow us to assess the critical non-climatic karst hydrological processes that modify the precipitation δ 18 O signal and discuss the implications for speleothem paleoclimate records from this cave and those with a similar karst setting. Our findings include evidence of multiple reservoirs, characterised by distinct δ 18 O values and recharge responses (‘low’ and ‘high’ flow sites). Dripwaters exhibit δ 18 O variations in wet versus dry years at low-flow sites receiving diffuse seepage from the epikarst with an attenuated isotopic composition that approximates mean rainfall. Recharge from high-magnitude rain events is stored in a secondary reservoir which is associated with high-flow dripwater that is 1‰ lower than our monitored low-flow sites (δ 18 O). One drip site is characterised by mixed-flow behaviour and exhibits a non-linear threshold response after the cessation of drainage from a secondary reservoir following a record dry year (2006). Additionally, our results yield a better understanding of the vadose zone hydrology and dripwater characteristics in Quaternary age dune limestones. We show that flow to our monitored sites is dominated by diffuse flow with inferred transit times of less than one year. Diffuse flow appears to follow vertical preferential paths through the limestone reflecting differences in permeability and deep recharge into the host rock.
ABSTRACTThe parapoxvirus orf virus encodes a novel soluble protein inhibitor of ovine granulocyte... more ABSTRACTThe parapoxvirus orf virus encodes a novel soluble protein inhibitor of ovine granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2). The GM-CSF- and IL-2-inhibitory factor (GIF) gene was expressed as an intermediate-late viral gene in orf virus-infected cells. GIF formed homodimers and tetramers in solution, and it bound ovine GM-CSF with aKdof 369 pM and ovine IL-2 with aKdof 1.04 nM. GIF did not bind human GM-CSF or IL-2 in spite of the fact that orf virus is a human pathogen. GIF was detected in afferent lymph plasma draining the skin site of orf virus reinfection and was associated with reduced levels of lymph GM-CSF. GIF expression by orf virus indicates that GM-CSF and IL-2 are important in host antiviral immunity.
The oversight of research involving human participants is widely believed to be inadequate. The U... more The oversight of research involving human participants is widely believed to be inadequate. The U.S. Congress, national commissions, the Department of Health and Human Services, the Institute of Medicine, numerous professional societies, and others are proposing remedies based on the assumption that the main problems are researchers' conflict of interest, lack of institutional review board (IRB) resources, and the volume and complexity of clinical research. Developing appropriate reform proposals requires carefully delineating the problems of the current system to know what reforms are needed. To stimulate a more informed and meaningful debate, we delineate 15 current problems into 3 broad categories. First, structural problems encompass 8 specific problems related to the way the research oversight system is organized. Second, procedural problems constitute 5 specific problems related to the operations of IRB review. Finally, performance assessment problems include 2 problems related to absence of systematic assessment of the outcomes of the oversight system. We critically assess proposed reforms, such as accreditation and central IRBs, according to how well they address these 15 problems. None of the reforms addresses all 15 problems. Indeed, most focus on the procedural problems, failing to address either the structure or the performance assessment problems. Finally, on the basis of the delineation of problems, we outline components of a more effective reform proposal, including bringing all research under federal oversight, a permanent advisory committee to address recurrent ethical issues in clinical research, mandatory single-time review for multicenter research protocols, additional financial support for IRB functions, and a standardized system for collecting and disseminating data on both adverse events and the performance assessment of IRBs.
American Journal of Physical Medicine & Rehabilitation, 1949
Advertisement. Close Window. Close Window. Thank you for choosing to subscribe to the eTOC for Am... more Advertisement. Close Window. Close Window. Thank you for choosing to subscribe to the eTOC for American Journal of Physical Medicine & Rehabilitation. Enter your Email address: Wolters Kluwer Health may email you for journal ...
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