G. Kurlberg | University of Gothenburg (original) (raw)

Papers by G. Kurlberg

Research paper thumbnail of Factors reducing mortality in typhoid ileal perforation

Transactions of the Royal Society of Tropical Medicine and Hygiene, 1991

A retrospective study of 42 patients treated surgically for typhoid ileal perforation found the m... more A retrospective study of 42 patients treated surgically for typhoid ileal perforation found the mortality to be 24%. The study suggested that general peritonitis was the main cause of death in typhoid ileal perforation. However, the high mortality was significantly improved by adequate preoperative rehydration. The combination of chloramphenicoVgentamicin/metronidazole was superior to other antibiotic regimes. No mortality was recorded with this triple drug therapy.

Research paper thumbnail of Accelerated acute rejection of the intestinal graft in CD28-Deficient mice

Research paper thumbnail of Graft mucosal blood flow is reduced prior to histologic evidence of rejection in mouse small bowel transplantation: a murine model

T HE SUCCESS of small bowel transplantation is hampered by vigorous and early acute rejection res... more T HE SUCCESS of small bowel transplantation is hampered by vigorous and early acute rejection responses. At present, the diagnosis of acute rejection is based mainly on histology and endoscopy. The late onset of morphologic changes and the initial patchy pattern makes it hard to discover early. Therefore efforts continue to identify novel and effective means for early diagnosis of acute rejection in intestinal transplantation.

Research paper thumbnail of 6041 Evaluation of folate derivates in the neoadjuvant treatment of resectable rectal cancer with the antifolate pemetrexed

Research paper thumbnail of DONOR PRETREATMENT USING LOW DOSE FK506 IMPROVES GRAFT MORPHOLOGY AND MICROVASCULAR PERFUSION AFTER INTESTINAL TRANSPLANTATION

Transplantation Journal, 2004

The time course of heat shock protein 60 (hsp 60) expression after intestinal transplantation in ... more The time course of heat shock protein 60 (hsp 60) expression after intestinal transplantation in syngeneic and allogeneic combination was correlated with the degree of rejection. Hsp 60 expression was assessed by immunostaining; rejection degree was established by histologic examination on posttransplantation days 1, 3, 6, and 8. No signs of rejection occurred in syngeneic grafts at any time. In the allogeneic setting, rejection was absent in all but 1 case on postoperative day 3. Three days later moderate rejection was evident based on focal crypt destruction and focal mucosal ulceration, whereas at postoperative day 8 extensive mucosal sloughing was the dominant feature, consistent with advanced rejection. Hsp 60 remained undetectable in the syngeneic setting at all times. In allografts, hsp 60 was initially expressed on posttransplant day 3, increasing synchronously with the progression of rejection at days 6 and 8. Hsp 60 expression was localized almost exclusively to the crypt area and the lower third of the villi. In conclusion, the rejection of murine allogeneic intestinal grafts is characterized by a progressive expression of hsp 60 in the epithelium.

Research paper thumbnail of Alternative Pathway Activation of Complement by Shiga Toxin Promotes Exuberant C3a Formation That Triggers Microvascular Thrombosis

The Journal of Immunology, 2011

Shiga toxin (Stx)-producing E.coli O157:H7 has become a global threat to public health; it is a p... more Shiga toxin (Stx)-producing E.coli O157:H7 has become a global threat to public health; it is a primary cause of diarrheaassociated hemolytic uremic syndrome (HUS), a disorder of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure with thrombi occluding renal microcirculation. In this study, we explored whether Stx triggers complementdependent microvascular thrombosis in in vitro and in vivo experimental settings of HUS. Stx induced on human microvascular endothelial cell surface the expression of P-selectin, which bound and activated C3 via the alternative pathway, leading to thrombus formation under flow. In the search for mechanisms linking complement activation and thrombosis, we found that exuberant complement activation in response to Stx generated an increased amount of C3a that caused further endothelial Pselectin expression, thrombomodulin (TM) loss, and thrombus formation. In a murine model of HUS obtained by coinjection of Stx2 and LPS and characterized by thrombocytopenia and renal dysfunction, upregulation of glomerular endothelial P-selectin was associated with C3 and fibrin(ogen) deposits, platelet clumps, and reduced TM expression. Treatment with anti-P-selectin Ab limited glomerular C3 accumulation. Factor B-deficient mice after Stx2/LPS exhibited less thrombocytopenia and were protected against glomerular abnormalities and renal function impairment, indicating the involvement of complement activation via the alternative pathway in the glomerular thrombotic process in HUS mice. The functional role of C3a was documented by data showing that glomerular fibrin(ogen), platelet clumps, and TM loss were markedly decreased in HUS mice receiving C3aR antagonist. These results identify Stx-induced complement activation, via P-selectin, as a key mechanism of C3a-dependent microvascular thrombosis in diarrhea-associated HUS.

Research paper thumbnail of Heterotopic uterine transplantation by vascular anastomosis in the mouse

Journal of Endocrinology, 2002

A method of heterotopic uterine transplantation was developed in the mouse as a model system for ... more A method of heterotopic uterine transplantation was developed in the mouse as a model system for studies of uterine function and transplant immunology of the uterus. The model involved transplantation of the right uterine horn and the cervix by vascular anastomosis to a donor animal with the intact native uterus remaining in situ. F1-hybrids of inbred C57BL/6 CBA/ca (B6 CBAF1) mice of 6-8 weeks of age (n=42) were used. The specific pelvic vascular anatomy of these mice was first examined by intra-aortal injection of a two-component siliconrubber curing agent. The surgery of the donor animal involved microsurgical isolation of the right uterine horn and the cervix, with preserved vascular supply from the aorta through the right uterine artery. After isolation of the uterine horn with vascular supply and venous drainage, including approximately 3 mm of the inferior vena cava and aorta, the organ was put on ice. The recipient animal was prepared by exposing and mobilizing the infrarenal part of the aorta and the vena cava. The grafted uterus was placed in the abdomen on the left side and the aorta and vena cava of the graft were anastomosed end-to-side to the aorta and vena cava of the recipient animal with 11-0 sutures. The total time for these procedures declined with time and was 125 4 min for the last 28 operations. Viability of the uterus was confirmed, several days later, by demonstrating a blood flow similar to that of the native uterus, and histology of the grafted uterus demonstrated normal morphology, including intact ultrastructure of the endothelial cells. The overall survival rate of the recipient animals increased with learning from approximately 40% in animals 1-21 to 71% in animals 22-42. The proportion of viable grafts, as judged by normal blood flow and histology among the surviving mice was 25% in animals 1-21 and 87% in animals 22-42. An undisturbed function of the transplanted uterus horn was finally demonstrated by its ability to implant inserted blastocysts and to carry pregnancy with fetal weight being similar to that of fetuses in the native uterus and controls. In conclusion, this is the first report of successful transplantation of the uterus with proven functionality in the mouse. The model should be useful for many aspects of research in uterine physiology and pathophysiology.

Research paper thumbnail of Pregnancy in transplanted mouse uterus after long-term cold ischaemic preservation

Human Reproduction, 2003

BACKGROUND: The aim of this study was to evaluate the viability of the transplanted murine uterus... more BACKGROUND: The aim of this study was to evaluate the viability of the transplanted murine uterus after cold ischaemic preservation. METHODS: Uteri of mice (6±8 weeks old) were isolated and kept at 4°C in vitro for 24 or 48 h in 0.154 mol/l NaCl or University of Wisconsin (UW) solution. Viability was evaluated by assessment of morphology and contractility in vitro. Furthermore, uteri were transplanted by vascular anastomoses to syngeneic recipients after 24 or 48 h cold ischaemic preservation in UW solution and morphology, blood¯ow and capacity to implant transferred blastocysts were assessed 2 weeks later. RESULTS: Uteri that had been preserved for 24 h exhibited normal morphology but after 48 h preservation minimal degenerative changes were seen. Spontaneous contractions occurred in uteri after 24 h as well as 48 h cold ischaemic preservation and prostaglandin F 2a -stimulated responses were preserved. Blood¯ow and morphology were normal 2 weeks after transplantation in uteri preserved for 24 h, while grafts preserved for 48 h had a decreased blood¯ow and morphology showed total necrosis of the transplants. Transplanted uteri that had been preserved for 24 h developed pregnancies (in ®ve out of six animals) after embryo transfer, with offspring showing normal weight and growth trajectory. CONCLUSIONS: This study shows for the ®rst time that the mouse uterus tolerates cold ischaemic preservation and that pregnancies can be carried in transplanted uteri that have been preserved for 24 h.

Research paper thumbnail of Rejection patterns in allogeneic uterus transplantation in the mouse

Human Reproduction, 2005

BACKGROUND: Transplantation of the uterus in the mouse has been developed as a model system for r... more BACKGROUND: Transplantation of the uterus in the mouse has been developed as a model system for research towards human uterine transplantation. Previous studies in a mouse model have demonstrated that a syngeneic uterus transplant can give rise to normal offspring. The aim of this study was to characterize the time course of rejection in a fully allogeneic mouse uterus transplantation model. METHODS: Uteri of BALB/c mice were transplanted to a heterotopic position in C57BL/6 recipients, whose native uteri were left in situ. The blood flow of the uteri, their gross appearance and general histology and the density of T-lymphocytes were examined on postoperative days 2-28. RESULTS: Macroscopic signs of rejection were apparent from day 5. At the light microscopy level, minimal inflammatory changes were seen from day 5 and massive inflammation was seen from day 10 to day 15. At day 28, necrosis and fibrosis were seen. The density of T-lymphocytes (CD3 + ) was increased in the grafted uterus from day 2 in the myometrium and from day 5 in the endometrium. Blood flow in the grafted uteri was reduced from day 15. CONCLUSION: A murine model to study rejection of allogeneic uterus transplants was characterized. Signs of rejection were seen from day 2 to day 5 and severe rejection was seen from day 10 to day 15. The data will be useful in future studies on immunosuppressants in this model.

Research paper thumbnail of Short-term ischaemic storage of human uterine myometrium--basic studies towards uterine transplantation

Human Reproduction, 2005

Transplantation of the uterus has been suggested as a possible future treatment of absolute uteri... more Transplantation of the uterus has been suggested as a possible future treatment of absolute uterine infertility. The tolerability of human uterine tissue to cold ischaemic storage was tested in the present study. Small tissue samples of human uteri were subjected to cold (4 degrees C) ischaemia (6 and 24 h) in Ringer acetate (RIN), the intracellular-like University of Wisconsin solution (UW) or the extracellular-like Perfadex solution (PER). The ability of myometrial strips to contract, histology by light and electron microscopy as well as tissue concentrations of glutathione, ATP and protein were used as parameters to detect cold ischaemic injuries. Contractile ability and response to prostaglandin F(2alpha) (PGF(2alpha)) was better preserved after 6 h cold ischaemia in UW and PER in comparison with the other groups. Histological examination did not reveal any major changes after 6 and 24 h cold ischaemic storage in UW and PER solutions, while specimens stored in RIN for 24 h displayed degenerative changes on the electron microscopy level. UW and PER preserved ATP concentrations significantly better than RIN. Myometrium stored in UW contained more total glutathione but also a larger proportion of oxidized glutathione than specimens stored in RIN and PER. Protein concentrations did not change with storage time in any of the solutions. The results show that human uterine myometrial tissue is resistant towards cold ischaemia for at least 6 h if stored in UW and PER solutions.

Research paper thumbnail of Factors reducing mortality in typhoid ileal perforation

Transactions of the Royal Society of Tropical Medicine and Hygiene, 1991

A retrospective study of 42 patients treated surgically for typhoid ileal perforation found the m... more A retrospective study of 42 patients treated surgically for typhoid ileal perforation found the mortality to be 24%. The study suggested that general peritonitis was the main cause of death in typhoid ileal perforation. However, the high mortality was significantly improved by adequate preoperative rehydration. The combination of chloramphenicoVgentamicin/metronidazole was superior to other antibiotic regimes. No mortality was recorded with this triple drug therapy.

Research paper thumbnail of Accelerated acute rejection of the intestinal graft in CD28-Deficient mice

Research paper thumbnail of Graft mucosal blood flow is reduced prior to histologic evidence of rejection in mouse small bowel transplantation: a murine model

T HE SUCCESS of small bowel transplantation is hampered by vigorous and early acute rejection res... more T HE SUCCESS of small bowel transplantation is hampered by vigorous and early acute rejection responses. At present, the diagnosis of acute rejection is based mainly on histology and endoscopy. The late onset of morphologic changes and the initial patchy pattern makes it hard to discover early. Therefore efforts continue to identify novel and effective means for early diagnosis of acute rejection in intestinal transplantation.

Research paper thumbnail of 6041 Evaluation of folate derivates in the neoadjuvant treatment of resectable rectal cancer with the antifolate pemetrexed

Research paper thumbnail of DONOR PRETREATMENT USING LOW DOSE FK506 IMPROVES GRAFT MORPHOLOGY AND MICROVASCULAR PERFUSION AFTER INTESTINAL TRANSPLANTATION

Transplantation Journal, 2004

The time course of heat shock protein 60 (hsp 60) expression after intestinal transplantation in ... more The time course of heat shock protein 60 (hsp 60) expression after intestinal transplantation in syngeneic and allogeneic combination was correlated with the degree of rejection. Hsp 60 expression was assessed by immunostaining; rejection degree was established by histologic examination on posttransplantation days 1, 3, 6, and 8. No signs of rejection occurred in syngeneic grafts at any time. In the allogeneic setting, rejection was absent in all but 1 case on postoperative day 3. Three days later moderate rejection was evident based on focal crypt destruction and focal mucosal ulceration, whereas at postoperative day 8 extensive mucosal sloughing was the dominant feature, consistent with advanced rejection. Hsp 60 remained undetectable in the syngeneic setting at all times. In allografts, hsp 60 was initially expressed on posttransplant day 3, increasing synchronously with the progression of rejection at days 6 and 8. Hsp 60 expression was localized almost exclusively to the crypt area and the lower third of the villi. In conclusion, the rejection of murine allogeneic intestinal grafts is characterized by a progressive expression of hsp 60 in the epithelium.

Research paper thumbnail of Alternative Pathway Activation of Complement by Shiga Toxin Promotes Exuberant C3a Formation That Triggers Microvascular Thrombosis

The Journal of Immunology, 2011

Shiga toxin (Stx)-producing E.coli O157:H7 has become a global threat to public health; it is a p... more Shiga toxin (Stx)-producing E.coli O157:H7 has become a global threat to public health; it is a primary cause of diarrheaassociated hemolytic uremic syndrome (HUS), a disorder of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure with thrombi occluding renal microcirculation. In this study, we explored whether Stx triggers complementdependent microvascular thrombosis in in vitro and in vivo experimental settings of HUS. Stx induced on human microvascular endothelial cell surface the expression of P-selectin, which bound and activated C3 via the alternative pathway, leading to thrombus formation under flow. In the search for mechanisms linking complement activation and thrombosis, we found that exuberant complement activation in response to Stx generated an increased amount of C3a that caused further endothelial Pselectin expression, thrombomodulin (TM) loss, and thrombus formation. In a murine model of HUS obtained by coinjection of Stx2 and LPS and characterized by thrombocytopenia and renal dysfunction, upregulation of glomerular endothelial P-selectin was associated with C3 and fibrin(ogen) deposits, platelet clumps, and reduced TM expression. Treatment with anti-P-selectin Ab limited glomerular C3 accumulation. Factor B-deficient mice after Stx2/LPS exhibited less thrombocytopenia and were protected against glomerular abnormalities and renal function impairment, indicating the involvement of complement activation via the alternative pathway in the glomerular thrombotic process in HUS mice. The functional role of C3a was documented by data showing that glomerular fibrin(ogen), platelet clumps, and TM loss were markedly decreased in HUS mice receiving C3aR antagonist. These results identify Stx-induced complement activation, via P-selectin, as a key mechanism of C3a-dependent microvascular thrombosis in diarrhea-associated HUS.

Research paper thumbnail of Heterotopic uterine transplantation by vascular anastomosis in the mouse

Journal of Endocrinology, 2002

A method of heterotopic uterine transplantation was developed in the mouse as a model system for ... more A method of heterotopic uterine transplantation was developed in the mouse as a model system for studies of uterine function and transplant immunology of the uterus. The model involved transplantation of the right uterine horn and the cervix by vascular anastomosis to a donor animal with the intact native uterus remaining in situ. F1-hybrids of inbred C57BL/6 CBA/ca (B6 CBAF1) mice of 6-8 weeks of age (n=42) were used. The specific pelvic vascular anatomy of these mice was first examined by intra-aortal injection of a two-component siliconrubber curing agent. The surgery of the donor animal involved microsurgical isolation of the right uterine horn and the cervix, with preserved vascular supply from the aorta through the right uterine artery. After isolation of the uterine horn with vascular supply and venous drainage, including approximately 3 mm of the inferior vena cava and aorta, the organ was put on ice. The recipient animal was prepared by exposing and mobilizing the infrarenal part of the aorta and the vena cava. The grafted uterus was placed in the abdomen on the left side and the aorta and vena cava of the graft were anastomosed end-to-side to the aorta and vena cava of the recipient animal with 11-0 sutures. The total time for these procedures declined with time and was 125 4 min for the last 28 operations. Viability of the uterus was confirmed, several days later, by demonstrating a blood flow similar to that of the native uterus, and histology of the grafted uterus demonstrated normal morphology, including intact ultrastructure of the endothelial cells. The overall survival rate of the recipient animals increased with learning from approximately 40% in animals 1-21 to 71% in animals 22-42. The proportion of viable grafts, as judged by normal blood flow and histology among the surviving mice was 25% in animals 1-21 and 87% in animals 22-42. An undisturbed function of the transplanted uterus horn was finally demonstrated by its ability to implant inserted blastocysts and to carry pregnancy with fetal weight being similar to that of fetuses in the native uterus and controls. In conclusion, this is the first report of successful transplantation of the uterus with proven functionality in the mouse. The model should be useful for many aspects of research in uterine physiology and pathophysiology.

Research paper thumbnail of Pregnancy in transplanted mouse uterus after long-term cold ischaemic preservation

Human Reproduction, 2003

BACKGROUND: The aim of this study was to evaluate the viability of the transplanted murine uterus... more BACKGROUND: The aim of this study was to evaluate the viability of the transplanted murine uterus after cold ischaemic preservation. METHODS: Uteri of mice (6±8 weeks old) were isolated and kept at 4°C in vitro for 24 or 48 h in 0.154 mol/l NaCl or University of Wisconsin (UW) solution. Viability was evaluated by assessment of morphology and contractility in vitro. Furthermore, uteri were transplanted by vascular anastomoses to syngeneic recipients after 24 or 48 h cold ischaemic preservation in UW solution and morphology, blood¯ow and capacity to implant transferred blastocysts were assessed 2 weeks later. RESULTS: Uteri that had been preserved for 24 h exhibited normal morphology but after 48 h preservation minimal degenerative changes were seen. Spontaneous contractions occurred in uteri after 24 h as well as 48 h cold ischaemic preservation and prostaglandin F 2a -stimulated responses were preserved. Blood¯ow and morphology were normal 2 weeks after transplantation in uteri preserved for 24 h, while grafts preserved for 48 h had a decreased blood¯ow and morphology showed total necrosis of the transplants. Transplanted uteri that had been preserved for 24 h developed pregnancies (in ®ve out of six animals) after embryo transfer, with offspring showing normal weight and growth trajectory. CONCLUSIONS: This study shows for the ®rst time that the mouse uterus tolerates cold ischaemic preservation and that pregnancies can be carried in transplanted uteri that have been preserved for 24 h.

Research paper thumbnail of Rejection patterns in allogeneic uterus transplantation in the mouse

Human Reproduction, 2005

BACKGROUND: Transplantation of the uterus in the mouse has been developed as a model system for r... more BACKGROUND: Transplantation of the uterus in the mouse has been developed as a model system for research towards human uterine transplantation. Previous studies in a mouse model have demonstrated that a syngeneic uterus transplant can give rise to normal offspring. The aim of this study was to characterize the time course of rejection in a fully allogeneic mouse uterus transplantation model. METHODS: Uteri of BALB/c mice were transplanted to a heterotopic position in C57BL/6 recipients, whose native uteri were left in situ. The blood flow of the uteri, their gross appearance and general histology and the density of T-lymphocytes were examined on postoperative days 2-28. RESULTS: Macroscopic signs of rejection were apparent from day 5. At the light microscopy level, minimal inflammatory changes were seen from day 5 and massive inflammation was seen from day 10 to day 15. At day 28, necrosis and fibrosis were seen. The density of T-lymphocytes (CD3 + ) was increased in the grafted uterus from day 2 in the myometrium and from day 5 in the endometrium. Blood flow in the grafted uteri was reduced from day 15. CONCLUSION: A murine model to study rejection of allogeneic uterus transplants was characterized. Signs of rejection were seen from day 2 to day 5 and severe rejection was seen from day 10 to day 15. The data will be useful in future studies on immunosuppressants in this model.

Research paper thumbnail of Short-term ischaemic storage of human uterine myometrium--basic studies towards uterine transplantation

Human Reproduction, 2005

Transplantation of the uterus has been suggested as a possible future treatment of absolute uteri... more Transplantation of the uterus has been suggested as a possible future treatment of absolute uterine infertility. The tolerability of human uterine tissue to cold ischaemic storage was tested in the present study. Small tissue samples of human uteri were subjected to cold (4 degrees C) ischaemia (6 and 24 h) in Ringer acetate (RIN), the intracellular-like University of Wisconsin solution (UW) or the extracellular-like Perfadex solution (PER). The ability of myometrial strips to contract, histology by light and electron microscopy as well as tissue concentrations of glutathione, ATP and protein were used as parameters to detect cold ischaemic injuries. Contractile ability and response to prostaglandin F(2alpha) (PGF(2alpha)) was better preserved after 6 h cold ischaemia in UW and PER in comparison with the other groups. Histological examination did not reveal any major changes after 6 and 24 h cold ischaemic storage in UW and PER solutions, while specimens stored in RIN for 24 h displayed degenerative changes on the electron microscopy level. UW and PER preserved ATP concentrations significantly better than RIN. Myometrium stored in UW contained more total glutathione but also a larger proportion of oxidized glutathione than specimens stored in RIN and PER. Protein concentrations did not change with storage time in any of the solutions. The results show that human uterine myometrial tissue is resistant towards cold ischaemia for at least 6 h if stored in UW and PER solutions.