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.     

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.     

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.     

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.     

Role of disturbance of ependymal ciliary movement in development of hydrocephalus in rats

We have developed a new in vitro method of quantitatively analyzing ciliary movement in the ependymal wall of the aqueduct in rats. An axial slice of the midbrain containing ependymal wall was placed in a culture dish filled with a culture medium containing latex beads 1 m in diameter at a concentration of 10⁷ beads/ml. The movement of the beads caused by flow of culture medium generated by the to-and-fro ciliary movement was recorded by a high speed video system attached to an inverted phase-contrast microscope. Ciliary movement was expressed by the speed of the latex beads (m/s). Aqueductal ciliary movement in congenitally hydrocephalic HTX rats, congenitally hydrocephalic WIC-Hyd rats, and other normal rats was evaluated. The results suggest that in congenitally hydrocephalic WIC-Hyd rats the degree of hydrocephalus related strongly to the degree of ciliary dyskinesia, but in congenitally hydrocephalic HTX rats it did not. Considering this discrepancy, we attempted to see whether or not hydrocephalus was caused by artificial disturbance of ependymal ciliary movement in vivo. We found that continuous infusion of metavana date, an inhibitor of ciliary movement, into the III ventricle of normal Sprague-Dawley rats for 7 days induced dilatation of the ventricular system. Although the question whether or not disturbance of aqueductal ependymal ciliary movement is related to the development of human congenital hydrocephalus is debatable, the results of the present in vitro and in vivo experimental investigations appear to suggest that the disturbance of ciliary movement in the aqueduct could at least be one of the factors contributing to the inducement of hydrocephalus in experimental conditions.     

The significance of HLA-DRB1 matching in clinical renal transplantation.

We analyzed the genotype for HLA-DRB1 alleles by digestion of polymerase chain reaction-amplified genes with the restriction endonucleases (PCR-RFLP) method to investigate the influence of HLA-DR antigen "splits" at the DRB1 gene level on the incidence of acute graft rejection in the renal transplant. For all patients, the incidence of acute rejection was proportional to the number of the serological HLA mismatch (0% in patients with two-haplotype match; 18% with HLA-A, -B, and -DR zero mismatch; 33% with HLA-DR zero mismatch; and 48% with HLA-DR one mismatch). For the patients with serological HLA-DR zero mismatch, the incidence of acute rejection in patients with HLA-DRB1 one mismatch (10/13: 77%) was significantly higher than that in those with zero mismatch (2/27: 7%). It was concluded that genotyping for HLA-DRB1 alleles would be beneficial in predicting acute rejection in patients with serological HLA-DR zero mismatch, although no difference was noted in the graft survivals.     

Effects of intravenously administered lidocaine on pulmonary vagal afferents and phrenic nerve activity in cats

The ability of lidocaine to suppress activity of single vagal afferent fiber and that of phrenic nerve was studied in 20 cats anesthetized with pentobarbital. Slowly adapting stretch receptors (SAR, n = 16) and rapidly adapting stretch receptors (RAR, n = 7) were identified by their discharge pattern to pulmonary inflation. Intravenous lidocaine (1mg·kg^–1 or 2mg·kg^–1) produced a suppression of SAR activity but not of RAR activity. Suppression of phrenic nerve activity lasted much longer than that of SAR. These findings indicate that iv lidocaine acts more dominantly on CNS than on peripherals. We conclude that iv lidocaine prevents cough and hemodynamic changes caused by airway manipulation mainly through its action on CNS and not on peripherals (peripheral nerves or their receptor).(Aoki M, Harada Y, Namiki A, et al.: Effects of intravenously administered lidocaine of pulmonary vagal afferents and phrenic nerve activity in cats. J Anesth 6: 395–400, 1992)