Propofol infusions using a human target controlled infusion (TCI) pump in chimpanzees (Pan troglodytes).

Chimpanzees are genetically and physiologically similar to humans. Several pharmacokinetic models of propofol are available and target controlled infusion (TCI) of propofol is established in humans, but not in chimpanzees. The purpose of this study was to investigate if human pharmacokinetic models can accurately predict propofol plasma concentration (Cp) in chimpanzees and if it is feasible to perform TCI in chimpanzees. Ten chimpanzees were anaesthetized for regular veterinary examinations. Propofol was used as an induction or maintenance agent. Blood samples were collected from a catheter in a cephalic vein at 3-7 time points between 1 and 100 min following the propofol bolus and/or infusion in five chimpanzees, or TCI in six chimpanzees. Cp was measured using high-performance liquid chromatography. The Marsh, Schnider and Eleveld human pharmacokinetic models were used to predict Cp for each case and we examined the predictive performances of these models using the Varvel criteria Median PE and Median APE. Median PE and Median APE for Marsh, Schnider and Eleveld models were within or close to the acceptable range. A human TCI pump was successfully maintained propofol Cp during general anesthesia in six chimpanzees. Human propofol pharmacokinetic models and TCI pumps can be applied in chimpanzees.

Characterization of a novel member of the FGFR family, HrFGFR, in Halocynthia roretzi.

The cDNA for a novel member of the FGFR family, named HrFGFR, was isolated from a Halocynthia roretzi cDNA library prepared at the mid-tailbud stage. This cDNA was 3507b long, and the deduced amino acid sequence contained a motif characteristic of the vertebrate FGFRs. The existence of a single copy of the FGFR homologue gene in H. roretzi was suggested by restriction site analysis of multiple clones. HrFGFR mRNA was expressed strongly in the posterior region in the epidermis from the middle neurula stage. By contrast, Xenopus FGFR homologues are expressed in the anterior region and are known to induce anterior neural formation. A transition of the region expressing FGFR might have induced the more complicated brain or head formation characteristic of vertebrates.

An L1 element intronic insertion in the black-eyed white (Mitf[mi-bw]) gene: the loss of a single Mitf isoform responsible for the pigmentary defect and inner ear deafness.

Waardenburg syndrome type 2 (WS2) is an autosomal dominant disorder characterized by a combination of pigmentary and auditory abnormalities. Approximately 20% of WS2 cases are associated with mutations in the gene encoding microphthalmia-associated transcription factor (MITF). MITF plays a critical role in the development of both neural-crest-derived melanocytes and optic cup-derived retinal pigmented epithelium (RPE); the loss of a functional Mitf in mice results in complete absence of all pigment cells, which in turn induces microphthalmia and inner ear deafness. The black-eyed white Mitf mi-bw homozygous mouse normally has a pigmented RPE but lacks melanocytes essential for the pigmentation of the body and hearing. We show here that Mitf mi-bw is caused by an insertion into intron 3 of a 7.2 kb novel L1 element, L1bw, which belongs to an actively retrotransposing TF subfamily. The L1bw insertion reduces the amount of mRNAs for two Mitf isoforms, Mitf-A and Mitf-H, by affecting their overall expression levels and pre-mRNA splicing patterns, while it abolishes mRNA expression of another isoform, Mitf-M, which is specifically expressed in neural-crest-derived melanocytes. The consequence of the L1 insertion in the black-eyed white Mitf mi-bw mouse is that the developmental programme for RPE cells proceeds normally, most likely because of the presence of residual, full-length Mitf-A and Mitf-H proteins, whereas the lack of Mitf-M results in loss of the melanocyte population. The results suggest that melanocyte development depends critically on a single Mitf isoform, Mitf-M, and raise the possibility that specific mutations affecting MITF-M, the human equivalent of Mitf-M, may be responsible for a subset of WS2 conditions.

Structure and developmental expression of the ascidian TRP gene: insights into the evolution of pigment cell-specific gene expression.

The tyrosinase family in vertebrates consists of three related melanogenic enzymes: tyrosinase, tyrosinase-related protein-1 (TRP-1), and TRP-2. These proteins control melanin production in pigment cells and play a crucial role in determining vertebrate coloration. We have isolated a gene from the ascidian Halocynthia roretzi which encodes a tyrosinase-related protein (HrTRP) with 45-49% identity with vertebrate TRP-1 and TRP-2. The expression of the HrTRP gene in pigment lineage a8.25 cells starts at the early-mid gastrula stage, which coincides with the stage when these cells are determined as pigment precursor cells; therefore, it provides the earliest pigment lineage-specific marker, which enables us to trace the complete cell lineage leading to two pigment cells in the larval brain. In addition, the expression pattern of the HrTRP gene appears to share similar characteristics with the mouse TRP-2 gene although structurally the HrTRP gene is more closely related to mammalian TRP-1 genes. Based on these observations and on results from molecular phylogenetic and hybridization analyses, we suggest that triplication of the tyrosinase family occurred during the early radiation of chordates. Initially, duplication of an ancestral tyrosinase gene produced a single TRP gene before the urochordate and cephalochordate-vertebrate divergence, and a subsequent duplication of the ancestral TRP gene in the vertebrate lineage gave rise to two TRP genes before the emergence of teleost fishes. Evolution of the melanin synthetic pathway and possible phylogenetic relationships among chordate pigment cells that accommodate the metabolic process are discussed. Dev Dyn 1999;215:225-237.

Determinants of ventricular arrhythmias in hemodialysis patients. Evaluation of the effect of arrhythmogenic substrate and autonomic imbalance.

BACKGROUND/AIMS: In chronic hemodialysis patients, we evaluated determinants of repetitive ventricular tachyarrhythmias which included late potentials and heart rate variability. METHODS: We compared the presence of late potentials and heart rate variability obtained by ambulatory electrocardiogram (ECG), findings of echocardiography, and laboratory data between patients with and those without ventricular arrhythmias of Lown class 4A or 4B. Ambulatory ECG was recorded for 24 h from the beginning of hemodialysis. Heart rate variability was evaluated by the standard deviation of the normal RR interval (SDNN). RESULTS: Thirty patients (17%) had ventricular arrhythmias of Lown class 4A or 4B. They were older than patients without such arrhythmias (p=0.0021). Left-ventricular wall motion score (2.0+/-3.9 and 0.3+/-1.2, respectively, p < 0.0001) and left-ventricular mass index (167 +/-59 and 140+/-44 g/m2, respectively, p=0.0053) were larger in patients with ventricular arrhythmias of Lown class 4A or 4B than in those without. Stepwise logistic regression analysis was performed to select variables related to ventricular arrhythmias of Lown class 4A or 4B from the following 8 candidate variables; age, sex, presence of ischemic heart disease, diabetic nephropathy as the primary renal disease, presence of late potentials, SDNN, left-ventricular wall motion score and left-ventricular mass index. Higher left-ventricular wall motion score (p < 0.0001), older age (p=0.0022) and male sex (p=0.0235) were the variables associated with ventricular arrhythmias of Lown class 4A or 4B. CONCLUSION: In patients receiving hemodialysis, predominantly with chronic glomerulonephritis, ventricular arrhythmias of Lown class 4A or 4B were not associated with arrhythmogenic substrate revealed by late potentials or autonomic dysfunction assessed by heart rate variability. Left-ventricular wall motion abnormalities, age and sex were significant factors.

Identification of a novel isoform of microphthalmia-associated transcription factor that is enriched in retinal pigment epithelium.

Mutations at the mouse locus encoding microphthalmia-associated transcription factor (Mitf) affect the development of many cell types, including retinal pigment epithelium (RPE), melanocytes, mast cells, and osteoclasts. Here we have identified a novel Mitf isoform, Mitf-a, and its human homologue MITF-A by cDNA cloning. MITF-A consists of 520 amino acid residues and differs in the amino-terminus from authentic melanocyte-type MITF (MITF-M). MITF-A mRNA is widely expressed and represents a predominant MITF isoform in cultured RPE cells, whereas MITF-M mRNA is exclusively expressed in melanocytes and melanoma cells. In situ hybridization analysis suggested that Mitf-a mRNA is enriched in the prospective RPE of mouse embryo. Moreover, transient cotransfection assays suggested that MITF-A activated transcription of the tyrosinase and tyrosinase-related protein 1 genes. MITF-A/Mitf-a therefore may play an important role in melanogenesis in RPE.

Determinants of heart rate variability in chronic hemodialysis patients.

To clarify determinants of heart rate variability in hemodialysis patients, we evaluated 187 patients receiving chronic hemodialysis. Ambulatory electrocardiogram was recorded for 24 hours from the beginning of hemodialysis. Standard deviation of the normal RR interval (SDNN) was used as a marker of heart rate variability. Multiple regression analysis was performed to select independent variables associated with SDNN from the following 14 variables: age, sex, body mass index before hemodialysis, presence of ischemic heart disease, diabetic nephropathy as primary renal disease, smoking, duration of hemodialysis, mean blood pressure before hemodialysis, left ventricular mass index and fraction shortening in echocardiography, use of beta blockers, use of angiotensin-converting enzyme inhibitors, hematocrit, and blood urea nitrogen. Older age (P < 0.0001), presence of diabetic nephropathy as primary renal disease (P < 0.0001), lower hematocrit (P = 0.0121), larger body mass index before hemodialysis (P = 0.0133), longer duration of hemodialysis (P = 0.0200), and smoking (P = 0.0350) were associated with reduced SDNN. In hemodialysis patients, SDNN as a marker of cardiac autonomic modulation was associated with hematocrit, body mass index, and duration of hemodialysis, in addition to previously reported variables.

[Transcatheter arterial embolization for severely dysfunctioning kidney].

The authors performed Transcatheter Arterial Embolization (TAE) with pure ethanol in five cases of severely dysfunctioning kidneys, for which conventional surgical nephrectomy had been conducted. In 3 out of 5 cases, the dysfunctioning kidneys were complicated by renal hypertension, while the other two had the complication of refractory urinary fistula. 1. Single TAE trials in 4 out of 5 patients, and a secondary TAE trial in the remaining patient resulted in successful complete embolization of the kidneys. 2. The size of the kidney in the bidirectional measurement by CT after TAE was reduced markedly in all the five cases and the reduction rate of the kidney was from 89.29 to 62.84%, and 72.61% on the average. 3. Both the blood pressure (BP) and plasma renin activity (PRA) in the three patients with complicated renal hypertension were all normalized two weeks after the TAE. Twenty six months, 48 and 60 months have elapsed in these three cases and blood pressure has remained normal without antihypertensive agents. From this result it is considered that TAE will induce the reduction of juxtaglomerular cell functions. 4. Two patients with urinary fistula were healed. 5. TAE has a number of advantages over surgical nephrectomy in that it is bloodless and noninvasive. Further, the techniques of TAE are easier than nephrectomy and TAE is applicable to almost all poor risk patients.

[Ectopic prostatic tissue in the bladder].

A 55-year-old man with a 5-year history of microhematuria had a whitish sessile tumor at the ureteric ridge containing benign prostatic glandular tissue. The presence of benign prostatic polyps in the prostatic urethra is a common finding, but ectopic prostatic tissue elsewhere is rare, it has been described previously in a few cases in the trigonum. The origin of prostatic glands in this unlikely location is not yet fully understood. Prostatic tissue at any ectopic location is benign, although local recurrence has been reported. We reviewed 43 cases of ectopic prostatic tissue, 7 of which occurred in bladder include our case, reported in the Japanese literature. Ectopic prostatic tissue should be considered in the differential diagnosis of hematuria in the male.

[Endoscopic needle bladder neck suspension for female stress incontinence].

Thirteen operations of endoscopic bladder neck suspension (Raz method) were performed for 12 patients with stress incontinence between October, 1986 and August, 1988. In all patients, except for one with small bladder capacity, the operations were successful. Disappearance of incontinence was maintained in 10 patients 5-27 months (mean 15.3 months) after the operation, and the success rate of this operation was 77% (10/13) at this follow up point. The operative technique was easy except for the adjustment of pulling up strength of the thread for suspension. We believe that the endoscopic needle bladder neck suspension will be performed more widely because this operation can be done safely in a short time without major complications and can produce very good results.

[A case of renal leiomyoma with extensive cystic degeneration].

An extremely rare case of renal leiomyoma presenting as a cystic mass, involving the upper pole of the right kidney in a 59-year-old woman, complaining of right flank pain is reported. Some discussion regarding pathogenesis of leiomyoma with cystic change, diagnostic feature, malignant potential of leiomyoma and others was done. Since 1948, 19 cases including our own case of renal leiomyoma have been reported in the Japanese literature.

[243 cases of percutaneous nephrolithotomy--result of 5 years].

Between May, 1982 and April, 1987, upper urolithiasis of 247 kidneys of 243 patients, 174 male and 69 female, were treated by percutaneous nephrolithotomy (PNL). The main stone was successfully removed from 236 kidneys (about 95.5%). Seven cases of ureteral stone could not be removed by PNL, and were treated by traditional ureterolithotomy. In 3 cases of pelvic stone, the stone descended to the ureter during the PNL procedure, and was also removed by ureterolithotomy. In one case of pelvic stone, complete obstruction of uretero-pelvic junction after PNL occurred, and pyeloplasty was needed. One pelvic stone patient who had basical hypertension and arrhythmia died soon after PNL, because of acute myocardial infarction. Blood transfusion was needed in 31 cases (12.8%). The residual stones over 5 mm were noticed in 48 cases (20.3%). The most important point to succeed in PNL is to make a nephrostomy through the most suitable calyx to the stone. The easiest way to identify the location and connection of the aimed calyx with the stone in three dimensional position, is to take X-ray films in intravenous pyelograms not only from postero-anterior but also oblique positions. Additional transureteral lithotripsy (TUL) for the fragment descending to the ureter after PNL produces a much better result.

[Clinical application of third generation extracorporeal shock wave lithotriptor (TRIPTER X-1) to upper urinary tract stones].

Clinical trials of the third generation extracorporeal shock wave lithotriptor (TRIPTER X-1) on 30 patients with upper urinary tract calculi were performed from May to July, 1988. Eighteen patients (60%) were free from stones and 5 (16.7%) had stone fragments less than 5 mm, the effective rate of treatment which is sum of both group being 76.7 per cent, at one month after the treatment. The effective rate was 72.7 per cent for stones in the kidney and 87.5 per cent for those in the upper ureter. And the effective rate as to stone size was 100, 66.7 and 71.4 per cent, in stones less than 1 cm, 1 cm to less than 2 cm and 2 to 2.5 cm, respectively. Although gross hematuria skin ecchymosis, pain and fever were observed as side effects, none was serious enough to be mentioned. And post operative changes in blood chemistry were mild and transient. We confirmed extracorporeal shock wave lithotripsy using this machine for upper urinary tract stones is an effective treatment without any serious side effects.

[The influence of percutaneous nephrolithotomy on renal function evaluated by 99m-Tc-DTPA renoscintigram].

The influence of percutaneous nephrolithotomy (PNL) on renal function was evaluated by 99m-Tc-DTPA renoscintigraphy. The renoscintigram was recorded and regions of interest of both kidneys (R) and background (BKG) were settled. Renal uptake ratio was calculated by the following formula. Renal uptake ratio = (formula; see text). The renal uptake ratio of 50 patients were compared before and up to 6 months after PNL. Most cases showed an increase or no change in post-PNL renal uptake ratio in operated kidney. Five cases (10%) showed decreased renal uptake ratio of post-PNL. No risk factors for the renal damage caused by PNL such as age, sex, stone size, number of nephrostomy and course of PNL were detected when compared with increased or no change groups. In cases of complete staghorn calculi in the decreased renal uptake ratio group, compensatory hypertrophy of contralateral kidney PNL course might occur, and the function of the operated kidney might not have recovered. More during cases and longer follow-up is necessary for the recovery of renal function.

[Influences of percutaneous nephrolithotomy on renal function, an observation using the NAG-index and beta 2-microglobulin as indices].

To examine the influence of percutaneous nephrolithotomy (PNL) on renal function, we measured the activity of urinary N-acetyl-beta-D-glucosaminidase (NAG) and beta 2-microglobulin (beta 2MG) in patients with nephrolithiasis, before and 3, 5, 7, 14 days and 1 month after PNL. With PNL, renal function was recovered within one month, and PNL was thought to be a more protective method than pyelolithotomy. Recovery of renal function was delayed in the cases in which PNL had been attempted over three times. In the patients with preoperative high-grade hydronephrosis, the excretion of NAG and beta 2MG in the urine was delayed. NAG-index was considered to be a more sensitive parameter than beta 2MG to evaluate renal function. The NAG-index and beta 2MG values of bladder urine were in good correlation with those of nephrostomy urine 5 days or more postoperatively. Measurement of the urinary NAG-index 3, 7, 14, 30 days after PNL operation was considered valuable for determining changes in renal function.

[Clinical study of amoxicillin used for treatment of infections of the lower urinary tracts (author's transl)].

The following results were obtained from treatment of 29 cases of lower urinary tract infections with amoxicillin. 1. Amoxicillin was remarkably effective in 13 cases of acute cystitis, in terms of effect according to dose and bacterial species. 2. The effective rate of amoxicillin in 10 cases of chronic cystitis amounted only to 30% due to complications and resistant bacteria. (The group given 1,500 mg/day was a little higher in the effective rate than the 750 mg/day group.) 3. Amoxicillin was low in effect against infections with Pseudomonas aeruginosa and hardly effective against bacteria resistant to amoxicillin. 4. So far as this study is concerned, amoxicillin produced good clinical results at a half dose of ampicillin, as in the fundamental experiment. 5. Any severe side effect was observed in no case.