Relationship Between Stress Coping Mechanisms and Depression in Kidney Transplant Recipients.

BACKGROUND: It has been reported that transplant recipients are exposed to physical and psychosocial stresses even after transplant surgery and exhibit psychological disorders such as depression. PURPOSE: In this study, we extracted trends concerning how recipients of kidney transplants cope with stress, and we also examined how they cope with depression and its countermeasures. METHOD: We administered questionnaire surveys to 109 kidney transplant recipients. These included items on personal attributes, medical information, depression, and stress-coping type scales. Statistical analysis was performed using factor analysis and multiple regression analysis. RESULTS: Fifteen out of 109 (13.8%) were found to be high-risk patients for depression based on responses to the questionnaire using the depression scale. We extracted 2 factors of stress-coping type, namely Factor 1, "Directly coping with the problem," of patients who try to directly resolve the problem in a positive manner and Factor 2, "Stress-release while avoiding the problem," for those who relieve their feelings in response to the stress without resolving the problem itself. When multiple regression analysis was conducted with the depression scale as the dependent variable and the stress-coping factor as the independent variable, Factor 1 tended to be associated with reduced depression and Factor 2 with increased depression. CONCLUSIONS: Results showed that to improve the mental health of those who receive kidney transplants, it is necessary to examine the depression and stress-coping types of such patients at an early stage and carry out education on stress-coping, focusing on resolving the actual problem.

Characteristics of histologically confirmed endometriosis in cynomolgus monkeys.

STUDY QUESTION: What are the characteristics of spontaneous endometriosis in cynomolgus monkeys? SUMMARY ANSWER: Spontaneous endometriosis in cynomolgus monkeys exhibited similar characteristics to the human disease. WHAT IS KNOWN ALREADY: One previous report described the prevalence and the basic histopathology of spontaneous endometriosis in cynomolgus monkeys. STUDY DESIGN, SIZE, DURATION: Endometriotic lesions that had been histologically confirmed in 8 female cynomolgus monkeys between 5 and 21 years old were subjected to study. PARTICIPANTS/MATERIALS, SETTING, METHODS: The monkeys died of, or were sacrificed because of, sickness consequent on endometriosis. Specimens were evaluated histopathologically with haematoxylin and eosin staining, iron staining and immunohistochemistry (CD10, CD31, α-SMA and PGP9.5), and by observing them under a microscope. MAIN RESULTS AND THE ROLE OF CHANCE: Endometriotic and stromal cells (CD10-positive) with haemorrhage and inflammation were observed. Smooth muscle metaplasia and nerve fibres were also noted in the endometriotic lesions. Endometriotic lesions in lymph nodes were incidentally found. LIMITATIONS AND REASONS FOR CAUTION: Since laparoscopic analysis for monitoring the disease state was not set as a parameter of the current study, time course changes (progression) of the disease were not assessed. WIDER IMPLICATIONS OF THE FINDINGS: Further investigation of spontaneous endometriosis in cynomolgus monkeys may contribute to better understanding of the disease pathobiology. STUDY FUNDING/COMPETING INTERESTS: No external funds were used for this study. A.N.K., S.M., S.H., T.I., O.K., A.K. and M.S. are full-time employees of Chugai Pharmaceutical Co., Ltd. R.K. received lecture fees from Chugai Pharmaceutical Co., Ltd., unrelated to the submitted work. S.N., S. O., L.Y., K.Y. and T.S. have nothing to declare. TRIAL REGISTRATION NUMBER: N/A.

Excellent results with high-dose mizoribine combined with cyclosporine, corticosteroid, and basiliximab in renal transplant recipients: multicenter study in Japan.

We performed a multicenter study in Japan to assess the efficacy and safety of immunosuppressive therapy with high-dose mizoribine (MZR; 6 mg/kg) combined with basiliximab (Bas), cyclosporine (CyA), and a corticosteroid in 90 patients. MZR was adjusted to maintain a target trough level of 1 to 2 µg/mL. CyA was started at 7 mg/kg to maintain blood levels in the target therapeutic range of 200 ng/mL (trough [C0]), 1200 ng/mL (2-hour post-dose [C2]), and 6000 ng·h/mL (area under the curve(0-9)). Bas (20 mg/body weight) was administered on the day of transplantation and on postoperative day 4. Rejection was diagnosed by episode and protocol biopsies. Cytomegalovirus (CMV) antigenemia (direct immunological staining of leukocytes using peroxidase-labeled monoclonal antibody [C7-HRP]) levels were measured every 2 weeks for 6 months. At 12 months, all patients and grafts were surviving except for one death from infection: the 1-year patient and graft survival rate was 98.9%. The acute rejection rate was 21.1%. The mean serum creatinine level at 1 year was 1.51 ± 0.61 mg/dL. The incidence of CMV disease was 0% with 28.9%, CMV antigenemia and 5.6%, ganoyclovir treatment. The incidence of BK virus disease was 2.2%. The mean serum uric acid level was 7.15 ± 1.79 mg/dL at 1 month and 7.06 ± 1.78 mg/dL at 3 months. We observed that a high-dose MZR regimen in combination with CyA, Bas, and corticosteroid was safe and effective to reduce the frequency of CMV and BK virus-related events in renal transplant recipients.

Low survival rate of renal transplant recipients from unrelated living donors with renal diseases.

In three hospitals within a restricted area in Japan in November, 2006, 42 patients were revealed to have received kidneys transplanted from unrelated living donors who displayed renal diseases. All of these cases were performed by one doctor without any ethical discussion in the hospitals nor any reports to the public. Almost all medical records were discarded legally in two hospitals. Only one hospital, Uwajima City Hospital, kept the almost complete records including the survivals of 25 cases. The Japan Society for Transplantation was asked to analyze these cases leading to this report on the long-term outcome of cases at Uwajima City Hospital. The diseased kidney grafts were procured in four hospitals. The cases of removal of the kidneys from the donors were malignant diseases (n = 11) or benign diseases (n = 14). The survival rates of the donors were 86.1% at 1, 70.8% at 5, and 57.7% at 10 years. The survival rates of the recipients transplanted from donors with malignant versus benign diseases were 80.8% versus 92.3% in 1, 48.5% versus 84.6% at 5% and 48.5% versus 76.2% at 10 years, respectively. The survival rates of the grafts from donors with malignant versus benign diseases were 71.6% versus 71.4% at 1, 15.3% versus 50.0% at 5, and 15.3% versus 33.3% at 10 years, respectively. In conclusion, we have reported herein the low survival rates of renal transplantation recipients and grafts from unrelated living donors with preexistent renal diseases.

National survey of laparoscopic live donor nephrectomy in Japan from 2002 to 2008.

Laparoscopic nephrectomy (LN) has been accepted for live donor kidney transplantation. Continuous surveys on the status of LN in live donors were made from 2002 to 2008 in Japan. At first, we reported the status in 2008 at 148 Japanese kidney transplantation centers. Of 148 centers, 109 responded, and 58 performed LN. These centers performed 764 live donor nephrectomies, including 659 LN and 105 open nephrectomies. In 58 centers, 20 were performed as hand-assisted (HA) LN, 27 as non-HA (pure laparoscopic), 2 as both HA and non-HA, and 8 as laparoscope-assisted. There were 24 centers that carried out a peritoneal approach and 34 had a retro-peritoneal approach. Among 764 LN donors, not 1 had a life-threatening complication. Blood transfusions were performed in only 1 donor. Open conversions from LN were required in 13 (2.0%) cases. Minor complications not requiring a prolonged hospital stay were reported in 20 cases. The mortality after LN was 0. Among 659 recipients, 1 case was reported as primary nonfunction, but ten recipients (1.5%) needed hemodialysis after transplantation because of delayed graft function. Urinary tract complications were noted in 18 recipients (2.7%). We have discussed the trends in LN from 2002 to 2008 in Japan. At the beginning of LN, many surgeons performed LN, so the open conversion rate was low and the blood transfusion rate was high. But in the later years, surgeons performed LN in the same manner as general laparoscopic surgeries with high intention for donor safety.

Outcome of laparoscopic living donor nephrectomy in 2007: national survey of transplantation centers in Japan.

Laparoscopic nephrectomy (LN) has been accepted for a donor in living donor kidney transplantation. However, the current status of LN in living donors is not yet clarified in Japan. In this study, we surveyed 138 Japanese kidney transplantation centers to investigate the outcomes of living donor LN in 2007. Of 138 centers, 107 responded, and 48 performed LN. These centers performed 840 living donor nephrectomies, including 623 LN and 217 open nephrectomies. Among 47 centers, 23 performed hand-assisted (HA) LN, 18 non-HA (pure laparoscopic), 3 both HA and non-HA, and 3 laparoscope-assisted. Seventeen centers utilized a peritoneal approach, 26 a retroperitoneal approach, and 4 both approaches. Among 623 LN donors, the 2 who had the life-threatening complications of bleeding and intestinal injury both survived. Blood transfusions were performed in 5 donors (0.8%). There were 8 (1.3%) open conversions from LN. Minor complications not requiring a longer hospital stay were reported in 10. There was no donor mortality after LN. However, among the recipients, there was 1 case of primary nonfunction. Thirteen recipients (2.0%) required hemodialysis after transplantation because of delayed graft function. Urinary tract complications were noted in 13 recipients (2.0%). This survey presented the current status of this procedure among donors who provided informed consent.

Outcome of laparoscopic living donor nephrectomy: current status and trends in Japan.

Laparoscopic nephrectomy (LN) has been accepted for donors in living donor kidney transplantation. But the current status of LN in living donors is not clarified yet in Japan. In this study, we surveyed 124 Japanese kidney transplantation centers to investigate the outcomes of living donor LN in 2006. Of 124 centers, 100 responded, and 52 performed LN. These centers performed 831 living donor nephrectomies, including 589 LN, and 242 open procedures. In 52 centers, 20 were performed as hand-assisted (HA) LNs, 23 non-HA (pure laparoscopic), five both HA and non-HA, and four laparoscope-assisted. Eighteen centers used a peritoneal approach, 31 used a retroperitoneal approach and three, both. Among 589 LN donors, three experienced life-threatening complications of bleedings and intestinal injury, but all of them survived. Blood transfusions were performed in nine donors (1.5%), and open conversions of LN in 33 (5.6%). Minor complications not requiring a long hospital stay were reported in 45. The mortality of LN was 0. Among the 589 recipients, there was one case of primary nonfunction after venous injury at the operation. Twenty eight recipients (4.8%) needed hemodialysis after transplantation because of delayed graft function. Urinary tract complications were noted in 11 recipients (2.5%). This survey presented the current status of LN in Japan.

Outcome of laparoscopic live donor nephrectomy in 2005: National survey of Japanese transplantation centers.

The increased acceptance of laparoscopic nephrectomy (LN) has been a driving force for live donor kidney transplantation. However, the outcomes of LN in live donors has not yet been clarified in Japan. In this study, we surveyed 125 Japanese kidney transplantation centers to investigate the current status of live donor LN. Of 125 centers, the 98 that responded had performed 695 live donor nephrectomies. Among these centers, 43 had performed LN. Among the 695 nephrectomies, 441 donors had undergone LN and 254, open nephrectomies. In 43 centers, 16 were performed as hand-assisted (HA) LN; 20, non-HA; 3, both HA and non-HA; and 5 laparoscope-assisted. Ten centers used a peritoneal approach; 30, a retroperitoneal; and 3, both. In 441 LN donors, 1 had a life-threatening complication of deep venous thrombosis and survived. Blood transfusions were performed in 7 donors. Open conversions from LN were necessary in 24. Minor complications not requiring prolonged hospital stay were reported in 52. The mortality of LN was zero. In contrast, among the 441 recipients, 1 case was reported as primary nonfunction after venous misadventure in the operation and 30 recipients needed hemodialysis after transplantation because of delayed graft function. Urinary tract complications were noted in 11 recipients. This survey presented the current status of the procedure, providing a base for informed consent from potential donors.

Effects of tetrabromobisphenol A, brominated flame retardant, in ICR mice after prenatal and postnatal exposure.

Tetrabromobisphenol A (TBBPA), brominated flame retardant, is produced in the largest amounts globally for use in plastics or building materials. TBBPA has been detected in sediment, air at the dismantling plant or human serum samples. In the present study, we examined the effects of prenatal and postnatal exposure to TBBPA in mice. TBBPA (99.1% pure) in diet was administered to pregnant ICR mice at doses of 0% (control), 0.01%, 0.1% or 1.0% from gestational day 0 to weaning at postnatal day 27. The average daily food intake and body weight of dams showed no significant differences between the control and treated groups. There were no dose-related effects on reproductive data. Serum concentrations of total-cholesterol and liver weights of treated dams and offspring were higher than those of the control mice. Histological findings in treated dams or offspring showed the increase of focal necrosis of hepatocytes and inflammatory cell infiltration in the liver, and increase of dilation or atrophy of renal tubules and cyst in the kidney. TBBPA was developed as a new, safe class of flame retardant and was not highly toxic. However, the present data suggested that TBBPA caused a lipid metabolic disorder and hepatic or kidney lesion, under these conditions.

Backtransplantation for survival of the graft.

To assess survival of grafts after uncontrollable rejection, one performs backtransplantation from the recipient to the donor. This study investigated backtransplantation in an animal model. Hearts were transplanted heterotopically in rats. After a few days, the transplanted heart grafts were harvested from the recipients and backtransplanted to the donor strain heterotopically and a drug was administered. Cardiac grafts survived 6.2 days in the first recipients. After backtransplantation on day 5 or 6, all backtransplanted grafts survived well in the second recipients. After backtransplantation on day 7, when 4 of 5 grafts had no beat, 2 of 5 grafts recovered beating on day 3 after backtransplantation without any drug treatment. After backtransplantation on day 7, when 4 of 5 grafts had no beat, all (5 of 5 grafts) recovered beating well with the administration of FTY720 on day 3 after backtransplantation. CsA or FK506 had no effect on survival after backtransplantation. Pathological findings revealed mild cellular infiltration in the cases of FTY720 and severe necrosis in the cases of no drug, CsA, or FK506. After backtransplantation on day 8, no grafts (0 of 5 grafts in each drug) recovered beating with any drugs. These data document the possibility of backtransplantation.

Chronic toxicity of thiabendazole (TBZ) in CD-1 mice.

Male and female CD-1 mice (50 mice per group) were administered thiabendazole (TBZ) in diet at levels of 0 (control), 0.031, 0.125 and 0.5% for 78 weeks. A life time study was terminated after 78 weeks due to enhanced strain specific mortality. There were no significant differences in mortality between the control and treated groups. Mean body weights of high-dose groups showed significant decreases compared with the controls. The bladder weights of male and female mice of the 0.5% group were significantly higher than those of the control mice. Gross findings in treated mice included the renal atrophy, hydronephrosis, calculi in renal pelvis and/or bladder and ovarian atrophy. Microscopic findings in the kidneys of treated mice included the nephrosis, hydronephrosis or hyperplasia of transitional epithelium of renal pelvis or papilla. In the bladder of treated mice, hyperplasia or squamous metaplasia of transitional epithelium and one transitional cell papilloma were observed. Dose-dependent decreases in the incidence of spontaneous lesion in the male or female reproductive system were recognized. It is concluded that TBZ is not carcinogenic to CD-1 mice of both sexes. However, caution should be exercised in the long-term application of high TBZ doses.

Protection against Fas-mediated and tumor necrosis factor receptor 1-mediated liver injury by blockade of FADD without loss of nuclear factor-kappaB activation.

OBJECTIVE: To investigate the role of FADD (Fas-associated protein with death domain) in Fas and tumor necrosis factor receptor 1 (TNFR1)-mediated hepatic injury and inflammatory response in vivo. SUMMARY BACKGROUND DATA: Fas and TNFR1 are cell surface molecules that trigger apoptosis or inflammation on engagement by a specific ligand or antibody. FADD is recruited to the cytoplasmic domain of these receptors on their activation and works as a common mediator to induce apoptosis. It is known that a blockade of FADD can inhibit apoptosis mediated by Fas or TNFR1 in vitro. However, it is not known whether the blockade can prevent organ injury and whether the inflammatory cascade is affected in vivo. METHODS: A FADD deletion mutant lacking the death effector domain was introduced into mice by transduction with an adenovirus vector, and the effect of this FADD dominant negative mutant was examined in several liver injury models. RESULTS: Hepatic injury induced by anti-Fas monoclonal antibody or tumor necrosis factor (TNF)-alpha plus D-galactosamine was markedly ameliorated by the FADD dominant negative transduction, which abrogated the death rate. Further, the FADD dominant negative transduction efficiently blocked T cell- mediated concanavalin A-induced hepatitis while not affecting TNF-alpha production or TNF-alpha-induced nuclear factor-kappaB activation in the liver. CONCLUSIONS: These results provide the basis for a novel therapeutic modality in which an unfavorable apoptotic process can be inhibited without affecting a favorable response for liver regeneration; this would be relevant to the clinical treatment of acute and chronic liver diseases as well as to some inflammatory disorders with hypercytokinemia, such as sepsis.

Utility of serum CA 19-9 monitoring in preoperative radiotherapy for pancreatic cancer.

BACKGROUND/AIMS: Pancreatic cancer is extremely refractory even to aggressive treatments including surgery, resulting in early metastasis and/or local recurrence. We investigated changes in serum tumor marker CA 19-9 levels during preoperative radiotherapy in conjunction with initial treatment failure. METHODOLOGY: Twenty-three patients presenting with localized disease and an increased serum CA 19-9 level, who were slated to undergo pancreatectomy and/or intraoperative radiotherapy following preoperative radiotherapy were reviewed. CA 19-9 response, the ratio of post-radiotherapy level before laparotomy to pre-radiotherapy level, was analyzed in relation to disease-control time and survival. RESULTS: Eleven patients revealed metastasis at restaging or laparotomy; 12 patients (52%) completed aggressive treatments. Initial failure was identified at the liver (52%), peritoneum (52%), or local site (26%) with a median disease-control time of 91 days; 7 patients showed combined failure. All but 1 patient died of cancer with a median survival time of 264 days. CA 19-9 response (range: 0-1185%) did not correlate with disease-control time or survival; 8 progressive-disease patients (> 140% response), however, showed significantly shorter disease-control time than 15 nonprogressive-disease patients (< or = 140% response). CONCLUSIONS: CA 19-9 monitoring is useful in preoperative radiotherapy for identifying patients who will not benefit by succeeding aggressive treatments by predicting early metastasis.

Thiabendazole induces urinary tract toxicity in male ICR mice.

Male ICR mice were administered thiabendazole (TBZ) in the diet at concentration of 0 (control), 0.8, 1.2 and 1.6% for 44 weeks. The mortality was 10, 6, 40 or 90% in control, 0.8, 1.2 or 1.6% TBZ group, respectively. In dead mice, the gross findings included the abnormalities of kidney such as atrophy, hydronephrosis or swelling in 2, 67, 95 or 96% of the 0, 0.8, 1.2 or 1.6% TBZ group, respectively. In surviving mice at the end of study, the right kidney weight of treated groups was significantly lower than that of control group. The urinary bladder weight of treated groups was significantly higher than that of control group. Gross findings in treated mice included the renal atrophy, hydronephrosis, calculi in renal pelvis or urinary bladder and thickening of the bladder wall. Microscopic findings in the kidneys of treated mice included nephrosis, hydronephrosis and hyperplasia of transitional epithelium of renal pelvis and/or papilla. In the urinary bladder, hyperplasia or squamous metaplasia of transitional epithelium were found in treated mice. Administration of TBZ in the diet for 44 weeks results in nephrosis and calculus formation in the renal pelvis and urinary bladder of male ICR mice, and is associated with hyperplasia of transitional epithelium of renal pelvis or urinary bladder.

Hepatic resection for metastatic tumors from noncolorectal carcinoma.

BACKGROUND/AIMS: The role of liver resection for hepatic metastases from noncolorectal carcinomas has yet to be clarified. The present study examines a single institutional experience of hepatic resection for noncolorectal metastases. METHODOLOGY: From January 1987 to March 1999, 14 patients underwent curative resection for liver metastases from noncolorectal carcinomas. Records of these patients were reviewed. RESULTS: Resections were performed for liver metastases from gastric cancers (n = 8), pancreatic cancers (n = 2), and cancers of bile duct, the papilla of Vater, kidney, and breast (n = 1, each). Six patients (5 with gastric cancers and 1 with pancreas cancer) presented with synchronous disease and 8 with metachronous disease. In the gastric cancer patients, there are 2 disease-free survivors (26 and 53 months) in the metachronous group, though all of the 5 patients with synchronous disease died within 29 months. All of the 4 patients with pancreatobiliary carcinomas died within 2 years. One case of breast cancer and another of renal cell cancer are alive without disease at 49 and 9 months, respectively. CONCLUSIONS: For metastases from gastric cancers, better survival after hepatic resection is expected in metachronous cases than in synchronous cases. Hepatic resection may afford little benefit for patients with liver metastases from pancretobiliary cancers.

Role of platelet-activating factor in hepatectomy with Pringle's maneuver.

BACKGROUND: Interruption of hepatic inflow is commonly used to reduce blood loss during extensive liver resection, but may cause liver dysfunction. The present study investigated the effects of platelet-activating factor (PAF) antagonist E5880 on total liver warm ischemia and 70% hepatectomy. METHODS: Rabbits were used in this study and were divided into four groups: group 1, those treated with only 70% hepatectomy; group 2, those treated with only 20 min Pringle's maneuver; group 3, those treated with both Pringle's maneuver and 70% hepatectomy without pretreatment; and group 4, those pretreated with PAF antagonist E5880 (0.3 mg/kg) followed by Pringle's maneuver and 70% hepatectomy. The remnant liver function was then evaluated after reperfusion. RESULTS: Seven-day survival rates in both groups 1 and 2 were 100%. E5880 treatment significantly increased 7-day survival rate (group 4: 38% vs group 3: 0%, P < 0.05) after a combination of Pringle's maneuver and 70% hepatectomy. The elevations of serum liver enzymes (GOT, GPT, mGOT, and LDH) were significantly inhibited in group 4 at 1 and 4 h after reperfusion. Portal venous pressure and the energy charge of liver were also significantly improved in group 4, compared with those in group 3. Endothelin-1 levels of arterial and portal venous blood progressively increased after reperfusion; however, there were no significant differences between the two groups. Leukocyte infiltration into the liver was significantly inhibited in group 4. CONCLUSION: E5880 pretreatment has protective effects on liver function after 70% hepatectomy with Pringle's maneuver in rabbits.

Goitrogenic effects of green tea extract catechins by dietary administration in rats.

The effects of green tea extract catechins on the rat thyroid were examined in a 13-week feeding study and subsequent 2-,4- and 8-week studies. Commercially available polyphenon-60 (P-60) which contains green tea extract catechins at 66.2% was used as a source of catechins. A basic diet containing different concentrations of P-60 was used for experiments. In the 13-week study, 10 rats of each sex were administered diets containing P-60 at 0 (control), 0.625, 1.25, 2.5 and 5.0%. Goiters were observed in the 13-week test. The mean thyroid weight of rats fed a diet containing 5.0% of P-60 (5.0% group) significantly increased to 444% of the control in males and to 304% of the control in females. Histological examinations of the thyroid of the 5.0% group revealed marked hypertrophy and/or hyperplasia of the follicles, some with depletion of colloid and some with rich colloid, and formation of a fibrous capsule. Slight hypertrophy of follicular cells was observed in male rats fed a diet containing 1.25% of P-60 (1.25% group) and female rats fed a diet containing 2.5% of P-60 (2.5% group). Degree and incidence of thyroid lesions were higher in males than in females in the 1.25, 2.5 and 5.0% groups. In the 2-8-week studies, five rats of each sex were given diets containing 0 (control) and 5.0% of P-60. In the 5.0% group, the mean thyroid weight in males significantly increased to 161% of the control as early as 2 weeks and increased to 357% of the control at 8 weeks. Histologically, these goiters were also associated with follicular cell hypertrophy/hyperplasia as in the 13-week study. The degree and incidence of thyroid lesions were higher in males than in females. These results indicate that dietary administration of the green tea extract catechins at high doses induced goiters in rats, and this may be due to antithyroid effects of catechins. In the 13-week study, the no-observed effect level (NOEL) of green tea extract catechins for F344 rats based on histological changes of the thyroid was considered to be 0.625% in males and 1.25% in females in the diet, respectively.