Background: Primary pulmonary angiosarcoma is extremely rare and the prognosis is very poor. We report a combination therapy of pneumonectomy and intrapleural hypotonic hyperthermic chemotherapy (IPHHC). Case report: ...Background: Primary pulmonary angiosarcoma is extremely rare and the prognosis is very poor. We report a combination therapy of pneumonectomy and intrapleural hypotonic hyperthermic chemotherapy (IPHHC). Case report: A 48-year-old male with exertional dyspnea was found to have a left massive pleural effusion. Bronchoscopic examination displayed endobronchial stenosis of the left lower bronchus B8,9,10?and diagnosed with pulmonary angiosarcoma. Chest computed-tomographic scanning revealed a 5-cm mass in the left inferior lobe, which invaded the left upperbronchus. Intrapleural dissemination and malignant pleural effusion were also suspected (cT3N1M1a,?c-stage IV). As a palliative initial therapy, we performed a pneumonectomy. On the 7th?postoperative day, under general anesthesia, we performed video-assisted IPHHC (43°C, 60 min, 200 mg/m2?of CDDP). After the IPHHC, there was no major adverse event (more than Grade 3) during the postoperative course. Histological examination of the resected specimen revealed a highly-cellular growth of atypical spindle cells with a storiform pattern. By immunohistochemical testing, the tumor cells stained positive for markers including CD31 and the factor VIII related antigen, and the diagnosis of pulmonary angiosarcoma was made. No adjuvant chemoradiotherapy was given, and the postoperative clinical course was uneventful. Although there had been a recurrence in the chest wall, the patient eventually died twenty-one months later. Conclusion: As a new therapeutic option, we performed IPHHC after the pneumonectomy for an advanced pulmonary angiosarcoma with malignant pleural effusion. Although the patient had a recurrence in the chest wall, he had a reasonable postoperative outcome, that is, he returned to a work, retained a good quality of life and had a longer survival in spite of the poor prognosis of the pulmonary angiosarcoma.展开更多
Cell-based assays represent a major end point of high throughput screening (HTS) but a key limitation of such assays is the potentially poor membrane permeability of test compounds. In this study, we optimized the con...Cell-based assays represent a major end point of high throughput screening (HTS) but a key limitation of such assays is the potentially poor membrane permeability of test compounds. In this study, we optimized the conditions for the delivery of the membrane impermeable compound 8-hydroxypyrene-1,3,6-trisulfonic acid trisodium salt (HPTS) into human cells using hypotonic shift;a method that can promote the uptake of molecules from the extracellular fluid into cell cytoplasm via endocytosis. We showed that uptake of HPTS by cells was a function of hypotonic buffer osmolarity and that delivery was highly efficient with almost 100% of cells displaying uptake. Delivery of HPTS was equally effective at 25°C and 37°C, with delivery of compound proportional to incubation time and concentration of HPTS within the loading medium. The experimental conditions identified in this study could be applied to HTS drug discovery studies providing an effective method of delivering small membrane impermeable compounds into cells.展开更多
Red blood cells(RBCs)can act as carriers for therapeutic agents and can substantially improve the safety,pharmacokinetics,and pharmacodynamics of many drugs.Maintaining RBCs integrity and lifespan is important for the...Red blood cells(RBCs)can act as carriers for therapeutic agents and can substantially improve the safety,pharmacokinetics,and pharmacodynamics of many drugs.Maintaining RBCs integrity and lifespan is important for the efficacy of RBCs as drug carrier.We investigated the impact of drug encapsulation by hypotonic dialysis on RBCs physiology and integrity.Several parameters were compared between processed RBCs loaded with l-asparaginase(“eryaspase”),processed RBCs without drug and non-processed RBCs.Processed RBCs were less hydrated and displayed a reduction of intracellular content.We observed a change in the metabolomic but not in the proteomic profile of processed RBCs.Encapsulation process caused moderate morphological changes and was accompanied by an increase of RBCs-derived Extracellular Vesicles release.Despite a decrease in deformability,processed RBCs were not mechanically retained in a spleen-mimicking device and had increased surface-to-volume ratio and osmotic resistance.Processed RBCs half-life was not significantly affected in a mouse model and our previous phase 1 clinical study showed that encapsulation of asparaginase in RBCs prolonged its in vivo half-life compared to free forms.Our study demonstrated that encapsulation by hypotonic dialysis may affect certain characteristics of RBCs but does not significantly affect the in vivo longevity of RBCs or their drug carrier function.展开更多
The regulation of body fluid balance is a key concern in health and disease and comprises three concepts. The first concept pertains to the relationship between total body water(TBW) and total effective solute and is ...The regulation of body fluid balance is a key concern in health and disease and comprises three concepts. The first concept pertains to the relationship between total body water(TBW) and total effective solute and is expressed in terms of the tonicity of the body fluids. Disturbances in tonicity are the main factor responsible for changes in cell volume, which can critically affect brain cell function and survival. Solutes distributed almost exclusively in the extracellular compartment(mainly sodium salts) and in the intracellular compartment(mainly potassium salts) contribute to tonicity, while solutes distributed in TBW have no effect on tonicity. The second body fluid balance concept relates to the regulation and measurement of abnormalities of sodium salt balance and extracellular volume. Estimation of extracellular volume is more complex and error prone than measurement of TBW. A key function of extracellular volume, which is defined as the effective arterial blood volume(EABV), is to ensure adequate perfusion of cells and organs. Other factors, including cardiac output, total and regional capacity of both arteries and veins, Starling forces in the capillaries, and gravity also affect the EABV. Collectively, these factors interact closely with extracellular volume and some of them undergo substantial changes in certain acute and chronic severe illnesses. Their changes result not only in extracellular volume expansion, but in the need for a larger extracellular volume compared with that of healthy individuals. Assessing extracellular volume in severe illness is challenging because the estimates of this volume by commonly used methods are prone to large errors in many illnesses. In addition, the optimal extracellular volume may vary from illness to illness, is only partially based on volume measurements by traditional methods, and has not been determined for each illness. Further research is needed to determine optimal extracellular volume levels in several illnesses. For these reasons, extracellular volume in severe illness merits a separate third concept of body fluid balance.展开更多
Objective: It has been suggested that the use of hypotonic intravenous fluid (IVF) puts hospitalized children at a greater risk of developing hyponatremia in children with increased arginine vasopressin (AVP) producti...Objective: It has been suggested that the use of hypotonic intravenous fluid (IVF) puts hospitalized children at a greater risk of developing hyponatremia in children with increased arginine vasopressin (AVP) production. To reduce its risk, the National Patient Safety Agency in UK issued alert 22 in 2007, of which recommendations were to use isotonic solutions for these children at risk of hyponatremia, instead of the previously most commonly used IVF (0.18% saline/ 4% dextrose) for maintenance fluid therapy. Recent observations, however, revealed that hypokalemia are also common in hospitalized patients who do not receive potassium in their IVF. This study was conducted to validate the potassium added IVF for the prevention of hospital-acquired hypokalemia in maintenance fluid therapy. Design: For maintenance fluid therapy, a commercially available IVF solution in Japan named as Solita-T2R (Na 84 mmol/L, K 20 mmol/L, Cl 66 mmol/L, glucose 3.2%) was infused for 41 sick children with a median age of 3.01 years. Its composition is close equivalent to 0.45% saline/5% dextrose (Na 77 mmol/L, K 0 mmol/L, Cl 77 mmol/L, dextrose 5%) except K content. The patients in states of AVP excess were excluded from the analysis. Results: Median serum potassium value did not drop significantly at a median interval of 48 hours (before IVF: 4.30 mmol/L, after IVF: 4.10 mmol/L, p > 0.05), whereas median serum sodium level significantly increased from 136.0 mmol/L to 139.0 mmol/L (p < 0.001). Conclusion: Potassium added (20 mmol/L) IVF solution reduces the risk of developing “hospital-acquired hypokalemia” in children who are not in states of AVP excess in maintenance fluid therapy. It is worthwhile to study prospectively in a larger number of sick children.展开更多
Introduction: Intracellular calcium concentration ([Ca2+]i) is a critical parameter in cellular homeostasis, including articular chondrocytes. Perturbed [Ca2+]i of chondrocytes may be associated with joint disease. Th...Introduction: Intracellular calcium concentration ([Ca2+]i) is a critical parameter in cellular homeostasis, including articular chondrocytes. Perturbed [Ca2+]i of chondrocytes may be associated with joint disease. The objective of the study was to compare large animal models for investigating Ca2+ homeostasis in chondrocytes. Materials and Methods: The gross anatomy of the metacarpophalangeal joint (MCP) of cattle and sheep was compared, along with the effect of various manoeuvres used to study the mechanisms of Ca2+ homeostasis in chondrocytes from load-bearing areas. The gross anatomy was observed before and after dissection, and internal architecture was examined after sectioning. Cartilage thickness was measured with a digital micrometer. Chondrocyte yield was determined after isolation. Chondrocytes were incubated with Fura-2 and Ca2+i followed in different extracellular conditions. A hypotonic shock (HTS) was used to mimic removal of a load. Results: The results showed that ovids and bovids were skeletally immature and aspects of Ca2+ homeostasis were similar. Ovine chondrocytes had higher resting fluorescence, consistent with elevated resting Ca2+ levels. Results from ion substitution experiments were consistent with a role for Na+/Ca2+ exchange, and swelling-induced Ca2+ enters into the cytoplasm via the plasma membrane and intracellular stores. Conclusions: Ca2+ homeostasis in chondrocytes from both species behaved in a similar manner to HTS and ion substitutions. Differences in resting [Ca2+]i could be associated with species, stage of maturation, or Fura-2 itself and require further investigation. These findings contribute to our understanding of the physiology of articular cartilage in different species, and their potential use as models for studying joint disease in humans.展开更多
Objective:To evaluate the effectiveness of the use of a modified Zhukovsky double(vaginal and uterine)balloon to improve the results of treatment in women with obstetric hemorrhage.Methods:We conducted an observationa...Objective:To evaluate the effectiveness of the use of a modified Zhukovsky double(vaginal and uterine)balloon to improve the results of treatment in women with obstetric hemorrhage.Methods:We conducted an observational controlled study including 701 puerperas,which were divided into two groups:The main group consisted of 508 women,who underwent a combined management,that is,traditional(transfusion of fresh frozen plasma,erythrocyte mass,uterotonics,hemostatic agents),surgical hemostasis in cases of caesarean section,and insertion of a double Zhukovsky balloon;while the comparison group included 193 patients,who were managed traditionally.The main group and the comparison group were divided into subgroups according to the main etiology of obstetric hemorrhage:ⅠA andⅠB-postpartum;ⅡA andⅡB-placenta accreta;ⅢA andⅢB-postpartum hysterectomy.Results:The most frequent causes of massive obstetric hemorrhage were atony of the uterus(39.2%),placenta previa(29.1%),and placental abruption(11.5%).Of the 508 balloon insertions,345(70.7%)were inserted for hemorrhage during cesarean section and 148(29.3%)for obstetric hemorrhage after spontaneous delivery.Among the obstetric hemorrhage at caesarean section,lower segment bleeding prevailed(78.1%),caused mainly by placenta previa,placenta accreta,placental abruption,polyhydramnios,and uterine scar defects.Combined management,including surgical hemostasis and insertion of vaginal and uterine balloon of Zhukovsky,reduced blood loss by 1.5 times and the number of hysterectomies by 6.72 times compared to controls.Conclusion:The use of a modified Zhukovsky double balloon in the management of obstetric hemorrhage may reduce the number of hysterectomies and the amount of blood loss.展开更多
文摘Background: Primary pulmonary angiosarcoma is extremely rare and the prognosis is very poor. We report a combination therapy of pneumonectomy and intrapleural hypotonic hyperthermic chemotherapy (IPHHC). Case report: A 48-year-old male with exertional dyspnea was found to have a left massive pleural effusion. Bronchoscopic examination displayed endobronchial stenosis of the left lower bronchus B8,9,10?and diagnosed with pulmonary angiosarcoma. Chest computed-tomographic scanning revealed a 5-cm mass in the left inferior lobe, which invaded the left upperbronchus. Intrapleural dissemination and malignant pleural effusion were also suspected (cT3N1M1a,?c-stage IV). As a palliative initial therapy, we performed a pneumonectomy. On the 7th?postoperative day, under general anesthesia, we performed video-assisted IPHHC (43°C, 60 min, 200 mg/m2?of CDDP). After the IPHHC, there was no major adverse event (more than Grade 3) during the postoperative course. Histological examination of the resected specimen revealed a highly-cellular growth of atypical spindle cells with a storiform pattern. By immunohistochemical testing, the tumor cells stained positive for markers including CD31 and the factor VIII related antigen, and the diagnosis of pulmonary angiosarcoma was made. No adjuvant chemoradiotherapy was given, and the postoperative clinical course was uneventful. Although there had been a recurrence in the chest wall, the patient eventually died twenty-one months later. Conclusion: As a new therapeutic option, we performed IPHHC after the pneumonectomy for an advanced pulmonary angiosarcoma with malignant pleural effusion. Although the patient had a recurrence in the chest wall, he had a reasonable postoperative outcome, that is, he returned to a work, retained a good quality of life and had a longer survival in spite of the poor prognosis of the pulmonary angiosarcoma.
文摘Cell-based assays represent a major end point of high throughput screening (HTS) but a key limitation of such assays is the potentially poor membrane permeability of test compounds. In this study, we optimized the conditions for the delivery of the membrane impermeable compound 8-hydroxypyrene-1,3,6-trisulfonic acid trisodium salt (HPTS) into human cells using hypotonic shift;a method that can promote the uptake of molecules from the extracellular fluid into cell cytoplasm via endocytosis. We showed that uptake of HPTS by cells was a function of hypotonic buffer osmolarity and that delivery was highly efficient with almost 100% of cells displaying uptake. Delivery of HPTS was equally effective at 25°C and 37°C, with delivery of compound proportional to incubation time and concentration of HPTS within the loading medium. The experimental conditions identified in this study could be applied to HTS drug discovery studies providing an effective method of delivering small membrane impermeable compounds into cells.
基金funds from the FEDER through the Operational Programme for Competitiveness Factors and Employment 2007-2013 (France)from the Cancérop?le Ile de France (France)
文摘Red blood cells(RBCs)can act as carriers for therapeutic agents and can substantially improve the safety,pharmacokinetics,and pharmacodynamics of many drugs.Maintaining RBCs integrity and lifespan is important for the efficacy of RBCs as drug carrier.We investigated the impact of drug encapsulation by hypotonic dialysis on RBCs physiology and integrity.Several parameters were compared between processed RBCs loaded with l-asparaginase(“eryaspase”),processed RBCs without drug and non-processed RBCs.Processed RBCs were less hydrated and displayed a reduction of intracellular content.We observed a change in the metabolomic but not in the proteomic profile of processed RBCs.Encapsulation process caused moderate morphological changes and was accompanied by an increase of RBCs-derived Extracellular Vesicles release.Despite a decrease in deformability,processed RBCs were not mechanically retained in a spleen-mimicking device and had increased surface-to-volume ratio and osmotic resistance.Processed RBCs half-life was not significantly affected in a mouse model and our previous phase 1 clinical study showed that encapsulation of asparaginase in RBCs prolonged its in vivo half-life compared to free forms.Our study demonstrated that encapsulation by hypotonic dialysis may affect certain characteristics of RBCs but does not significantly affect the in vivo longevity of RBCs or their drug carrier function.
文摘The regulation of body fluid balance is a key concern in health and disease and comprises three concepts. The first concept pertains to the relationship between total body water(TBW) and total effective solute and is expressed in terms of the tonicity of the body fluids. Disturbances in tonicity are the main factor responsible for changes in cell volume, which can critically affect brain cell function and survival. Solutes distributed almost exclusively in the extracellular compartment(mainly sodium salts) and in the intracellular compartment(mainly potassium salts) contribute to tonicity, while solutes distributed in TBW have no effect on tonicity. The second body fluid balance concept relates to the regulation and measurement of abnormalities of sodium salt balance and extracellular volume. Estimation of extracellular volume is more complex and error prone than measurement of TBW. A key function of extracellular volume, which is defined as the effective arterial blood volume(EABV), is to ensure adequate perfusion of cells and organs. Other factors, including cardiac output, total and regional capacity of both arteries and veins, Starling forces in the capillaries, and gravity also affect the EABV. Collectively, these factors interact closely with extracellular volume and some of them undergo substantial changes in certain acute and chronic severe illnesses. Their changes result not only in extracellular volume expansion, but in the need for a larger extracellular volume compared with that of healthy individuals. Assessing extracellular volume in severe illness is challenging because the estimates of this volume by commonly used methods are prone to large errors in many illnesses. In addition, the optimal extracellular volume may vary from illness to illness, is only partially based on volume measurements by traditional methods, and has not been determined for each illness. Further research is needed to determine optimal extracellular volume levels in several illnesses. For these reasons, extracellular volume in severe illness merits a separate third concept of body fluid balance.
文摘Objective: It has been suggested that the use of hypotonic intravenous fluid (IVF) puts hospitalized children at a greater risk of developing hyponatremia in children with increased arginine vasopressin (AVP) production. To reduce its risk, the National Patient Safety Agency in UK issued alert 22 in 2007, of which recommendations were to use isotonic solutions for these children at risk of hyponatremia, instead of the previously most commonly used IVF (0.18% saline/ 4% dextrose) for maintenance fluid therapy. Recent observations, however, revealed that hypokalemia are also common in hospitalized patients who do not receive potassium in their IVF. This study was conducted to validate the potassium added IVF for the prevention of hospital-acquired hypokalemia in maintenance fluid therapy. Design: For maintenance fluid therapy, a commercially available IVF solution in Japan named as Solita-T2R (Na 84 mmol/L, K 20 mmol/L, Cl 66 mmol/L, glucose 3.2%) was infused for 41 sick children with a median age of 3.01 years. Its composition is close equivalent to 0.45% saline/5% dextrose (Na 77 mmol/L, K 0 mmol/L, Cl 77 mmol/L, dextrose 5%) except K content. The patients in states of AVP excess were excluded from the analysis. Results: Median serum potassium value did not drop significantly at a median interval of 48 hours (before IVF: 4.30 mmol/L, after IVF: 4.10 mmol/L, p > 0.05), whereas median serum sodium level significantly increased from 136.0 mmol/L to 139.0 mmol/L (p < 0.001). Conclusion: Potassium added (20 mmol/L) IVF solution reduces the risk of developing “hospital-acquired hypokalemia” in children who are not in states of AVP excess in maintenance fluid therapy. It is worthwhile to study prospectively in a larger number of sick children.
文摘Introduction: Intracellular calcium concentration ([Ca2+]i) is a critical parameter in cellular homeostasis, including articular chondrocytes. Perturbed [Ca2+]i of chondrocytes may be associated with joint disease. The objective of the study was to compare large animal models for investigating Ca2+ homeostasis in chondrocytes. Materials and Methods: The gross anatomy of the metacarpophalangeal joint (MCP) of cattle and sheep was compared, along with the effect of various manoeuvres used to study the mechanisms of Ca2+ homeostasis in chondrocytes from load-bearing areas. The gross anatomy was observed before and after dissection, and internal architecture was examined after sectioning. Cartilage thickness was measured with a digital micrometer. Chondrocyte yield was determined after isolation. Chondrocytes were incubated with Fura-2 and Ca2+i followed in different extracellular conditions. A hypotonic shock (HTS) was used to mimic removal of a load. Results: The results showed that ovids and bovids were skeletally immature and aspects of Ca2+ homeostasis were similar. Ovine chondrocytes had higher resting fluorescence, consistent with elevated resting Ca2+ levels. Results from ion substitution experiments were consistent with a role for Na+/Ca2+ exchange, and swelling-induced Ca2+ enters into the cytoplasm via the plasma membrane and intracellular stores. Conclusions: Ca2+ homeostasis in chondrocytes from both species behaved in a similar manner to HTS and ion substitutions. Differences in resting [Ca2+]i could be associated with species, stage of maturation, or Fura-2 itself and require further investigation. These findings contribute to our understanding of the physiology of articular cartilage in different species, and their potential use as models for studying joint disease in humans.
基金The publication was prepared with the support of the Omsk State Medical University and RUDN University Program 5-100
文摘Objective:To evaluate the effectiveness of the use of a modified Zhukovsky double(vaginal and uterine)balloon to improve the results of treatment in women with obstetric hemorrhage.Methods:We conducted an observational controlled study including 701 puerperas,which were divided into two groups:The main group consisted of 508 women,who underwent a combined management,that is,traditional(transfusion of fresh frozen plasma,erythrocyte mass,uterotonics,hemostatic agents),surgical hemostasis in cases of caesarean section,and insertion of a double Zhukovsky balloon;while the comparison group included 193 patients,who were managed traditionally.The main group and the comparison group were divided into subgroups according to the main etiology of obstetric hemorrhage:ⅠA andⅠB-postpartum;ⅡA andⅡB-placenta accreta;ⅢA andⅢB-postpartum hysterectomy.Results:The most frequent causes of massive obstetric hemorrhage were atony of the uterus(39.2%),placenta previa(29.1%),and placental abruption(11.5%).Of the 508 balloon insertions,345(70.7%)were inserted for hemorrhage during cesarean section and 148(29.3%)for obstetric hemorrhage after spontaneous delivery.Among the obstetric hemorrhage at caesarean section,lower segment bleeding prevailed(78.1%),caused mainly by placenta previa,placenta accreta,placental abruption,polyhydramnios,and uterine scar defects.Combined management,including surgical hemostasis and insertion of vaginal and uterine balloon of Zhukovsky,reduced blood loss by 1.5 times and the number of hysterectomies by 6.72 times compared to controls.Conclusion:The use of a modified Zhukovsky double balloon in the management of obstetric hemorrhage may reduce the number of hysterectomies and the amount of blood loss.
