Guideline adherence by physicians for management of glucocorticoid-induced osteoporosis in Japan: a nationwide health insurance claims database study.

Risk of fracture due to glucocorticoid-induced osteoporosis (GIO) can be reduced by anti-osteoporosis (OP) medications. The proportion of patients on long-term glucocorticoid therapy who received anti-OP medications according to the GIO management guidelines has increased in recent years, but is still suboptimal. INTRODUCTION: Adherence of physicians to guidelines for glucocorticoid (GC)-induced osteoporosis (GIO) management is currently unclear. This study aimed to clarify the state of guideline adherence by physicians in Japan and identify factors associated with guideline adherence using a nationwide health insurance claims database (NDBJ). METHODS: Patients aged ≥ 50 years who were prescribed GC for ≥ 90 days after 180 days without a GC prescription and who were followed up for osteoporosis (OP) management for the subsequent 360 days during the period spanning 2012-2018 were selected from the NDBJ. Guideline adherence was evaluated with the proportion of patients who received OP management as recommended by the Japanese guidelines. Information on previous vertebral and hip fractures, dementia, and polypharmacy was obtained. Factors associated with OP management were evaluated by logistic regression analysis. RESULTS: A total of 512,296 patients were considered to be at high risk of fracture according to the guidelines. Proportions of patients receiving OP management (BMD testing or anti-OP medications) have increased in recent years. In 2017, 33.7% of men and 55.3% of women received OP management in the initial 90 days of GC therapy. Female sex, previous anti-OP medications, polypharmacy, and higher GC dose were significantly associated with receiving OP management, while dementia showed an inverse association. A prior history of hip fracture, a strong risk factor for future fracture, was not significantly associated with receiving OP management. CONCLUSIONS: Although guideline adherence by physicians has increased in recent years, it remains suboptimal. Further efforts to improve guideline adherence are necessary. TRIAL REGISTRATION NUMBER: The present study is not registered.

Estimates of hip fracture incidence in Japan using the National Health Insurance Claim Database in 2012-2015.

Using the nationwide health insurance claims database, we found that the age-standardized hip fracture incidence rates in Japan indicated significant increase in males but no significant change in females during 2012-2015. The fracture risk in subjects aged 75-84 years indicated decrease in females but no change in males. INTRODUCTION: Nationwide registry data on hip fractures have not yet been established in Japan. Using the newly developed National Database of Health Insurance Claims (NDB), which covers the entire Japanese population, we investigated the incidence rates of hip fractures and the associated regional differences. We also assessed the frequency of osteoporosis prescriptions, bone turnover marker (BTM) level, and bone mineral density (BMD) measurements. METHODS: The annual numbers of hip fractures, osteoporosis prescriptions, and BTM level and BMD measurements by prefecture from 2012 to 2015 were obtained from NDB data. We calculated the standardized claims-data ratio (SCR) in each prefecture. RESULTS: The age-standardized incidence rates from 2012 to 2015 indicated no significant change in females and significant increase in males (p value for trend; 0.920, 0.002, respectively). The fracture risk decreased in females aged 75-84 years and indicated no increase in females aged 85-89 years during 2012-2015, while the fracture risk indicated no change in males aged 75-84 years and increased in males aged 85-89 years. The frequency of osteoporosis prescriptions, BTM level measurements, and BMD measurements in the general population in the corresponding period increased with statistical or marginal significance in females and males. West-east regional differences were observed in the incidence rates; the highest SCR values in the western prefectures were approximately double the lowest values in the eastern prefectures. CONCLUSIONS: The age-standardized hip fracture incidence rates indicated no significant change in females and significant increase in males in Japan from 2012 to 2015.

Lymphoepithelioma-like carcinoma of the uterine cervix: a case report.

Lymphoepithelioma-like carcinoma (LELC) is a rare variant of carcinoma of the uterine cervix, of which Epstein-Barr virus (EBV) and/or human papilloma virus (HPV) may play an important role in the pathogenesis. The authors report a case of a patient with cervical LELC who was also examined for the presence of EBV and HPV. A 31-year-old Japanese female presented with irregular genital bleeding. The biopsy showed an invasive squamous cell carcinoma. Based on the clinical data, the patient was diagnosed as having squamous cervical carcinoma, and radical hysterectomy with ovarian conservation was performed. A diagnosis of cervical LELC was then made by histological methods. An additional examination revealed that the patient was infected with HPV types 16 and 71, but not infected with EBV.

Malignant mixed Müllerian tumor of the fallopian tube: a case report.

Malignant mixed Müllerian tumor (MMMT) of the female genital tract is uncommon and extremely rare in the Fallopian tube. We describe a case of primary MMMT of the Fallopian tube with carcinomatous and heterologous mesenchymal components in a 60-year-old woman. The patient underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, infracolic omentectomy, pelvic and paraaortic lymph node dissection, and resection of intrapelvic metastases. The tumor formed a large polypoid mass within the right Fallopian tube and had penetrated the wall to the paraovarian space. Microscopic examination revealed two components of poorly differentiated adenocarcinoma and high-grade sarcoma with chondromatous differentiation. The patient received six courses of adjuvant chemotherapy with ifomide and cisplatin and is currently in remission. Although MMMT in the Fallopian tube shows poor prognosis, primary cytoreductive surgery with platinum-based combination chemotherapy may improve survival.

Identification of a novel prostaglandin f(2alpha) synthase in Trypanosoma brucei.

Members of the genus Trypanosoma cause African trypanosomiasis in humans and animals in Africa. Infection of mammals by African trypanosomes is characterized by an upregulation of prostaglandin (PG) production in the plasma and cerebrospinal fluid. These metabolites of arachidonic acid (AA) may, in part, be responsible for symptoms such as fever, headache, immunosuppression, deep muscle hyperaesthesia, miscarriage, ovarian dysfunction, sleepiness, and other symptoms observed in patients with chronic African trypanosomiasis. Here, we show that the protozoan parasite T. brucei is involved in PG production and that it produces PGs enzymatically from AA and its metabolite, PGH(2). Among all PGs synthesized, PGF(2alpha) was the major prostanoid produced by trypanosome lysates. We have purified a novel T. brucei PGF(2alpha) synthase (TbPGFS) and cloned its cDNA. Phylogenetic analysis and molecular properties revealed that TbPGFS is completely distinct from mammalian PGF synthases. We also found that TbPGFS mRNA expression and TbPGFS activity were high in the early logarithmic growth phase and low during the stationary phase. The characterization of TbPGFS and its gene in T. brucei provides a basis for the molecular analysis of the role of parasite-derived PGF(2alpha) in the physiology of the parasite and the pathogenesis of African trypanosomiasis.

The new strategy of liver transplantation from marginal donors using serine protease inhibitor.

OBJECTIVES: The purpose of this study was to establish a safe technique to procure liver grafts from marginal donors such as non-heart-beating donors (NHBD). MATERIALS AND METHODS: Male Wistar rats were divided into five groups: (1) heart-beating (HB) group, livers were retrieved from HB donors; (2) non-HB (NHB) group, livers were retrieved from uncontrolled NHBD that had experienced the apnea-induced agonal condition; (3) nafamostat mesilate (NM) group, livers retrieved in the same manner as NHBD but pretreated with NM (0.2 mg/kg/h for 30 minutes); (4) prostaglandin I2 (PG) group, livers retrieved in the same manner as NHBD but pretreated with the (33 ng/kg/h, for 30 minutes); (5) NM + PG group, livers retrieved the same manner as NHBD but pretreated with NM and PG. After 1-hour cold preservation, the organs were transplanted according to Kamada's method. We examined aspartate transferase (AST) alanine transferase (ALT), lactate dehydrogenase, interleukin-1 beta, tumor necrosis factor-alpha, and thromboxane B2 (TXB2) at 24 hours after transplantation. We also performed histological examinations using electron microscopy. RESULTS: The number of survivors at 7 days after liver transplantation among the groups were 9/9, 0/9, 1/9, 1/9, and 3/9. The values of AST, ALT, and lactate dehydrogenase at 24 hours after transplantation in the NM + PG groups were slightly lower than those in the NHB group, but there were no significant differences among those groups. On the histological examination, the NM + PG group showed well-preserved sinusoidal endothelial cells. CONCLUSION: The strong serine protease inhibitor, NM, and PG may support sinusoidal endothelial cells, a promising strategy for liver transplantation from marginal donors.

The influence of brain death on tissue factor expression in the pancreatic tissues and isolated islets in rats.

INTRODUCTION: Tissue factor (TF) in islets has been identified as the main trigger of the instant blood-mediated inflammatory reaction. Because the crucial events that directly induce TF remain to be determined, we focused on the influence of brain death (BD) on TF expression in pancreatic tissues and isolated islets. MATERIALS AND METHODS: BD was induced in male Lewis rats weighing 250-300 g by inflation of a Fogarty catheter placed intracranially. The rats were mechanically ventilated for 6 hours until removal of the pancreas. The expression of TF protein in pancreatic tissues was examined using Western blotting assay. Messenger RNA (mRNA) expressions of TF in pancreatic tissue and isolated islets were analyzed using real-time polymerase chain reaction (PCR) assay. The influence of BD on the isolation outcome was evaluated by islet yield, purity, viability, and function. RESULTS: TF protein and mRNA levels in the pancreatic tissues were similar between the groups. However, TF mRNA in the isolated islets of the BD group was significantly greater than that of the control group (P = .04). Islet yield was considerably lower, and purity significantly lower in the BD than the control group (P = .002). Unexpectedly, ATP/DNA ratio and respiratory activity were comparable between the groups. CONCLUSIONS: Although BD per se was not sufficient to induce TF expression in pancreatic tissues, BD combined with subsequent warm ischemic damage during isolation procedures remarkably up-regulated TF expression in isolated islets, suggesting that BD is of great importance as an initiator of TF induction in the islet grafts. The present study demonstrated that the expression of inflammatory mediators rather than islet viability is more susceptible to BD.

C5a inhibitory peptide combined with gabexate mesilate is a clinically available candidate for preventing the instant blood-mediated inflammatory reaction.

BACKGROUND: The instant blood-mediated inflammatory reaction, characterized by activation of both the coagulation and complement cascades, is a serious obstacle to successful islet engraftment. No attractive protocol is clinically available as yet. The objective of the present study was to examine whether complementary peptide against an active region of C5a in combination with a clinically available anticoagulant could provide an effective protocol for suppression of the instant blood-mediated inflammatory reaction. METHODS: Three islet equivalents per gram of syngeneic rat grafts were transplanted intraportally into 6 pairs of rats with streptozotocin-induced diabetes. Islets from the same donor were transplanted into each pair. In each pair, one rat was treated with C5a inhibitory peptide in addition to continuous intravenous infusion of gabexate mesilate and the other rat, injected with equivalent amount of saline solution, served as the control. In addition, 6 rats that received transplants from irrelevant donors were treated with the same dose of gabexate mesilate. We evaluated the cure rate, time to normoglycemia, liver insulin concentration in recipients, and results of in vivo glucose tolerance tests. RESULTS: The cure rate was remarkably improved and the time to normoglycemia in cured animals was significantly shortened with C5a inhibitor plus gabexate treatment. In six rats that received only gabexate mesilate, normoglycemia was not restored during the study. CONCLUSIONS: These data suggest that C5a inhibitory peptide combined with gabexate mesilate could be an attractive drug candidate without adverse effects to control the detrimental innate immune responses induced in clinical islet transplantation.

Superiority of fresh islets compared with cultured islets.

INTRODUCTION: It has recently been reported that the outcomes of islet transplantation with short periods of culture are comparable with those of freshly isolated islets. To clarify the influence of culture, fresh islets were compared with cultured islets in terms of quality. MATERIALS AND METHODS: The quality of freshly isolated islets was compared with that of cultured islets with CMRL 1066 including 10% allogeneic serum, CMRL 1066 including 0.5% human serum albumin, or Miami medium. We evaluated static glucose stimulation tests, insulin/DNA contents, ADP/ATP ratios, and an intraportal transplantation model into syngeneic diabetic rats. The expression of inflammatory mediators in the islets was examined using Western blotting for tissue factor (TF), which is the initiator of detrimental instant, blood-mediated, inflammatory reactions (IBMIR). RESULTS: Although the survival rate was similar in all groups, the stimulation index upon glucose challenge and the insulin/DNA ratio were significantly higher among fresh islets. Most importantly, the expression of TF on islets was significantly lower in fresh islets, suggesting that culture enhanced TF-dependent IBMIR after transplantation. In an in vivo transplantation model, the curative rate and insulin production by the recipient liver was considerably greater in the fresh islet group. CONCLUSIONS: Isolated islets without prior culture showed results superior to cultured islets.

The use of recipient superficial femoral vein as a venous graft for portal vein reconstruction in right lobe living donor liver transplantation.

In living donor liver transplantation (LDLT), portal vein thrombosis (PVT) in the recipient is frequently regarded as a contraindication. To reconstruct the PV of a right-lobe liver graft (RLG) using an interposition or jump graft from the splenomesenteric junction, various vein grafts and technical modifications have been introduced. The internal jugular, external iliac, or great saphenous veins have been utilized in such reconstructive procedures. However, the superficial femoral vein (SFV) is preferable to the autologous vein grafts in terms of caliber, wall thickness, and length. We employed the recipient SFV to reconstruct PVT among 40 adult LDLT using RLG. Thirty-three were reconstructed by single end-to-end anastomosis with the right or left recipient PV. Three patients were transplanted with a RLG using 2 separated PVs reconstructed by double anastomoses with both the right and left PVs of the recipient. The remaining 4 patients required venous grafting for portal reconstruction. We used the recipient SFV as an interposition or jump graft from the splenomesenteric junction to the graft PV. There were 2 cases of anastomotic PV stenosis; 1 in portal reconstruction without a venous graft and the other with a SFV graft. Both were treated successfully by balloon angioplasty. The recipient SFV is an excellent size match for the PV reconstruction as a long interposition or jump conduit when the venous system from the deceased donor is not available. The indication for LDLT in patients with complete PVT should be carefully decided before transplantation in terms of portal reconstruction.

Management of living donor liver transplant patients using twice-daily 4-hour intravenous cyclosporine therapy.

Oral administration of cyclosporine (CsA) is the currently favored route in most liver transplant centers. From October 1998 to January 2008, 86 living donor liver transplantations (LDLTs) were performed in 85 patients (46 adults and 39 children) at our institution. Seventy-three patients received tacrolimus (Tac), and 12 intravenous CsA twice daily at a dose of 3 mg/kg/d as a 4-hour continuous infusion. Thirteen of 73 Tac-based patients were switched to CsA because of side effects. Five were switched to intravenous CsA because they were unable to take the drug orally because of severe Tac-related complications. The remaining eight patients switched to oral CsA. We evaluated patients (11 adults and three children), including 12 with induction therapy and two with conversion therapy within 2 weeks of LDLT. The patients were given a 4-hour intravenous infusion of CsA at an initial dose of 3 mg/kg/d. Stable and adequate blood CsA concentrations were achieved by 4-hour intravenous CsA administration. Among several factors, only graft-to-recipient weight ratio (r = .743, P < .0001) showed significant correlations with initial blood CsA concentration. No adverse effects were observed after intravenous CsA. No patients developed biopsy-proven acute cellular rejection (ACR) during intravenous CsA administration, whereas two patients had histopathologically diagnosed episodes of ACR after conversion from intravenous to oral CsA. Our findings suggest that immediate administration of a 4-hour intravenous infusion of CsA at an initial dose of 3 mg/kg/d is practical and effective for routine clinical use.

A novel predictive method for assessing the quality of isolated pancreatic islets using scanning electrochemical microscopy.

INTRODUCTION: The current methods for evaluating islet potency are not useful in clinical transplantation. Therefore, we need reliable, rapid methods enabling accurate prediction of islet quality. MATERIALS AND METHODS: We evaluated respiratory activity using scanning electrochemical microscopy (SECM), glucose-stimulated respiratory activity, glucose-stimulated insulin release, ADP/ATP assays, insulin/DNA levels, and Trypan blue exclusion tests as predictive methods for the ability of isolated rat islets to cure syngeneic diabetic rats. RESULTS: Although glucose-stimulated respiratory activity, basal respiratory activity, ADP/ATP ratio, and glucose-stimulated insulin release were significantly correlated with the outcome of transplantation into diabetic rats, there was no correlation between outcomes, insulin/DNA ratios, and Trypan blue exclusion tests. The glucose-stimulated respiratory activity in islet preparations that could cure diabetic rats was significantly greater than those unable to cure diabetes. Rat islets with >1.5-fold glucose-stimulated respiratory activity consistently cured diabetic rats, whereas those with a value <1.5 hardly cured any rats. CONCLUSION: Measurement of the glucose-stimulated respiratory activity using SECM technique is a novel method that may be useful as a rapid, potent predictor of the outcome of clinical islet transplantation.

Effects of serine protease inhibitor and prostaglandin I2 on liver transplantation from non-heart-beating rat donors.

OBJECTIVES: We sought to preserve the microcirculation as a keystone in liver transplantation from a non-heart-beating donor (NHBD). The purpose of this study was to investigate the cytoprotective effects of a serine protease inhibitor, nafamostat mesilate, and prostaglandin I2 (PGI2) on livers transplanted from NHBDs. METHODS: Male Wistar rats were used in five groups of nine rats each. In group 1, livers were retrieved from heart-beating donors (HB group); in group 2, livers were retrieved from NHBDs that had experienced agonal apnea (NHB group); in group 3, livers were retrieved in the same manner as in the NHBD group but were pretreated with nafamostat mesilate (NM), 0.2 mg/kg/h, (NM group); in group 4, livers were retrieved in the same manner as in the NHBD group but were pretreated with prostaglandin (PG) I2, 33 ng/kg/h for 30 minutes (PG group); and in group 5, livers were retrieved in the same manner as in the NHBD group but were pretreated with NM plus PG, (NM+PG group). Livers were perfused for 60 minutes with Krebs-Henseleit bicarbonate buffer after 6 hours of cold preservation, after which the perfusate and liver tissue were analyzed in one set of experiments. In another set of experiments, livers retrieved and after 1 hour of cold preservation were transplanted according to the Kamada method. RESULTS: In the NM+PG group, the values of interleukin-1beta, tumor necrosis factor-alpha, and thromboxane B2 were significantly lower than those in the NHB group. At histologic analysis, sinusoidal endothelial cells were well preserved in the NM+PG group. The number of survivors at 7 days after liver transplantation in the 5 groups were 9, 0, 1, 1, and 3, respectively. CONCLUSION: The serine protease inhibitor, NM, and PGI2 supported sinusoidal endothelial cells and preserved microcirculation.

Microsurgical back wall support suture technique with double needle sutures on hepatic artery reconstruction in living donor liver transplantation.

OBJECTIVES: In living-donor-liver transplantation (LDLT), microsurgical reconstruction of the hepatic artery is an essential but challenging issue. Especially using a living donor graft, the hepatic artery is short, the intimal damage may be severe, and the usable vessel grafts are limited compared with cadaveric donors. Thus, sometimes it is difficult to use a conventional twist reconstruction technique in which one needs to turn over the hepatic artery. METHODS: To overcome these difficulties, we began to use a back wall support suture technique. From July 1991 to June 2007, we performed 110 LDLTs. In 87 cases, we used the conventional twist technique. In the most recent 23 cases, we used a back wall support suture technique. To put it briefly, we placed 2 sutures at the deepest, most difficult points in the artery for backside support. Each stitch was placed from the inner side of the arterial wall to the outer side with double needle sutures. The subsequent sutures were placed forward on either side adjacent to the previous suture. RESULTS: The total ratio of hepatic artery thrombosis (HAT) was 8.2% (9/110). In the conventional twist technique group, HAT occurred in 8 cases (9.2%). In the new technique group, it occurred in only 1 case that had an intimal dissection in the recipient artery (4.3%). Thus there was no HAT associated with the arterial anastomosis in the new technique group. CONCLUSION: Our technique allows for safe intimal adaptation without turning over the artery. In conclusion, this back wall support suture technique may contribute to more satisfactory results.

Parkinsonism during cyclosporine treatment in liver transplantation: an unusual case report.

OBJECTIVES: Cyclosporine (CyA) has been associated with various neurological reactions but parkinsonism is not generally recognized as a nervous system side effect. We describe herein a rare case, in that the patient developed parkinsonism with rest tremor after receiving CyA following orthotopic liver transplantation (OLT). METHODS: The patient was a 42-year-old man who had liver cirrhosis with hepatitis C. We performed OLT because of liver failure and started immunosuppressive therapy with CyA + methylprednisolone + CD25 antibody. Ten days after OLT, he developed parkinsonism with a rest tremor. The patient did not have a pre-existent neurological disorder, and had not received significant amounts of dopamine-blocking drugs. RESULTS: We administered levodopa with marked improvement. Three days after that event, the neurologist suggested the possibility of drug-induced parkinsonism. We converted the immunosuppressive drug from CyA to tacrolimus. After that, the symptom disappeared. At 75 days after OLT, he was discharged with no neurological medication and now he is completely recovered. CONCLUSION: We think that parkinsonism may be an occasional consequence of CyA because of its relation to withdrawal of the drug and the lack of another evident cause.

Influence of a current style of culture on the quality of isolated pancreatic islets.

OBJECTIVE: Comparable outcomes of islet transplantation with short periods of culture may be achieved with various culture media. To clarify the influence of a style of culture on isolated pancreatic islets, islet quality of fresh islets was compared with those cultured in several different fashions including not only for viability but also for inflammatory mediators. MATERIALS AND METHODS: Wistar rat islets were cultured for 48 hours with CMRL including 10% allogeneic serum; CMRL including 0.5% human serum albumin (HSA); and Miami medium including 0.5% HSA. The influence of culture conditions on islet integrity was evaluated by survival rate of islets during culture and visual scoring. The influence of culture conditions on islet function and viability was examined by ADP/ATP tests, insulin/DNA content, and glucose stimulation tests. RESULTS: Although the survival rates were similar for all groups, the visual scoring was lower in Miami medium. The stimulation index in glucose challenge tests was higher for fresh islets than the media (P = .02). Insulin/DNA ratios revealed the same tendency as glucose challenge tests (P = .0005). ADP/ATP ratio was lower in both the fresh and serum groups than in the others (P = .38), suggesting that apoptotic islets are relatively fewer in both fresh and serum groups. Most importantly, the expression of tissue factor (TF) on the islets was considerably lower in the fresh group, suggesting that a current style of culture could enhance TF-dependent instant blood-mediated inflammatory reactions after transplantation. CONCLUSION: In conclusion, Isolated islets without prior culture shows characteristics beneficial for transplantation using current modes of culture.

Optimization of a prominent oxygen-permeable device for pancreatic islets.

BACKGROUND: We have demonstrated a culture bag system that is useful for pancreatic islet transplantation. To improve and simplify islet transplantation procedures from culture to transplantation, we developed a novel device specific for both islet culture and transplantation (TUBERO Device [TD]) using an oxygen-permeable material. MATERIALS AND METHODS: Porcine islets with 30 minutes warm ischemia time were cultured for 24 hours at 37 degrees C in 5% CO2 and humidified air under three different procedures: (1) ordinary culture flask, (2) culture bag suitable for platelets, and (3) TD. Loss of islets during culture, glucose-stimulated insulin release as an islet functional test, and ADP/ATP ratio as an index of islet viability tests were evaluated to compare the devices. TD was further applied in two clinical islet transplantations using non-heart-beating donors in Japan. RESULTS: The loss of islets during culture was considerably lower in the TD group. The stimulation index upon glucose challenge tests was significantly higher in the TD group than the others. The ADP/ATP ratio in TD group was significantly lower than that in the ordinary flask group, suggesting that the apoptotic islets were relatively lower among TD. Most importantly, TD was successfully applied both in the clinical islet cultures and in transplantation, resulting in excellent graft function. CONCLUSIONS: We propose that the TD, a novel product, not only simplifies islet transplantation procedures, but also maintain the quality of isolated islets.

Determination of weathering rate of the Morro do Ferro Th-REEs deposit, Brazil using U-isotope method.

The weathering rate was estimated by changes in (234)U/(238)U activity ratio (AR) and U content of rocks, borehole spoil and surface water samples at the Morro do Ferro Th-REEs deposit. The deposit is situated in the Poços de Caldas alkaline massif, Brazil. The south stream basin investigated in this paper has not been significantly affected by anthropogenic inputs of pollutants as compared to the Corumbataí River basin in São Paulo State, where the method was previously applied. The weathering rate derived utilizing the U-isotopes modeling corresponded to 0.015 mm/yr (67,000 years to weather 1m of rock under the actual climatic conditions). The estimated rate is very reasonable in comparison with the range of 0.015-0.05 mm/yr of land surface lowering within the entire caldera. It is also compatible with a rate of 0.013 mm/yr determined for the Salgado River basin in a semi-arid region in Bahia State, Brazil. The value generated is reliable and increases the potential use of the method for other different areas in Brazil and elsewhere, because it may be used in regions with different climatic conditions and (un)polluted basins.

Continuous low-dose human atrial natriuretic peptide promotes diuresis in oliguric patients after living donor liver transplantation.

Human atrial natriuretic peptide (ANP) is beneficial for the prophylaxis of acute renal failure (ARF) after liver transplantation (OLT). We evaluated renal function in OLT patients with or without ARF, describing cases unresponsive to loop diuretics successfully treated with continuous low-dose ANP infusion without hemodialysis. Twenty-seven consecutive adult-to-adult living donor liver transplantations (LDLTs) were performed in 26 patients. One case was excluded due to the need for continuous hemodialysis (HD) during the operation. Of the 26 cases, 6 (23%, group 2) developed ARF in the first 30 days after LDLT; the other 20 were ARF-free (group 1). The median follow-up was 24 months. No patient required either continuous or intermittent HD. Only one patient died due to multiple liver abscesses. Mean preoperative serum creatinine (sCr) value and intraoperative blood loss in group 2 were significantly higher than those in group 1. Three cases in group 2 failed to improve on high-dose loop diuretics with low-dose dopamine, exhibiting fluid overload. The remaining three cases in group 2 responded to conventional diuretic treatments. Continuous low-dose ANP was started 2, 4, or 5 days after LDLT, and urine output significantly increased after ANP administration. The serum creatinine values were 1.1, 1.2, and 1.1 at 1 month and 1.0, 0.9, and 0.6 mg/dL at 6 months after LDLT. Massive blood loss during the operation caused ARF, but did not affect renal function after LDLT. Continuous low-dose ANP improved renal function and diuresis for oliguric ARF patients, preventing the need for HD or continuous venovenous hemodialysis.

An analysis of monoclonal antibody distribution in microscopic tumor nodules: consequences of a "binding site barrier".

Rational in vivo application of monoclonal antibodies for diagnosis and therapy of cancer requires an understanding of both the global and microscopic pharmacology of macromolecular ligands. Here, we introduce a new mathematical model for antibody distribution into small, prevascular, densely packed nodules (representing either primary or metastatic tumor). For the analysis, we link together several aspects of antibody pharmacology: the global (whole body) pharmacokinetics; transcapillary transport into normal tissue interstitium surrounding the nodule; diffusion into the nodule; nonspecific binding and/or partitioning; specific binding to tumor antigen; metabolism; and lymphatic outflow from the tissue space. Input parameter values are estimated from experimental studies in vitro, in animals, and in clinical trials. Our aim is to explore the sensitivity of antibody localization to variation in three of the important parameters of this model: the rate of transcapillary transport; the rate of lymphatic outflow; and the antigen density. Predictions based on this analysis include the following: (a) High rates of transcapillary transport influx or low rates of lymphatic efflux will enhance antibody percolation into the tumor nodule at early times after injection and increase the average antibody concentration in the tumor at all times; (b) Changes in antibody influx rate will affect the antibody distribution in the tumor at earlier times than do changes in the efflux rate; (c) Reducing the antigen concentration will increase the uniformity of antibody penetration but lower the average concentration in the tumor at all times after injection; and (d) Counter to intuition, lowering the antigen concentration can increase the peak concentrations achieved toward the center of the nodule. If, in addition, there is any metabolism of bound antibody, the concentration-time integral (i.e., the "area under the curve") for the center of the nodule will also be increased by decreasing the antigen concentration. These predictions directly reflect the "binding site barrier" hypothesis of Weinstein et al. (Ann. NY Acad. Sci., 507: 199-210, 1987) and Fujimori et al. (Cancer Res., 49:5656-5663, 1989; J. Nucl. Med., 31:1191-1198, 1990). In general, and perhaps surprisingly until one considers the problem carefully, the parameters governing antibody percolation can have opposite effects on the uniformity of antibody distribution at early and late times. These calculations, using the PERC program set, were done for antibodies, but we believe that the "binding site barrier" will also prove important for other injected macromolecules, for at least some highly bindable injected small molecules, for lymphokines and cytokines released from transfected cells injected in vivo, and, indeed, for endogenous species such as the autocrine-paracrine factors.