Histological factors of 1-h biopsy influencing the delayed renal function and outcome in cadaveric renal allografts

The morphological characteristics of a kidney biopsy specimen taken 1 h after reperfusion of blood into the graft (1-h biopsy) during a cadaveric transplant operation were studied. The aim of the 1-h biopsy is to evaluate the pre-transplant risk factors for the delayed graft function, assess the renal function of the graft, and predict long-term graft survival. The total number of 1-h biopsies was 113, consisting of 86 male and 27 female donors. The mean age of the donors is 39.5 +/- 17.3 yr. Arteriosclerosis (AS) and tubulo-interstitial injury (TI) were both estimated using a semi-quantitative scale. AS score was graded into four categories, according to the severity of the thickening of interlobular artery: 0: none, 1: mild, 2: moderate and 3: severe. No biopsy revealed severe AS of grade 3. The TI score was graded from 0 to 5, according to the morphological injury: 0: none, 1-2 non-specific tubulo-interstitial injury (NSTI), and 3-5 compatible with acute tubular necrosis (ATN) in terms of pathological diagnosis. The mean ages of donors showing as AS of score 0, 1, and 2 were 30.6 +/- 14.6, 49.7 +/- 13.5, and 56.9 +/- 6.30, respectively. The mean donor age of the AS 1 group and AS 2 group was significantly lower than for the AS 0 group. The lowest serum creatinine values after operation (best Cr) of recipients with AS scores of 0, 1, and 2 were 1.31 +/- 0.45, 1.60 +/- 0.70, and 1.84 +/- 0.71 mg/dL, respectively; the best Cr of AS scores of 1 and 2 was significantly higher than in the AS score 0 group. The mean creatinine level at the final point of the AS 0 group was significantly lower than in the combined AS 1 and AS 2 group (serum creatinine 1.44 +/- 1.03 vs 1.87 +/- 1.53 mg/dL: p < 0.01). The duration of severe hypotension less than 50 mmHg or 80 mmHg was significantly shorter in the NSTI group than in the ATN group (less than 50 mmHg was 29.7 +/- 124 vs 72.5 +/- 174, less than 80 mmHg 105 +/- 234 vs 193 +/- 261 min: p < 0.01). The post-operative (po) day expressing diuresis in excess of 1000 mL of urine per d was 8.28 +/- 17.5 and 13.7 +/- 23.3 (p < 0.01) in the NSTI and ATN group, respectively. The po-d of the last hemodialysis and the po-d showing serum creatinine less than 2.0 mg/dL in NSTI and ATN group was 7.74 +/- 17.4 and 13.3 +/- 23.2 (p < 0.01), and 25.0 +/- 30.5 and 38.0 +/- 35.2 (p < 0.01), respectively. We concluded that 1-h renal biopsy is useful for assessing the outcome of renal allograft. AS of a donor kidney is one of the most important risk factors for both short and long-term outcome of the graft. The TI score was useful to predict the outcome of delayed graft function.     

Case study of paired cadaver renal allografts from the same donor: influence of local DIC kidney and concomitant acute rejection on early graft outcome

We report the clinical course of 2 recipients whose renal allografts were obtained from the same cadaver donor after cardiac arrest. The recipients showed different outcomes after transplantation. Graft biopsy after reperfusion revealed disseminated intravascular coagulation (so-called DIC kidney) and severe acute tubular necrosis (ATN) in both recipients. While one graft showed primary nonfunction, the other graft became functional after a post-operative anuric period. Serial graft biopsies performed during the oligo-anuric period revealed recovery of ATN and no intra-glomerular fibrin thrombi, but development of acute rejection was detected in both recipients. The left kidney graft showed more severe local DIC kidney than the right kidney, as well as more severe acute rejection in the oligo-anuric period. Despite aggressive anti-rejection therapy, the left kidney graft showed primary nonfunction. Therefore, severe acute rejection leading to primary nonfunction might have been related to more severe ischemic injury and more extensive local DIC kidney in the left kidney.     

Protective effect of nitric oxide against iron-induced neuronal damage

We investigated the effect of nitric oxide (NO) on iron-induced neuronal damage. Incubation of PC12 cells after the addition of FeCl2 induced rapid increases (within 1 hr) in lipid peroxidation and a concentration (0.1-2 mM)-dependent decrease in cell viability at 48 hr, both of which were blocked by deferoxamine and 2-methyl-6-(p-methoxyphenyl)-3,7-dihydroimidazo[1,2-a]pyrazine-3-o ne hydrochloride (MCLA) (a superoxide scavenger) but not by mannitol (a hydroxyl radical scavenger). Iron-induced cytotoxicity was also antagonized by superoxide dismutase with catalase. On the other hand, the NO donors S-nitroso-N-acetylpenicillamine (SNAP), 3-?(+/-)-(E)-ethyl-2'-[(E)-hydroxylamino]-5-nitro-3-hexenecarbo moyl?-pyridine (NOR-4), and 2,2'-(hydroxynitrosohydrazono)bis-ethanamine (NOC-18) decreased cell viability 48 hr after addition without increasing lipid peroxidation. However, when added with 1 mM FeCl2, NO donors including NOC-18, SNAP and NOR-4 (0.1-1 mM) inhibited lipid peroxidation in a concentration-dependent manner and suppressed cell death at lower concentrations. Addition of MCLA and NOC-18 also suppressed decreases in iron-induced [3H]thymidine incorporation. In rat brain homogenate, NOC-18 and SNAP both suppressed iron-induced lipid peroxidation. These findings suggest that NO has a dual effect on neuronal viability and can act as an antioxidant which protects neurons from iron-induced damage.     

Roles of CD4+ and CD8+ T cells in discordant skin xenograft rejection

An essential role of murine CD4+ T cells in immune reactivity and skin graft rejection in discordant xenogeneic combinations have been reported. Our study was conducted to further clarify the roles of CD4+ and CD8+ T cells in discordant skin xenograft rejection, by using CD4 and CD8 knockout [C57BL/6 Cr Slc (B6; H-2b) background] mice. When human skins were grafted on CD8 knockout mice or B6 mice, both hosts rejected human skin grafts within 12 days after grafting. By contrast, survival of human skin grafts was significantly prolonged in CD4 knockout mice (mean survival times=19.3+/-(SD) 1.6 days; median 19 days). Fully allogeneic C3H/He Slc (H-2k) skin grafts were rejected within 14 days in CD4 knockout mice, suggesting that non-CD4+ T cells in CD4 knockout mice were immunocompetent for allograft rejection. In spleens of these recipient mice, CD8+ T cells seemed to be activated 10 days after human skin grafting. Immunohistological analysis revealed the infiltration of CD8+ T cells at the site of transplanted human skin on CD4 knockout mice. To further examine the role of CD8+ T cells in CD4 knockout mice, human skin grafting was performed on day 0 followed by administration of anti-CD8 monoclonal antibody on days 0, 5, and 14. The administration of anti-CD8 monoclonal antibodies caused the significant prolongation of human skin graft survival. These results indicate the following two conclusions: (1) CD4+ T cells have an essential role in rejecting discordant human skin xenografts rapidly and (2) however, CD8+ T cells also are capable of rejecting discordant human skin xenografts.     

Effects of high temperature on the emergence and survival of adult Culex pipiens molestus and Culex quinquefasciatus in Japan.

The emergence rate and adult survival (longevity) of Japanese strains of Culex pipiens molestus and Culex quinquefasciatus were compared at temperatures of 21, 25, and 30 degrees C. The pupation and emergence rates in both strains were higher at 21 and 25 degrees C than at 30 degrees C. The adult emergence rate, especially in females, was lower in Cx. p. molestus than in Cx. quinquefasciatus. Longevity of females and males was lower in Cx. p. molestus at 25 degrees C and above. The survival of Cx. p. molestus was adversely affected by temperatures of 28 degrees C and higher. High temperature may restrict the distribution of this species. Therefore, if Cx. p. molestus infests the Okinawa region, the likelihood that it will become established is minimal.     

Study on the effectiveness of toborinone (OPC-18790) in the treatment of heart failure in patients following cardiac surgery.

Toborinone ((+/-)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]-2(1H)-qui nolinone, CAS 128667-95-8, OPC-18790), a novel cardiotonic agent with an inhibitory action on phosphodiesterase, is known to have a potent positive inotropic action with no positive chronotropic effect. The effectiveness of this drug in the treatment of heart failure occurring immediately after extracorporeal circulation (ECC) in cardiac surgery was investigated. The study was conducted in 12 patients with valvular heart disease showing a cardiac index (CI) of below 2.8 l/min/m2 and/or pulmonary capillary wedge pressure (PCWP) or pulmonary arterial diastolic pressure (PAD) of above 8 mmHg immediately after extracorporeal circulation. In group A (n = 6), toborinone was infused at a rate of 40 micrograms/kg/min for the first 5 min and then at 10 micrograms/kg/min for 85 min. In group B (n = 6), the drug was infused at a rate of 10 micrograms/kg/min for the entire 90 min. CI, mean systemic arterial pressure (mSAP), mean pulmonary artery pressure (mPAP), CVP, PCWP, and heart rate were measured at 5, 15, 30, 60, and 90 min after the start of infusion. The infusion volume required to maintain a constant PCWP was also estimated. In group A, CI increased rapidly and significantly from the baseline of 2.48 +/- 0.23 l/min/m2 to 3.57 +/- 1.07 l/min/m2 at 5 min after the start of infusion, and at that time mSAP was slightly decreased. In group B, CI increased gradually from the baseline of 2.53 +/- 0.18 l/min/m2 to 3.08 +/- 0.34 l/min/m2 at 15 min after the start of infusion, but almost no change was seen in mSAP. During the first 30 min, group A required a significantly larger infusion volume (983 +/- 395 ml) than group B (475 +/- 184 ml). From 30 to 90 min after the start of infusion, CI remained increased to similar levels in both groups and mSAP levels were also similar. There were no significant differences between the two groups in any other parameter. Continuous infusion of toborinone appears to be effective for treating heart failure occurring immediately after ECC in cardiac surgery. Initial loading at a rate of 40 micrograms/kg/min rapidly increased CI but was accompanied by mild hypotension. Constant infusion at 10 micrograms/kg/min brought about a more gradual effect that was similar to that of loading at 40 micrograms/kg/min, but without inducing hypotension. Thus, infusion at 10 micrograms/kg/min is considered preferable in order to avoid a larger-than-necessary infusion volume.     

An evaluation of non-clinical animal data from the point of view of a clinical pharmacologist

The development of a new chemical entity for human use is a stepwise process based on an assessment of both animal and human data on efficacy and safety of the drug. Clinical pharmacologists always refer to animal data through an Investigator's Brochure (IB) when planning and performing a clinical trial(s). The IB should provide the investigator(s) with useful information to select doses, dosing intervals, and safety monitoring procedures and also to support the clinical management of subjects during the trial(s). Non-clinical animal studies contained in the IB, however, lack a relationship to the pharmacological and toxicological findings of the investigated product(s). Most of the non-clinical animal studies address the methodology and the results obtained, but are lacking in a discussion of the relevance of the findings. The IB should include not only a summary of the findings in each field of animal study but also relationships of the findings through some indicator(s) such as blood and tissue concentrations of the parent drug and/or metabolites. I do hope Pharmaceutical Companies will provide much useful information about their product(s) through the improvement of their system of research and development.     

Zelkovamycin, a new cyclic peptide antibiotic from Streptomyces sp. K96-0670. II. Structure elucidation

The structure of antibiotic zelkovamycin was elucidated as a cyclic peptide comprising glycyl, 2-aminobutanoyl, 2-amino-2-butenoyl, N-methyl glycyl, alanyl, 1,3-thiazoyl, 7-methoxytryptophanyl and 2-methyldehydrothreonyl residues. The sequence of the amino acids was established by spectroscopic studies including 1H-1H COSY, 13C-1H COSY, 13C-1H HMQC, 13C-1H HMBC, 15N-1H HMQC and 15N-1H HMBC NMR experiments.     

Repair of a ruptured aortic arch aneurysm complicated by postoperative paraplegia: Report of a case

We report herein the rare case of a 79-year-old man who suffered permanent paraplegia after undergoing an otherwise successful total arch replacement for a ruptured aortic arch aneurysm. During cardiopulmonary bypass, perfusion to the distal aorta was maintained from the femoral artery, and postoperative aortography showed intact tributaries from the aorta including the intercostal arteries. Postoperative paraplegia is an extremely rare complication of operations on the aortic arch; however, we speculate that the paraplegia in this patient could be attributed either to a steal phenomenon involving the radicular artery, or to the anatomical particularity of the spinal cord artery described by Cole and Gutelius as the segmental system.