Deferoxamine and aluminum clearance in pediatric hemodialysis patients

Mobilization of aluminum by deferoxamine and the subsequent clearance from plasma by hemodialysis with or without charcoal hemofiltration was studied in four pediatric patients. Deferoxamine, 10–20 mg/kg, followed by dialysis with a Travenol CA50 dialyzer produced reductions in mean plasma aluminum levels from 2433±729 nmol/l (65.5±19.6 g/l) to 1727±554 nmol/l (46.5±14.9 g/l) during dialysis. The use of a charcoal cartridge in the circuit resulted in a reduction in mean plasma aluminum levels 2459±591 nmol/l (66.2±15.9 g/ml) to 1380±106 nmol/l (35.8±2.9 g/l). In one patient, high-flux dialysis produced a reduction from 2140 nmol/l (55.6 g/l) to 1134 nmol/l (29.4 g/l). No patients suffered direct adverse reactions to low-dose deferoxamine, although two patients had previously exhibited potential aluminum neurotoxicity after rapid increases in plasma aluminum levels with deferoxamine in higher doses. Aluminum levels must be monitored closely during deferoxamine therapy in uremic children to minimize the risk of exacerbating aluminum neurotoxicity.     

Effects of infusion of parathyroid hormone and primary hyperparathyroidism on formation and breakdown of type I collagen

The influence of chronic and acute exposure to parathyroid hormone (PTH) on formation and breakdown of type I collagen, using two recently developed radioimmunoassays for serum PICP (the carboxyterminal propeptide of type I procollagen) and serum ICTP (the carboxyterminal telopeptide of type I collagen), have been evaluated. Fasting morning values were obtained from 18 women with primary hyperparathyroidism (HPT) and an equal number of age-matched, healthy controls. A 24-hour infusion of synthetic human parathyroid hormone (PTH 1-38) was performed in 14 healthy females. The patients with HPT had higher values for serum ICTP than the controls (6.0±3.0 and 4.1±2.1 g/liter; P<0.05), whereas the serum PICP concentrations were not different (170±72 and 151±65 g/liter; n.s.). During infusion of PTH in healthy subjects, there was an increase of the serum ICTP concentrations (from 3.6±1.3 to 4.4±1.8 g/liter; P<0.001) whereas those of serum PICP decreased (from 185±78 to 118±42 g/liter; P0.0001). The increase of serum ICTP during infusion of PTH was positively related to the increase of serum calcium and other indices of bone resorption, i.e., fasting urinary excretions of hydroxyproline and calcium. The decrease of serum PICP was also related to the changes of serum ICTP and hydroxyproline in urine, serum calcium, and alkaline phosphatase but not to osteocalcin, an established marker of osteoblastic activity. The findings support the fact that serum ICTP is a valuable method for evaluating bone resorption and is also easy to perform. Furthermore, the discordant results for the different markers of osteoblastic activity indicat that they reflect different functions of the cell.     

Effects of Cilostazol on Human Venous Smooth Muscle

In this study, we evaluated the effect of therapeutic doses of cilostazol on human venous smooth muscle. Saphenous vein rings (two to four per patient sample) were suspended in tissue baths for isometric tension recordings. At the beginning of the experiment, optimal tension for isometric contraction was achieved for each ring in a stepwise fashion in the presence of norepinephrine (10^–2 M). Norepinepherine was then added cumulatively in half-molar increments and isometric tension developed by the rings was measured, thereby obtaining a dose-response curve. Following washout and reequilibration, the rings were precontracted with a 30-50% submaximal dose of norepinepherine determined from the dose-response curve and allowed to contract until a stable plateau was reached. Cilostazol was then added in a cumulative manner (680-2,720 g/L), and the tension generated was recorded. A total of 76 venous rings were tested, and all relaxed in the presence of cilostazol. The amount of relaxation increased as the concentration of cilostazol increased. Relaxation of 15±1.9% (mean±SEM) at low cilostazol doses (680 g/L) to 37±3% at high cilostazol doses (2,720 g/L) was demonstrated. A second finding of this study was demonstrated when the patient samples were divided according to the presence or absence of risk factors for arteriosclerosis. The specific risk factors examined included diabetes mellitus, smoking, hypercholesterolemia, and hypertension. The presence or absence of hypertension (n=52) or hypercholesterolemia (n=18) did not affect the amount of relaxation of the venous rings. Smokers (n=46) had less relaxation 16±2.4% (680 g/L) to 41±3.6% (2,720 g/L) compared to nonsmokers (n=53) who relaxed 22±3.5% (680 g/L) to 48±5.7% (2720 g/L). This did not reach statistical significance at any concentration cilostazol (p=0.11-0.18). Diabetics (n=53) did have statistically significantly less relaxation at every concentration of cilostazol compared to nondiabetics (n=11, p < 0.05). All venous rings relaxed in the presence of cilostazol. Veins of nondiabetics relaxed statistically significantly more than those of diabetics. Smokers had less relaxation than non-smokers, but this was not statistically significant. We are the first to demonstrate that human venous smooth muscle cells undergo relaxation when exposed to therapeutic concentrations of cilostazol.     

Human pancreatic tumor GH-releasing factor

Summary Within the past year, three similar peptides with specific growth hormone (GH) releasing effects have been extracted from human tissue, identified, and synthesized. Human pancreatic tumor GH releasing factor (1–40)-OH (hpGRF-40) was the sole hpGRF isolated from the pancreatic tumor of a patient in Charlottesville and was the predominant peptide isolated from the pancreatic tumor of a patient in Lyon. The Lyon tumor also contained hpGRF(1–37)-OH and hpGRF(1–44)-NH₂. Both immunological and biochemical data suggest that hpGRF-40 and hpGRF-44 are present in the human hypothalamus and may be the human GH releasing hormone(s) (GHRH).In cultures of rat pituitary cells, hpGRF stimulates GH but affects neither basal and dopamine-inhibited prolactin release nor basal and gonadotropin releasing hormone (GnRH)-stimulated luteinizing hormone (LH) release. hpGRF stimulates cyclic AMP production within seconds, an effect which is blocked by somatostatin. In contrast, while hpGRF stimulates phosphatidylinositol turnover in the pituitary, the effect is not inhibited by somatostatin.In the human, hpGRF-40 (1 g/kg) given intravenously (i.v.) stimulates GH release within 5 minutes. hpGRF-40 does not elevate serum prolactin levels, thyrotropin (TSH), LH, or corticotropin (measured indirectly through plasma cortisol), or blood glucose or plasma concentrations of insulin, glucagon, pancreatic polypeptide, cholecystokinin, gastrin, gastric inhibitory peptide, motilin, or somatostatin. When graded doses of hpGRF (0.1–10 g/kg) are given i.v., no differences are noted in the maximal levels of serum GH achieved. Doses of 1, 3.3 and 10 g/kg hpGRF-40 elicits a prolonged and biphasic pattern of GH release. Twenty-four hours after hpGRF-40 administration, serum somatomedin C is increased in 66% of subjects tested. Side effects including a feeling of warmth and facial flushing are observed in 66% (3.3 gmg/kg) and 100% (10 g/kg) of men given hpGRF-40. hpGRF-40 (3.3 g/kg, i.v.) selectively stimulates GH release and somatomedin C production in normal women, although no differences are found in GH responsivity during the menstrual cycle. hpGRF-40 given intranasally to normal men (30 g/kg) stimulates GH release within 30 minutes. The calculated metabolic clearance rate for hpGRF-40 is 194±17.51/m²/d; the disappearance rate occurs as two phases: an initial equilibration phase (7.6±1.2 minutes) and a subsequent elimination phase (51.8±5.4 minutes). hpGRF-40 administered i.v. stimulates the release of GH in some adult patients with GH deficiency documented in childhood. Serum somatomedin C concentrations may increase in patients in whom hpGRF-40 fails to stimulate GH release. If patients with GH deficiency who do not respond to hpGRF-40 administration (10 g/kg i. v.) are given the peptide (0.33 g/kg i. v. every 3 hours) for five days, some will respond to a subsequent 10 g/kg challenge. Of those who do respond initially, the response to the subsequent challenge may be greater. Serum somatomedin C increases significantly following the 5 days of intermittent administration of hpGRF-40.hpGRF-40 and/or hpGRF-44 may be the long sought GHRH. Clinical studies with hpGRF suggest that GH deficiency may often result from hypothalamic GHRH deficiency rather than pituitary disease. hpGRF and its analogues and antagonists may find therapeutic application in the treatment of GH deficiency and in other disorders in which an increase or decrease in the secretion of GH would be beneficial.     

Human pancreatic growth hormone releasing factor (hpGRF): GRF-and GH-levels after bolus injection and infusion of hpGRF1–44

Summary Synthetic human pancreatic growth hormone releasing factor (hpGRF^1–44) was given as an i.v. bolus to healthy volunteers in 5 different dosages (3.3g to 200g hpGRF^1–44). In addition 11 healthy subjects were infused over 2 respectively 5 hours in a dosage of 100g hpGRF^1–44/h after receiving a bolus of 50 g hpGRF^1–44. Four healthy subjects served as placebo controls. GH, PRL, TSH, and GRF were measured by specific radioimmunoassays. The results show the clearcut dose response relationship between the administered GRF dosage and the resulting GH response from 3.3 to 50g hpGRF^1–44 i.v. Higher dosages of hpGRF^1–44 did not lead to a more pronounced GH response though there was a linear dose response relationship between the administered hpGRF^1–44 and the GRF immunoreactivity 5 minutes after injection. Infusion of hpGRF could not sustain elevated GRF levels and a second bolus of 50g hpGRF^1–44 given at the end of the 2-respectively 5-hour infusion led to a minor increase compared to the first bolus.100g hpGRF^1–44 was given to 14 patients with active acromegaly leading to a significant rise of the GH levels with the exception of 3 patients. Of the latter 3 two had received previous therapy, and one patient suffered from ectopic GRF hypersecretion. When GH responses to hpGRF^1–44 were compared to the responses to other releasing hormones there was no correlation. After transsphenoidal surgery divergent responses of GH were seen. In one patient with low basal GH and an exaggerated rise after GRF before surgery there was no response after successful transsphenoidal operation.We conclude that there is marked heterogeneity of the GH response to hpGRF^1–44 in normal subjects with a dose response relationship in the low dose range which is not apparent when higher dosages above 50 g hpGRF^1–44 are used. Long-term infusion can not sustain elevated GH levels which may be explained by antagonizing factors like somatostatin. Patients with active acromegaly who have not been treated show regularly a response to hpGRF^1–44, which may disappear after transsphenoidal surgery. In addition lack of GH responsiveness to hpGRF^1–44 does not exclude active acromegaly in already treated patients. If untreated patients do not have a GH response after hpGRF they may have an ectopic GRF source.     

Tetracycline double-labeling of iliac trabecular bone in 41 normal adults

Summary A histomorphometric evaluation of the iliac crest trabecular bone remodeling was performed after tetracycline double-labeling in 41 normal Danes (12 males and 29 females) aged 19 to 56 years. The fraction of formative (osteoid covered) and resorptive surfaces was unrelated to age but higher in males than in females (P<0.02 andP<0.05, respectively). The appositional rate (0.65±0.12 m/day) was unrelated to age and sex, whereas the fractional labeled surfaces were higher (P<0.01) in the males (0.18±0.08 m²/m²) than in the females (0.12±0.05 m²/m²), and among the females inversely related to age (R=–0.38,P<0.05). The bone formation rate at BMU level (0.50±0.20 m³/m²/day) was unrelated to sex, but among the females inversely related to age R=–0.49,P<0.01). The bone formation rate at tissue level was higher (P<0.02) in the males (0.13±0.07 m³/m²/day) than in the females (0.07±0.03 m³/m²/day) and among the females inversely correlated to age (R=–0.43,P<0.05). The age- and sex-dependent variations in the dynamic parameters underline the importance of a more elaborated normal material.     

Pharmacokinetic profile of a new fluoride preparation: Sustained-release monofluorophosphate

The pharmacokinetic profiles of a sustained-release monofluorophosphate (MFP-SR) preparation (76 mg) and of plain MFP (76 mg) were compared in six osteoporotic females. These studies were performed in a randomized, crossover, double-blind design to select a preparation that would result in therapeutic serum levels while avoiding high serum peak values. Following a single dose of 76 mg MFP-SR, the serum fluoride levels remained within the accepted therapeutic range (5–10 M/liter) for 24 hours. In contrast, following a single dose of 76 mg plain MFP, serum fluoride levels exhibited a wide circadian fluctuation and serum levels approximately threefold higher than those of the MFP-SR preparation (9.5±1.6 vs 3.5±0.8 M/liter, P<0.005). Compared with plain MFP, the sustained-release MFP had a significantly lower peak concentration (C_max MFP-SR: 10.6 ±3 vs C_maxMFP: 18.9±5 M/liter, P<0.005) and a significantly longer absorption lag time (T_maxMFP-SR 7.3±1.6 vs T_maxMFP: 3.0±0.6 h, P<0.05). Twenty-four-hour urinary fluoride excretion after ingestion of plain or SR fluoride was significantly increased from pretreatment values documenting absorption with either MFP formulation. Our results show that the use of sustained-release MFP preparation that we tested prevents the development of high peak levels associated with the use of plain MFP preparations. Furthermore, a single dose of MFP-SR resulted in serum fluoride levels within the accepted range of 5–10 M/liter for 24 hours.     

Pattern of elevation of urine catecholamines in intracerebral haemorrhage

Summary Autonomic nervous system dysfunction is a common complication of severe intracranial disease. The aim of this study was to reveal the autonomic changes in patients suffering from acute intracerebral haemorrhage (ICH). 25 patients with spontaneous ICH within 24 hours of onset of symptoms were included. All patients were treated with standardised medical management and the meta- and normetanephrines were detected by high performance liquid chromatography (HPLC) in 24-hour urine every day.The mean level of normetanephrine (709±579 g/day) and metanephrine (244±161 mg/day) were significantly elevated in comparison with a control group, p0,01. The norepinephrine elevation was of greater diagnostic and prognostic importance. Maximum urinary catecholamine metabolite levels occurred between day 3 to 10 after the bleeding.Normetanephrines correlated with the prognosis and the complications of ICH: intraventricular involvement resulted in significantly elevated normetanephrine levels (896±520 g/day versus 311±78 g/day) p0,01. Patients with a great volume of haematoma developed severe autonomic dysregulation (normetanephrines 1114±493 g/day), whereas patients with smaller haematoma did not (339±125 g/day) p0,0001; patients with bad outcome (1014±620 mg/day) had higher levels of normetanephrines than those with a good prognosis (322±110 g/day) p0,001. A close relationship to elevated intracranial pressure was established.This study demonstrated the feasibility of detecting autonomic nervous system dysfunction in neurological intensive care patients by means of examination of the metabolites of the catecholamines in the urine. The pattern of elevation in ICH and the relation to the clinical situation is presented. Norepinephrine offers the chance of simple and feasible monitoring of autonomic dysfunction.     

Isoamylase levels in bone marrow transplant patients are affected by total body irradiation and not by graft-versus-host disease

The mean total serum amylase levels in patients was 3.2±0.5 kat/l (±SE) before total body irradiation (TBI) prior to bone marrow transplantation of which 50% was due to pancreatic isoamylase and 50% salivary isoamylase. Total serum amylase increased to a maximum of 100.3±12.3 kat/l on the first day after TBI and most of this increase was due to an increase in salivary isoamylase (90.0±12.1 kat/l). In association with this, all patients had clinical symptoms of parotitis. An increase in pancreatic isoamylase was found in 27% of the patients; however; none of them had clinical symptoms of pancreatitis. Serum amylase levels returned to normal within 5 days after TBI but then decreased to subnormal values, remaining below the normal range for 3 weeks. Pancreatic isoamylase returned to pre-irradiation levels 1.5 months after TBI, while salivary isoamylase remained low for the rest of the observation time. TBI of 7.5 Gy at 26 cGy/min gave significantly lower salivary amylase at 2 days after TBI compared with 10 Gy at 4 cGy/min: 32±4 versus 76±13 kat/l (P<0.05). At 2.5 and 6 months after TBI significantly higher total amylase levels were recorded for patients treated with 7.5 Gy of TBI compared with 10 Gy: 2.5±0.4 and 2.7±0.3 versus 2.0±0.5 and 0.8±0.3 kat/l, respectively (P<0.01, P<0.05, respectively). Acute or chronic GVHD did not affect acinar cells in this investigation.     

Microscopic analysis of autograft bone applied at the interface of porous-coated devices in human cancellous bone

Summary This study describes the response of human cancellous bone when autologous bone chips are added at operation to the interface between host bone and porous-coated implants. During the first operation of a staged bilateral total knee arthroplasty, seven patients consented to have paired porous-coated devices implanted into their opposite medial femoral condyle. One device of each pair had autologous bone chips applied to the porous-coating, and the other was not grafted and was a control. The devices were removed en bloc at the second total knee arthroplasty 6 to 49 weeks later. Backscattered electron imaging showed significantly more bone (p0.05) in the porous-coating of the implant treated with autologous bone chips which significantly increased (p0.05) the amount of bone available at the interface. The grafted devices had a mineral apposition rate of 1.04±0.20 m/day for the interface and 0.81±0.09 m/day for the peripheral bone. This compared with corresponding figures of 1.03±0.38 m/day and 0.79±0.19 m/day at the ungrafted devices. The mineral apposition rate at the interface of the porous-coated implants was significantly increased (p0.05) relative to the host bone in the periphery. Our results support the view that autologous bone chips are effective in attaching cementless porous-coated total knee replacements to the human skeleton by bone ingrowth.

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Résumé Nous avons étudié la réponse de l'os spongieux humain et le taux de remodelage osseux aprés insertion chirurgicale de copeaux d'os autologue (COA) à l'interface entre os et implants poreux. Au cours du premier temps d'une arthroplastie totale bilatérale du genous, nous avons implanté, chez 7 malades consentants, deux dispositifs à revêtement poreux dans le condyle interne du fémur opposé. L'un a été recouvert de COA avant d'être mis en place, l'autre a été placé tel quel pour servir de contrôle. Ces dispositifs ont été explantés en bloc avec l'os avoisinant lors de la deuxième arthroplastie, 6 à 49 semaines après leur insertion. Les études en microscopie électronique ont montré une augmentation significative (p0.05) de la quantité d'os sur la surface poreuse recouverte de COA. Le taux d'apposition minérale (TAM) moyen était de 1,04±0,20 m/jour à l'interface et de 0,81±0,09 m/jour au niveau de l'os spongieux adjacent. Pour les implants non greffés le TAM était de 1,03±0,38 m/jour à l'interface et de 0,79±0,19 m/jour au niveau du spongieux périphèrique. Le TAM à l'interface des implants à revêtement poreux est significativement augmenté (p±0.05) par rapport à l'os receveur avoisinant.

     

Increased urinary albumin indicating urothelial leakage following intravesical bacillus Calmette-Guérin therapy for superficial bladder cancer

Summary This study on the increase in albumin in the urine of patients with superficial bladder cancer after intravesical bacillus Calmette-Guérin (BCG) treatment was initiated on the basis of two facts. First, extravasation of serum albumin could be expected as a result of the BCG-induced delayed-type hypersensitivity reaction in the bladder wall. Second, appearance of albumin in the urine was a possibility as cytokines also appear in the urine, although probably after being produced suburothelially by infiltrating leukocytes. Albumin and the cytokines interleukin (IL) 1, IL2, IL6, and tumor necrosis factor alpha (TNF) were determined in urine from 20 patients treated with 6 weekly intravesical BCG instillations, collected prior to each instillation and 2, 4, 6, 8, 12, and 24h thereafter. The mean concentration of albumin in pre-therapy specimens was 112±118 (range 2–432) g albumin/ml urine, approximating 14±14 g/ mol creatinine (creat) (n=15), which was comparable to the mean pre-instillation value of 16±32 g/mol creat (n=96). A significant increase in urinary albumin during the 6 weeks of BCG treatment was observed (P<0.001). However, a large variation existed between individual patients and in some patients no reaction was seen. Maximum albumin concentrations were observed after instillations 3–6. A significant correlation between albumin and concentration of the cytokines IL1, IL2, IL6, and TNF was found (P<0.01), correlation coefficients (r) being 0.56, 0.56, 0.67, and 0.71 (n=418), respectively. During the first 24h after instillation cytokines and albumin peaked in the following order: TNFIL2albuminIL6IL1. TNF peaked most frequently after 2–4h and IL1 after 6h, while IL2, albumin, and IL6 peaked between these time points. In conclusion, the presence of albumin in urine indicates a leakiness of the bladder wall after repeated BCG instillations. Since albumin was shown to be stable in urine and the assay is relatively simple and cheap, it may be performed in most hospitals. This will allow largescale investigations of the correlation between elevation of urinary albumin and (tumor) response on BCG therapy.     

Ascorbic acid and focal cerebral ischaemia in a primate model

Summary Neuronal cell damage following ischaemia is postulated to be due to free radical induced lipid peroxidation, and ascorbic acid is supposedly an important non-enzymatic scavenger of such free radicals. This study was undertaken to evaluate the protective effect of ascorbic acid on the brain in a primate model after focal cerebral ischaemia. Consumption of ascorbic acid in the monkey brain following ischaemia and its effect on macroscopic infarct size as demonstrated by 2, 3, 5, Triphenyl tetrazolium chloride (TTC) staining were used as parameters.The monkeys in the treated group were given 1 gram ascorbic acid parenterally every day for six days. The mean level of total ascorbic acid in right basal ganglia was 35.1±4.2 g/mg of protein in the treated group as opposed to 22.9±2.1 g/mg of protein in the nontreated group both before ischaemia. After right middle cerebral artery occlusion to produce focal cerebral ischaemia, the total ascorbic acid in the right basal ganglia 2 hours post ischaemia was 13.3±3.1 g/mg of protein in the treated group as opposed to 9±1.6 g/mg of protein in the untreated group. The average consumption of total ascorbic acid was 21.8 g/mg of protein in the treated group and 13.9 g/mg of protein in the nontreated group.Macroscopic infarct size as determined by TTC staining in the right cerebral hemisphere was 11.7±6.9 in treated group whereas it was 24.4±4.4 (expressed as percentage of right hemisphere) in the non-treated group. There was significant reduction in the size of the infarct in the treated group.A short course of mega-dose Ascorbic acid therapy was found to significantly decrease the macroscopic infarct size. Pretreatment with ascorbic acid enhanced its storage and utilization during ischaemia resulting in its protective effect.     

Serum immunosuppresive acidic protein in renal cell carcinoma

Summary Serum immunosuppresive acidic protein (IAP) was determined in 45 patients with renal cell carcinoma (20 preoperative and 25 postoperative) and 12 healthy adults. The mean values of serum IAP in patients with renal cell carcinoma of low stage (566.3±197.7 g/ml) and high stage (936.9±208.8 g/ml) were statistically higher than those of controls (368.8±84.5 g/ml). Positive rate of IAP levels was found in 58.3% and 100% of patients with low stage and high stage, respectively. The mean value of serum IAP was 756.4±361.0 g/ml in patients with metastases, while patients without metastases had a value of 434.7±170.9 g/ml. There was a statistically significant difference between the two populations. These results suggest that IAP levels appear to provide a useful diagnostic and followup marker in renal cell carcinoma patients.     

Biochemical bone markers compared with bone density measurement by dual energy X-ray absorptiometry

In contrast to medical imaging, the biochemical markers allow a more frequent determination and are not as invasive as histomorphometric methods. We investigated biochemical markers of type I collagen compared with bone density measurements in 85 females between 41 and 89 years of age (median: 57 years). The bone density measurements were performed by dual-energy X-ray absorptiometry (DXA) on the lumbar spine (L_1–4). The bone density measurements were stated as percentage of the norm. All patients were divided into three groups: I=<80%; II=80–120%; III=>120%. Based on this classification the median concentration of the I-carboxyterminal propeptide of type I procollagen in serum (S-PICP) as an anabolic marker of type I collagen increased significantly with rising bone density: I 65.0^* g/liter (interquartile range: 52.1–78.0 g/liter); II 85.9^* g/liter (52.1–115.5 g/liter); III 81.4 g/liter (62.0–101.0 g/liter); ^* P<0.05. The concentration of urinary pyridinolines (U-PYR) as a marker for degradation of type I collagen decreased. The I-carboxyterminal telopeptide (S-ICTP) and osteocalcin (S-BGP) did not change. The multivariate regression analysis showed no relationship between bone density measurement and biochemical bone markers. Only the age significantly correlated negatively with bone density measurement. For a better assessment of type I collagen metabolism we created a b-quotient by dividing the sum of S-PICP and S-BGP by U-PYR. The median b-quotient increased significantly: I 1.55^*+ (0.97–2.04); II 2.09^* (1.57–2.86); III 2.46⁺ (1.58–3.22);^*+ P<0.05. Changes in bone metabolism cannot be identified by the determination of a single marker. However, the improved biochemical diagnostic measurement using the b-quotient may provide early information about the progression of a metabolic disorder within the interval of imaging.     

Effects of calcium and temperature on tension in isolated canine coronary artery

The effects of calcium and temperature on the tension of isolated canine coronary arterial strips were studied.In 20mEq·l ^–1 K solution, the tension was significantly increased from 0mg with 0mEq·l ^–1 Ca to 33 ± 18mg with 0.2mEq·l ^–1 Ca at 37°C, from –40 ± 18mg with 0mEq·l ^–1 Ca to –17 ± 11mg with 0.2mEq·l ^–1 Ca at 30°C, from –77 ± 19mg with 0mEq·l ^–1 Ca to –52 ± 17mEq·l ^–1 with 1mEq·l ^–1 Ca at 25°C, from –88 ± 13mg with 0mEq·l ^–1 Ca to –41 ± 18mg with 2mEq·l ^–1 Ca at 20°C, from –125 ± 16mg with 0mEq·l ^–1 Ca to –116 ± 13mg with 2mEq·l ^–1 Ca at 15°C. Ca higher than 0.2mEq·l ^–1 produced a dose-dependent increase in tension between 37°C and 15°C. In spite of the presence of 4mEq·l ^–1 Ca, the development of tension was strongly supressed by lowering the temperature below 20°C, and completely inhibited at 10°C. The rate of a decrease in tension caused by cooling was about 5.5mg·°C^–1.This study demonstrated that Ca²⁺ produced a dose-dependent increase in tension in high-K solution, which was suppressed as the temperature was lowered.(Yoshida K, Fujii Y, Ina H, et al.: Effects of calcium and temperature on tension in isolated canine coronary artery. J Anesth 5: 172–176, 1991)     

Atrial natriuretic peptide (ANP) attenuates brain oedema accompanying experimental subarachnoid haemorrhage

Summary The effects of centrally administered atrial natriuretic peptide (ANP) on the brain water and electrolyte contents were investigated in a rodent subarachnoid haemorrhage (SAH) model. SAH caused statistically significant increases in the brain sodium and water contents, while the potassium content did not change significantly, indicating that the brain oedema could be classified as having a primarily vasogenic component. Two g or 5 g of rat ANP administered into the lateral ventricle at the time of SAH induction statistically significantly decreased the water and sodium accumulation measured 90 minutes following SAH. The same treatment did not inhibit development of brain oedema measured 3 hours following SAH. However, when 5 g of ANP was administered intraventricularly at the time of SAH induction and also 90 minutes later, the brain oedema 3 hours following SAH was again reduced statistically significantly. These effects of ANP were found not to be mediated by primary changes in serum osmolality and electrolyte concentrations.The present results confirm that centrally administered ANP may act directly on the central nervous system to inhibit brain water and sodium accumulation in SAH-induced brain oedema. The potentials of influencing the central neuro-endocrine system as a novel way of the treatment of brain oedema are discussed.Supported by Grant OTKA I/3 2728 and ETT T110/ 1990.     

Natural killer activity and serum immunosuppressive acidic protein levels in esophageal and gastric cancers

The natural killer (NK) activity of peripheral blood mononuclear cells and serum immunosuppressive acidic protein (IAP) levels were examined in patients with esophageal or gastric cancer, before and after surgery. Patients with stage IV esophageal or stage IV gastric cancer had significantly lower NK activity (39.5±14.8% and 37±11.6%, respectively), and also higher serum IAP levels (778±264 g/mL and 633±156 g/mL, respectively), than the corresponding control values (50±5.6% and 375±26 g/mL, respectively). Patients with esophageal or gastric cancer who underwent curative resection had high NK activity (54.8±11.6% and 54.8±8.0%, respectively), and low IAP levels (471±116 g/mL and 490±42 g/mL, respectively), compared with those who underwent non-curative resection. Patients who underwent non-curative resection had lower NK activity and higher serum IAP levels than those who underwent curative resection, even 1 month after surgery. Mononuclear cells in the regional lymph nodes and tumor specimens showed significantly lower NK activity than those in the peripheral blood and spleen. Thus, NK activity and the IAP level reflected the immunocompetence, clinical course, and surgical curability of those patients. NK cells appeared not to have any significant antitumor activity in the regional lymph nodes or in the tumor itself, although they were still active in the peripheral blood.     

Serum hippuric acid concentration in renal allograft rejection,ureter obstruction,and tubular necrosis

Plasma from 35 renal allograft recipients (21 males and 14 females) was sampled daily and analyzed for hippuric acid (HA) by highperformance liquid chromatography (HPLC) and serum creatinine. Twelve of these patients experienced an acute renal allograft rejection or a ureter obstruction as proven by clinical signs and biopsy, as well as by radiography or ultrasound, respectively. Two patients suffered from tubular necrosis followed by rejection during the postoperative period. Mean serum HA increased by 39.9 mol/l from baseline (range 20.4–115.5 mol/l) in patients with acute rejection 3 days after an initial increase that was observed 24 h before the mean serum creatinine increased by 107.1 mol/l (range 21–193 mol/l). In cases of ureter obstruction, HA rose by 1.6 mol/l (range 1–8.2 mol/l), significantly less than elevations due to rejection. The increase in creatinine, however, amounted to 65.3 mol/l (range 22–140 mol/l) and was not different from the change in rejecting patients. Successful antirejection treatment coincided with a decrease in serum HA starting 24 h earlier than the decrease in the serum creatinine concentration. Of special interest was the observation of a parallel decrease in HA with creatinine concentration in patients with tubular necrosis after allotransplantation; HA increased in cases of an additional rejection. Our data suggest that HA, which is excreted by tubular secretion and glomerular filtration, could be a sensitive and early marker of acute allograft rejection. Furthermore, it seems to discriminate between acute renal allograft rejection and ureter obstruction. It might, therefore, be of value in the diagnosis of rejection complicating tubular necrosis after transplantation.     

Renal tubular differentiation in mouse and mouse metanephric culture

Sodium-potassium adenosine triphosphatase (Na-K-ATPase) activity was measured by microassay, and the surface density of basolateral membranes was measured morphometrically in postglomerular segments of single tubules isolated from normally developing, intact mouse kidneys and from transfilter metanephric cultures. Proximal tubule Na-K-ATPase activity was 1092±480 pmol/mm per hour in newborn mice, increasing to 2462±258 in 1-week-old and 3470–578 pmol/mm per hour in adult mice. The Na-K-ATPase activity in newborn mice was approximately one-third of the activity in adult mice. Tubular Na-K-ATPase in transfilter metanephric culture was 972±536 pmol/mm per hour, a mean value almost identical to that in newborn mice. The surface density of basolateral cell membranes was 1.36±0.60 m²/m³ in newborn mice and 1.34±0.45 m²/m³ in 1-week-old mice, increasing to 2.70±0.98 m²/m³ in 4-week-old mice and 2.89±0.51 m²/m³ in adult mice. The surface density of tubular basolateral cell membranes in transfilter metanephric culture was 1.13±0.51 m²/m³, not significantly different from the surface density in newborn mice. The calculated mean surface area of basolateral membranes per unit tubular length was greater in cultures than in newborns, however, because total epithelial volume per unit length was significantly larger in the cultured tubules. Membrane surface area in intact mice increased with age, the surface area per unit length of tubule in adults being 4.6 times the area in newborn animals. The ratio of enzyme activity to membrane surface area more than doubled in the 1st week of life without any increase in the density or surface area of basolateral membranes. The ratio fell thereafter, as membrane area increased with maturation, to a value in the adult animal three-fourths of that in the newborn. The early postnatal increase in enzyme activity, beginning almost immediately after birth, possibly relates to an increased density of enzyme sites on the membrane. The postnatal spurt in enzyme activity, without a corresponding increase in membrane area, suggests that tubules have considerable functional reserve in generating a complement of sodium pumps. The studies of proximal tubules grown in metanephric culture show that the basolateral membranes and the sodium pump are initiated independently of renal blood flow and tubular fluid flow, presumably as inherent characteristics. The functional data confirm the similarity, already shown by morphometric studies, between natural tubules and those grown in culture.     

Influence of intravesical administration of tumor necrosis factor α and systemic γ-interferon on murine bladder cancer: Lack of dose response

Summary The effect of intravesical administration of high dose recombinant tumor necrosis factor- (rTNF) and in combination with systemic recombinant -interferon (rIFN) on murine bladder cancer was studied. RTNF was given at 12.5 g/mouse on days 7, 11 and 15 after tumor instillation or at 2.5 g/mouse on days 7, 9, 11, 13 and 15. Some groups were also injected i.v., 24-h prior to each rTNF treatment with rIFN at a dose of 1.3 g/mouse. RTNF treatment suppressed tumor growth up to 48% of control, although the difference was not statistically significant. Combined administration of rIFN did not provide additional benefit.