High Dialysate Calcium Concentration is Associated with Worsening Left Ventricular Function.

Dialysate calcium concentration (d[Ca]) might have a cardiovascular impact in patients on haemodialysis (HD) since a higher d[Ca] determines better hemodynamic tolerability. We have assessed the influence of d[Ca] on global longitudinal strain (GLS) by two-dimensional echocardiography using speckle-tracking imaging before and in the last hour of HD. This is an observational crossover study using d[Ca] 1.75 mmol/L and 1.25 mmol/L. Ultrafiltration was the same between interventions; patients aged 44 ± 13 years (N = 19). The 1.75 mmol/L d[Ca] was associated with lighter drop of blood pressure. Post HD serum total calcium was higher with d[Ca] 1.75 than with 1.25 mmol/L (11.5 ± 0.8 vs. 9.1 ± 0.5 mg/dL, respectively, p < 0.01). In almost all segments strain values were significantly worse in the peak HD with 1.75 mmol/L d[Ca] than with 1.25 mmol/L d[Ca]. GLS decreased from -19.8 ± 3.7% at baseline to -17.3 ± 2.9% and -16.1 ± 2.6% with 1.25 d[Ca] and 1.75 d[Ca] mmol/L, respectively (p < 0.05 for both d[Ca] vs. baseline and 1.25 d[Ca] vs. 1.75 d[Ca] mmol/L). Factors associated with a worse GLS included transferrin, C-reactive protein, weight lost, and post dialysis serum total calcium. We concluded that d[Ca] of 1.75 mmol/L was associated with higher post dialysis serum calcium, which contributed to a worse ventricular performance. Whether this finding would lead to myocardial stunning needs further investigation.

Chronic kidney disease is associated with low BMD at the hip but not at the spine.

Although chronic kidney disease is associated with other bone disorders, osteoporosis can be found in this context, and it is defined based on bone mineral density (BMD), measured by dual-energy X-ray absorptiometry. As CKD progresses, the percentage of normal BMD decreases, whereas that of osteopenia/osteoporosis increases, mostly due to hip involvement, particularly in patients with reduced renal function. INTRODUCTION: Osteoporosis is a highly prevalent disease in patients with chronic kidney disease (CKD). We investigated the features of bone mineral density (BMD) in patients with assorted kidney diseases and hypothesized that low BMD, as measured by dual-energy X-ray absorptiometry (DXA), would be more prevalent as kidney function decreased and would correlate with biomarkers of mineral and bone disease. METHODS: DXA obtained from January 1, 2008, to December 31, 2017, clinical, demographic, and biochemical data at the time of image acquisition were recorded. Data from 1172 patients were included in this study (81.3% women, 79.9% white, and 8.1% diabetic). RESULTS: Osteopenia and osteoporosis in at least one site (total hip or spine) were found in 32.7% and 20.0% of patients, respectively. As CKD progressed, the percentage of patients with normal BMD decreased, whereas the percentage of osteopenia and osteoporosis increased, which was mostly due to the total hip involvement, particularly in patients with estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2. Older age and hyperparathyroidism were independent risk factors for osteopenia/osteoporosis at the total hip; female gender, older age, and higher iCa were independently associated with the risk of osteopenia/osteoporosis at the spine. With eGFR > 90 ml/min as reference, the odds ratios for osteoporosis/osteopenia at the hip were 1.51 (95% CI 1.01-2.24) and 1.91 (95% CI 1.13-3.20) for patients with eGFR 30-60 and 15-30 ml/min/1.73 m2, respectively. No CKD stage was significantly associated with the risk of osteoporosis/osteopenia at the spine. CONCLUSION: Our results highlighted that low BMD in patients with CKD is associated with age and hyperparathyroidism, and affects predominantly the hip.

Biopsy vs. peripheral computed tomography to assess bone disease in CKD patients on dialysis: differences and similarities.

Results from bone biopsy and high-resolution peripheral quantitative computed tomography (HR-pQCT) were compared in 31 CKD patients. There was an agreement mainly for cortical compartment that may represent a perspective on the fracture risk assessment. HR-pQCT also provided some clues on the turnover status, which warrants further studies. INTRODUCTION: Chronic kidney disease (CKD) patients are at high risk of bone disease. Although bone biopsy is considered the best method to evaluate bone disease, it is expensive and not always available. Here we have compared, for the first time, data obtained from bone biopsy and HR-pQCT in a sample of CKD patients on dialysis. METHODS: HR-pQCT and dual-energy X-ray absorptiometry (DXA) were performed in 31 CKD patients (30 on dialysis). Biopsies were analyzed by quantitative histomorphometry, and classified according to TMV. RESULTS: We have found an inverse correlation between radius cortical density measured by HR-pQCT, with serum, as well as histomorphometric bone remodeling markers. Trabecular density and BV/TV measured through HR-pQCT in the distal radius correlated with trabecular and mineralized trabecular bone volume. Trabecular number, separation, and thickness obtained from HR-pQCT and from bone biopsy correlated with each other. Patients with cortical porosity on bone histomorphometry presented lower cortical density at the distal radius. Cortical density at radius was higher while bone alkaline phosphatase was lower in patients with low turnover. Combined, these parameters could identify the turnover status better than individually. CONCLUSIONS: There was an agreement between HR-pQCT and bone biopsy parameters, particularly in cortical compartment, which may point to a new perspective on the fracture risk assessment for CKD patients. Besides classical bone resorption markers, HR-pQCT provided some clues on the turnover status by measurements of cortical density at radius, although the significance of this finding warrants further studies.

Assessment of health implications related to processing and use of natural wool insulation products.

This paper discusses possible health implications related to dust particles released during the manufacture of sheep's wool-based non-woven insulation material. Such insulation may replace traditional synthetic insulation products used in roofs, wall cavities, etc. A review of the literature concerning organic dusts in general and sheep's wool fiber summarizes dust exposure patterns, toxicological pathways and the hazards imposed by inhalation and explosion risk. This paper highlights a need for more research in order to refrain from overgeneralizing potential pulmonary and carcinogenic risks across the industries. Variables existing between industries such as the use of different wool types, processes, and additives are shown to have varying health effects. Within the final section of the paper, the health issues raised are compared with those that have been extensively documented for the rock and glass wool industries.

Susceptibility of the different developmental stages of the asexual (schizogonic) erythrocyte cycle of Plasmodium chabaudi chabaudi to hyperimmune serum, immunoglobulin (Ig)G1, IgG2a and F(ab')2 fragments.

The mechanisms by which antibodies interfere with Plasmodium growth are still under debate. Characterizing the asexual erythrocyte stages susceptible to antibodies from hyperimmune individuals is therefore a relevant contribution to vaccine research. In this study, using a virulent and synchronous murine malaria parasite, Plasmodium chabaudi chabaudi AJ, we have shown that trophozoites and circulating schizonts are not the main targets for antibodies from hyperimmune serum. In drug-cured mice challenged with a high inoculum of ring-infected erythrocytes, parasitemias do not decline until the moment of erythrocyte rupture, suggesting that effector mechanisms operate immediately prior to reinvasion. Confirming these findings, treatment of primary-infected mice with hyperimmune serum inhibited the generation of new ring forms, but did not alter the numbers of schizont-infected erythrocytes, despite the fact that these cells were recognized by immunoglobulin (Ig)G antibodies. When these mice were treated with IgG1 or IgG2a purified from hyperimmune serum, both subclasses limited reinvasion, but IgG2a showed a stronger protective activity. The fact that Fc digestion decreases but does not abrogate protection suggests that both Fc-dependent and independent mechanisms participate in this process. Treatment with cobra venom factor did not interfere with the antibody-mediated protection, ruling out the participation of the complement system in both lysis and phagocytosis of merozoites or infected erythrocytes. Therefore, in mice suffering from P. c. chabaudi AJ malaria, merozoite neutralization seems to be a major mechanism of protection conferred by hyperimmune serum antibodies. However, FcgammaR-mediated interactions, or other mechanisms not yet defined, may also contribute to inhibit erythrocyte reinvasion.

Effect of outflow pressure on lymphatic pumping in vitro.

The objective of this study was to determine how lymphatic vessels responded to outflow pressure changes in vitro. Bovine mesenteric lymphatics were suspended in an organ bath preparation with both inflow and outflow ends cannulated. Input to the duct was provided from a reservoir filled with Krebs solution. To initiate pumping, a transmural pressure was applied to the ducts by elevating the fluid reservoir and outflow catheters and making their heights equal to one another. The outflow catheter was then elevated above the liquid in the reservoir in 2-cmH2O increments, and pumping activity was monitored for 10 min at each outflow pressure. Outflow pressures were calculated as the product of the flow rate and outflow cannula resistance plus the height of the tip of the outflow catheter above the liquid in the organ bath. At low transmural pressures (2-4 cmH2O), elevations in outflow pressure often had little effect on flow rates until high outflow pressures had been attained. In contrast, elevations in outflow pressures resulted in an increasingly rapid decline in flow rates as transmural pressures were incrementally increased. The mean power (in mu W) required to produce the observed flow rate was estimated at each outflow pressure as the product of the flow rate and the pressure across the lymphatic vessel. The ability of the lymphatics to generate sustained or enhanced power output in response to an increasing outflow pressure challenge was most pronounced at lower transmural pressures. As transmural pressures were increased, the range of outflow pressures that stimulated increased power production was diminished. We conclude that elevations in outflow pressure in an in vitro preparation result in a nonlinear decline in flow rates. This nonlinearity is due to an active lymphatic pump mechanism.

Role of endothelial cells in regulating hemoglobin-induced changes in lymphatic pumping.

Studies with a sheep isolated duct preparation in vivo demonstrated that the route of administration of hemoglobin was important in demonstrating its inhibitory effect on lymphatic pumping. With autologous oxyhemoglobin administered intravenously (final plasma concentration 5 x 10(-5) M), pumping was not inhibited. However, the addition of oxyhemoglobin (5 x 10(-5) M) into the reservoir (lumen of the duct) resulted in > 95% inhibition of pumping. The extraluminal administration of oxyhemoglobin (10(-5) M) to bovine mesenteric lymphatics in vitro resulted in a 40% inhibition of pumping, whereas the introduction of oxyhemoglobin (10(-5) M) into the lumen of the vessels suppressed pumping 95%. In vessels mechanically denuded of endothelium, intraluminal oxyhemoglobin inhibited pumping 50%. These results suggested that oxyhemoglobin depressed pumping through an effect on both smooth muscle and endothelium. Once pumping was inhibited with oxyhemoglobin administration, stimulation of the duct with elevations in transmural pressure restored pumping activity when endothelial cells were present. However, in the absence of endothelium, pumping decreased with increases in distending pressures. We conclude that oxyhemoglobin has a direct inhibitory effect on lymphatic smooth muscle. The ability of oxyhemoglobin to alter the pressure range over which the lymph pump operates appears to be dependent on an intact endothelium.

Heme-containing proteins suppress lymphatic pumping.

Red blood cells (RBCs) and lysate products (erythrolysate) are consistently observed in lymph draining inflammatory reactions and from tissues subjected to trauma or surgical procedures. We determined previously that erythrolysate modulates lymphatic pumping by altering the pressures over which the lymph pump is active. The purpose of this study was to test the hypothesis that oxyhemoglobin was the active material within erythrolysate. To quantitate lymphatic pumping, bovine lymphatics were suspended in an organ bath preparation with the vessels cannulated at both inflow and outflow ends. By raising the heights of the Krebs reservoir and the outflow catheters appropriately, a transmural pressure could be applied to the vessels. This procedure stimulated pumping activity. Erythrolysate was prepared from sheep RBCs by lysis in Tris buffer and a portion of this was purified by column chromatography using DEAE-Sephadex A-50. Both the purified hemoglobin (10(-5) M) and crude erythrolysate (the latter diluted appropriately in Krebs solution to contain 10(-5) M hemoglobin) reduced lymphatic fluid pumping approximately 70% over a period of 2 h. To determine whether this activity was due to the heme or the protein portion of the molecule, we compared the activity of purified oxyhemoglobin with that of its oxidized methemoglobin derivative. This was achieved by conversion with potassium ferricyanide. Methemoglobin was inactive, suggesting that the heme portion was important for the lymphatic effect. Further confirmation of this observation was provided by experiments with myoglobin which was purified from sheep heart. Oxymyoglobin, which shares an identical heme but has a different protein component, inhibited lymphatic pumping, when tested on the bovine lymphatics.(ABSTRACT TRUNCATED AT 250 WORDS)

Is endothelium necessary for transmural pressure-induced contractions of bovine truncal lymphatics?

The purpose of this study was to investigate the role of the endothelium in regulating lymphatic contractile activity in bovine mesenteric truncal lymphatics. To test the effects of endothelial denudation on lymphatic pumping, bovine lymphatics were suspended in an organ bath preparation with the vessels cannulated at both inflow and outflow ends. By raising the heights of the Krebs reservoir and the outflow catheters appropriately, a transmural pressure could be applied to the vessels. The relationship between transmural pressure and fluid pumping is expressed as a bell-shaped curve with pumping increasing up to a peak pressure (between 8 and 12 cm H2O), and declining at pressures above this level. We compared pressure/flow curves in endothelium-intact and endothelium-denuded vessels. Chemical methods to remove the endothelium were attempted (collagenase and dispase) but were unsuccessful since they resulted in inhibition of all contractile activity including that induced with KCl. A technique using suture silk (3-O to 6-O) threaded into PE 50 or PE 20 polyethylene catheters with a loop at one end proved to be effective. By passing the catheter with its exposed loop of silk through the lymphatic ducts and imparting a twisting motion, we were able to remove the endothelium and preserve the smooth muscle responses to KCl. Transmission electron microscopy as well as silver staining techniques confirmed that all of the endothelium had been removed leaving the subendothelium and smooth muscle undamaged. We established that removal of the endothelium had no effect on lymphatic pumping. Pumping could not have occurred without the normal function of the one-way valves indicating that the denudation procedures did not damage these elements. Maximum flow rates and the transmural pressures that induced peak flows were similar in the two groups. We conclude that the pumping activity of bovine mesenteric truncal lymphatics in response to transmural pressure changes does not depend on an intact endothelium.

Lymphatic pumping in response to changes in transmural pressure is modulated by erythrolysate/hemoglobin.

Red blood cells and lysate products (erythrolysate) are observed consistently in lymph draining acute and chronic inflammatory reactions and from tissues subjected to trauma or surgical procedures. Using hemoglobin as a marker for erythrolysate, we have measured hemoglobin in lymph up to the 10(-6) M range in a number of pathophysiological states. Data demonstrate that erythrolysate alters the pumping characteristics of lymphatic vessels. To test the effects of erythrolysate on lymphatic pumping, bovine lymphatics were suspended in an organ bath preparation with the vessels cannulated at both inflow and outflow ends. By raising the heights of the Krebs reservoir and the outflow catheters appropriately, a transmural pressure that stimulated pumping activity could be applied to the vessels. With a fixed transmural pressure of 6 cm H2O applied to the ducts, sheep erythrolysate depressed pumping activity between 40% and 100%, with dilutions containing between 10(-8) and 10(-5) M hemoglobin. Although the active principle in the red blood cells has not been characterized, evidence from precipitation purification experiments suggests that hemoglobin is an important component. Once suppressed, pumping could be restored in many but not all vessels (often to control levels) by elevating the distending pressure above 6 cm H2O. The relation between transmural pressure and fluid pumping is expressed as a bell-shaped curve, with pumping increasing up to a peak pressure (usually 8 cm H2O) and declining at pressures above this level. By comparing pressure/flow curves, we were able to ascertain that hemoglobin shifted the lymphatic function curve to the right and, on average, reduced the maximum pumping capability of the vessels. We speculate that the presence of erythrolysate/hemoglobin in lymph may modulate the ability of lymphatic vessels to drain liquid and protein from the tissue spaces.

Modulation of lymphatic pumping by lymph-borne factors after endotoxin administration in sheep.

The purpose of this study was to test the hypothesis that endotoxin administration to sheep results in host-derived lymph-borne factors that modulate lymphatic pumping activity. To achieve this, two sheep were used for each experiment. In the test animal, a segment of intestinal lymphatic was isolated from all lymph input and provided with lymph from a reservoir. Pumping activity was initiated with a fixed transmural pressure applied to the test vessel, and the only input to this duct was provided by lymph from an indwelling catheter in a second donor sheep. The intravenous administration of endotoxin to the donor animals (33 micrograms/kg) generally resulted in increased pumping in the test vessels over the 1st h, but this was followed by reductions in pumping until flow stopped in all preparations. In control experiments (no endotoxin administered) pumping was unaffected. Further investigation revealed that these activities were relatively unstable and, in the case of the inhibitory material, appeared to act by decreasing the sensitivity of the vessel to changes in transmural pressure, because flow could be reestablished in the test vessels by elevating transmural pressures above the level originally chosen for the experiment. Endotoxin itself had no direct effect on sheep lymphatics in vivo or on bovine lymphatic vessels in vitro. However, the appearance of erythrocyte hemolysate (erythrolysate) in lymph was regularly observed after endotoxin infusion, and we demonstrated that erythrolysate (diluted to contain 10(-5) M hemoglobin) was a potent inhibitor of lymphatic pumping in vivo and in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Suppression of fluid pumping in isolated bovine mesenteric lymphatics by interleukin-1: interaction with prostaglandin E2.

In addition to local physiological forces, the modulation of lymphatic pumping by chemical mediators may play an important role in the regulation of extravascular water in inflammation and shock. Since Interleukin-1 (IL-1) appears to be of major importance in the host's response to infection by mediating many inflammatory events, we thought it important to determine if this cytokine could affect the lymphatic circulation and in particular to ask whether IL-1 was capable of altering lymphatic pumping in response to changes in transmural pressure. Bovine lymphatic segments (6 to 8 cm in length) were cannulated at both ends and suspended in an organ bath preparation. The vessels were provided with Krebs solution from a reservoir. With no net driving pressure, a transmural pressure applied to the ducts elicited contractile activity and fluid pumping with increases in pumping up to 8 cm H2O and reductions in flow above this level of distension. Human recombinant IL-1 alpha (10(-7) to 10(-9) M) administered into the lumina of the vessels depressed pumping activity approximately 5-30% at transmural pressures between 2 and 16 cm H2O. With limited supplies, we could only assess the effects of human recombinant IL-1 beta at 10(-8) M. However, it was more potent than IL-1 alpha, inhibiting pumping at all transmural pressures with maximum suppression in the range of 70% at peak flows. The ability of IL-1 to induce prostaglandin synthesis may be one of its most important biologic functions. It is likely therefore that IL-1 and PGE2 are closely linked and are probably present together in inflammatory lesions. With this in mind, we investigated the effects of PGE2 alone and in combination with IL-1 alpha. PGE2 by itself reduced pumping at concentrations between 10(-6) and 10(-9) M. When mixed with IL-1 alpha (both agents at a final concentration of 10(-9) M), the mixture had a marked inhibitory effect on flow, reducing pumping 50 to 70% at peak flows. The effect of the mixture of IL-1 alpha and PGE2 compared with the two agents administered separately was greater than the predicted additive effect at transmural pressures above 6 cm H2O. At lower transmural pressures, however, the level of real inhibition was less than the predicted additive effect.(ABSTRACT TRUNCATED AT 400 WORDS)

Modulation of fluid pumping in isolated bovine mesenteric lymphatics by a thromboxane/endoperoxide analogue.

A thromboxane/endoperoxide analogue (compound U46619) is known to stimulate phasic and tonic contractions in quiescent bovine lymphatic vessels and enhance contractile activity in spontaneously active vessels. In order to determine how these effects relate to changes in fluid propulsion by the lymphatics, we have assessed the effects of U46619 on the ability of isolated bovine mesenteric lymphatics to pump fluid in vitro. Bovine lymphatic segments (up to 8 cm in length with a minimum of 4 valves) were cannulated at both ends and fluid input provided from a reservoir. Flow through the vessels was regulated by intraluminal pressures. On average, changes in transmural pressures up to 8 cm H2O resulted in enhanced pumping; pressures above this level depressed flow. The dominant effect of U46619 (added to the reservoir) was to depress pumping; 10(-7) and 10(-9)M decreased flow at all transmural pressures tested; 10(-8)M had a dual effect, slightly inhibiting flow at low transmural pressures and enhancing flow at higher pressures. These results suggest that thromboxane may stimulate or inhibit lymphatic pumping depending on the concentration of the agent and the transmural pressure applied to the vessel. These effects may relate to its ability to induce variable changes in luminal diameter and frequency and force of contractions.

Decreased lymphatic pumping after intravenous endotoxin administration in sheep.

The effects of endotoxin on the ability of lymphatic vessels to pump fluid in vivo have been assessed with the use of a sheep model system that permits analysis of lymph pumping in sheep without the complication of variable lymph inputs. This involved the isolation of intestinal lymphatic vessels from all lymph input, with saline or lymph provided from a reservoir. The blood and nerve supplies to the vessel were left intact. With no net driving pressure, but with a transmural pressure applied to the vessel to initiate spontaneous contractions and fluid pumping, the intravenous administration of endotoxin (3.3 micrograms/kg in anesthetized sheep and 33 micrograms/kg in nonanesthetized animals) reduced fluid propulsion in both groups of animals (P less than 0.02 and P less than 0.03, respectively). Comparisons with animals that did not receive endotoxin revealed maximum inhibition greater than 90% in anesthetized and 50% in nonanesthetized sheep. Normal pulsatile lymphatic pressures (produced from lymphatic contractions) were reduced in frequency and amplitude after endotoxin administration. Endotoxin itself had no effect on the vessels when added to the fluid in the reservoir, suggesting that the inhibition of the "lymph pump" was mediated through the interaction of endotoxin with cellular or humoral elements in the host. In addition to suppression of lymphatic contractile activity, the intravenous injection of endotoxin enhanced lymph formation as indicated by the 3- to 10-fold increases in lymph flow rates in the two groups. We conclude that, for a given transmural pressure, the systemic administration of endotoxin reduces lymphatic pumping activity. We speculate that this effect may be important in the pathogenesis of the edema associated with sepsis.

Role of the lymphatic circulatory system in shock.

That the lymphatic vessel participates in the regulation of interstitial dynamics through its ability to contract and propel fluid and protein from the extravascular tissues back to the bloodstream has not been fully appreciated. The "lymph pump" appears to be regulated by local physiologic forces as well as neurogenic and humoral factors. We have assessed the effects of hemorrhage and endotoxin on the ability of the lymph vessel to propel fluid in sheep using a model system that permits the quantitation of lymphatic pumping in vivo without the complication of variable lymph inputs. A major blood loss was found to enhance lymphatic contractile activity and fluid pumping. Considering the large reservoir of fluid and protein in the interstitium and lymph, we speculate that stimulation of the "lymph pump" after hemorrhage might help to re-expand the vascular space. On the other hand, the intravenous administration of endotoxin inhibited lymphatic pumping, suggesting that impaired lymph propulsion in sepsis may contribute to edema by reducing the ability of the lymphatic vessel to remove extravasated protein from the tissues.