DNA synthesis is dissociated from the immediate-early gene response in the post-ischemic kidney

OBJECTIVE: Fetal growth and development are closely related to normal placental growth and function. We performed a study to determine the effect of a 10-day period of fetal hypoxemia induced by umbilical-placental hypoperfusion on tissue deoxyribonucleic acid synthesis rates in the 0.84 to 0.91 of gestation ovine fetus and placenta. STUDY DESIGN: Daily fetal placental embolization was performed in four chronically catheterized sheep fetuses until fetal arterial oxygen content decreased by approximately 30% compared with preembolization values. Five control fetuses received vehicle only. On experimental day 10, the deoxyribonucleic acid synthesis rate was determined by injecting tritiated thymidine (1 mCi/kg) intravenously approximately 8 hours before the end of the study. RESULTS: Fetal arterial oxygen decreased from 3.2 +/- 0.1 (SEM) mmol/L preembolization to 2.2 +/- 0.2 mmol/L on day 10 (p < 0.001) and remained unchanged in controls. On day 10 deoxyribonucleic acid synthesis rates were significantly reduced in embolized fetuses compared with controls, by 38% in cotyledons (83.0 +/- 15.1 vs 133.7 +/- 9.9 disintegrations/min/micrograms deoxyribonucleic acid, p < 0.05), 28% in the left ventricular wall (36.8 +/- 3.7 vs 51.0 +/- 4.7 disintegrations/min/micrograms deoxyribonucleic acid, p < 0.05), and 45% in the quadriceps muscle (15.4 +/- 4.0 vs 28.1 +/- 3.0 disintegrations/min/micrograms deoxyribonucleic acid, p < 0.05). Tritiated thymidine autoradiography demonstrated that cotyledonary deoxyribonucleic acid synthesis occurred exclusively in the fetal trophoblasts cells. CONCLUSION: We concluded that a reduction in cotyledonary, quadriceps muscle, and left ventricular myocardium deoxyribonucleic acid synthesis rates are the earliest adaptive mechanisms of fetal growth associated with development of umbilical-placental insufficiency. We speculate that alteration in the myocardial deoxyribonucleic acid synthesis rate could be a major contributing factor in the deterioration of fetal myocardial function associated with increased placental vascular resistance.     

Polycystic kidney and liver disease in cats

This paper reviews 27 cases of polycystic disease of the kidneys and/or liver in cats. The multiple cysts in the kidneys were rounded in all but one case, as described in adult polycystic kidney disease in humans. In 68% of the cats presented with polycystic kidneys, there were also cystic changes of the liver (uni- or multilocular cysts and/or congenital hepatic fibrosis (CHF)). In 1 cat polycystic changes of kidneys and liver were accompanied by cysts in the pancreas. In 5 cases there was severe pancreas fibrosis. Twenty-one of the 27 cats were Persian or Persian-crossbred.     

Measurement of response to treatment in colorectal liver metastases

Assessment of tumour response to chemotherapy is important when assessing efficacy of treatment and comparing differing therapeutic regimens. Percentage hepatic replacement (PHR) is commonly used to assess response to treatment of colorectal hepatic metastases. PHR is dependent not only on tumour volume, but also on hepatic parenchymal volume. The effect of tumour growth on hepatic parenchymal volume is unclear but is of importance owing to its effect on PHR. We assessed tumour and hepatic parenchymal weights in an animal tumour model using dissection, and tumour and hepatic parenchymal volumes in patients with colorectal hepatic metastases using CT scanning, in order to establish how hepatic parenchyma varied with change in metastasis size. There was no significant correlation between tumour and liver parenchyma in either the animal model (r = -0.03, P > 0.05) or the patient study (r = 0.3, P < 0.05). This suggests that hepatic parenchymal volume was preserved in the presence of increasing tumour volume. In a further study of computerised tomographic (CT) scans before and after treatment in patients whose tumours either responded to chemotherapy or continued to grow, change in PHR (median proportion of PHR change = 0.40) significantly (P = 0.04) underestimated the change in tumour volume (median proportion of tumour volume change = 0.56), particularly at higher (> 400 ml) volumes. There was good correlation between change in tumour volume and WHO criteria in assigning patients to tumour growth, stable disease or tumour response categories. This study suggests that, in clinical trials comparing colorectal liver metastasis treatments, metastasis volume and not PHR should be used to assess extent of disease and the effect of treatment.     

Uptake of ATP by liver and kidney in vitro

Rat liver and kidney slices were incubated at 37 degrees C for 1 h in 1.0 ml of Krebs-HCO3 buffer containing 10mM glucose and one of the following: 5 mM [8-14C]ATP, 5 mM [8-14C]ADP, 5 mM [8-14C]AMP, or 5 mM [8-14C]ation medium and tissue extract were subjected to electrophoretic separation and the radioactivity present in ATP, ADP, AMP, IMP, inosine, adenosine, and hypoxanthine was counted. Extensive degradation of the added nucleotide was observed in the presence of both tissues. The concentrations of 14C-labeled ATP and ADP found in the liver and kidney indicated that these compounds were present within the cells. Evidence is presented which suggests that ATP, and to a lesser extent ADP, entered the liver and kidney as such and were not synthesized within the cell from 14C-labeled adenosine.     

Relationship of whole-blood FK506 concentrations to rejection and toxicity in liver and kidney transplants

FK506 (tacrolimus) has been shown to be a safe and effective immunosuppressant for the prevention of organ rejection after liver and kidney transplantation. Like cyclosporine, the use of FK506 has been associated with some adverse effects such as toxicity and organ rejection. Therapeutic monitoring of the whole-blood FK506 drug concentrations has been used in an effort to determine how the concentration of FK506 in the blood is related to the development of toxicity or the risk for organ rejection. Cox regression analysis of two recent clinical trials of FK506 in patients receiving kidney and liver transplants shows a significant correlation between the whole-blood FK506 concentrations and the incidence of both toxicity and organ rejection. Because of these relationships and the pharmacokinetics of FK506, therapeutic monitoring of the whole-blood FK506 levels is expected to be helpful for minimizing the risks of both toxicity and rejection in liver and kidney transplants.     

Functional response of the rat kidney to inhibition of nitric oxide synthesis: role of cytochrome p450-derived arachidonate metabolites

1. We tested the hypothesis that nitric oxide (NO) exerts a tonic inhibitory influence on cytochrome P450 (CYP450)-dependent metabolism of arachidonic acid (AA). 2. N(omega)-nitro-L-Arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase (NOS), increased mean blood pressure (MBP), from 91+/-6 to 137+/-5 mmHg, renal vascular resistance (RVR), from 9.9+/-0.6 to 27.4+/-2.5 mmHg ml(-1) min(-1), and reduced renal blood flow (RBF), from 9.8+/-0.7 to 6.5+/-0.6 ml min(-1)) and GFR from 1.2+/-0.2 to 0.6+/-0.2 ml 100 g(-1) min(-1)) accompanied by diuresis (UV, 1.7+/-0.3 to 4.3+/-0.8 microl 100 g(-1) min (-1)), and natriuresis (U(Na)V, 0.36+/-0.04 to 1.25+/-0.032 micromol 100 g(-1) min(-1)). 3. 12, 12 dibromododec-enoic acid (DBDD), an inhibitor of omega hydroxylase, blunted L-NAME-induced changes in MBP, RVR, UV and U(Na)V by 63+/-8, 70+/-5, 45+/-8 and 42+/-9%, respectively, and fully reversed the reduction in GFR by L-NAME. Clotrimazole, an inhibitor of the epoxygenase pathway of CYP450-dependent AA metabolism, was without effect. 4. BMS182874 (5-dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfo namide), an endothelin (ET)A receptor antagonist, also blunted the increases in MBP and RVR and the diuresis/natriuresis elicited by L-NAME without affecting GFR. 5. Indomethacin blunted L-NAME-induced increases in RVR, UV and U(Na)V. BMS180291 (1S-(1alpha,2alpha,3alpha,4alpha)]-2-[[3-[4-[(++ +pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl ]methyl]benzenepropanoic acid), an endoperoxide receptor antagonist, attenuated the pressor and renal haemodynamic but not the renal tubular effects of L-NAME. 6. In conclusion, the renal functional effects of the CYP450-derived mediator(s) expressed after inhibition of NOS with L-NAME were prevented by inhibiting either CYP450 omega hydroxylase or cyclooxygenase or by antagonizing either ET(A) or endoperoxide receptors. 20-hydroxyeicosatetraenoic acid (20-HETE) fulfils the salient properties of this mediator.     

Thyroid hormones and thyrotropin in liver and kidney insufficiency

In 22 patients with hepatic or renal insufficiency the serum concentrations of trijodothyronin, thyroxine and thyrotropin and also the T4-binding capacity of TBG were determined. The mean serum T3 concentration was found to be significantly lower in patients with hepatic coma when compared with euthyroid subjects. In the cases of renal insufficiency the serum T3 concentrations were in the normal range. Due to hormone loss through dialysis however, the mean value of the T3 concentrations was slightly lower than the average concentration of normal subjects. The obtained results agree with those of our earlier studies which showed that there are significant differences between liver artery and vein T3 concentrations in serum, whereas no such differences could be ascertained between serum concentrations in renal artery and vein. On the basis of these findings it is assumed that conversion of T4 into T3 occurs predominantly in the liver.     

Morphological equivalents of lymphocytic-epithelial interactions in kidney and liver regeneration

AIM: The trial of efficacy of 6-month therapy with madecassol (tablets, ointment, powder) of patients with systemic and focal scleroderma (SS and FS). MATERIALS AND METHODS: 54 patients (49 females and 5 males) aged 15 to 70 years with scleroderma running from 3 months to 15 years entered the study. 30 patients had typical SS, 24 patients had FS. Tablets were given to 18 patients, ointment was applied in 42 patients, powder in 3 and tablets + ointment in 9 patients. Madecassol 10 mg tablets were taken 3 times a day by patients with SS and advanced FS. The ointment was preferred in ulcers and scars on fingers and toes in SS and vascular trophic lesions in FS. In active focal scleroderma the ointment was applied to the skin lesions. The ointment was used 2 times a day (in the morning and evening) for 1-6 months. Madecassol powder was employed rarely, primarily of anal and vulval lesions. RESULTS: 6-month oral course (30 mg/day) in 12 SS patients brought about a decrease of indurative lesions, hyperpigmentation (8), vascular trophic disorders (6) and improvement of general condition (5). Subjective response was good in 10 patients and corresponded to absence of progression. In progressive disease and diffuse skin lesions the drug was ineffective. The best response was obtained in local application of madecassol ointment on digital ulcers in SS. CONCLUSION: Madecassol is effective and well tolerated and therefore recommended for oral and local use in combined treatment of SS adn FS. Indications for per os utelization are: chronic or subchronic SS with limited skin involvement, advanced and/or prone to progression FS in which combined administration of the tablets and ointment is proposed.     

The response of heat shock proteins 25 and 72 to ischaemia in different kidney zones

Class III malocclusion with retrusive maxilla can be orthopedically corrected in the deciduous and mixed dentition, with reverse-pull headgear in combination with rapid palatal expansion. The literature recommends this procedure be carried out before the patient is 8 years old to obtain the optimal orthopedic result. This statement, however, has not been supported by scientific data. The current study examined the treatment effects of patients younger than 8 years old (5 to 8 years) and patients older than 8 years old (9 to 12 years). Thirty patients treated with maxillary protraction and expansion in the Department of Children's Dentistry and Orthodontics, University of Hong Kong were included in this study. Cephalometric radiographs were taken 6 months before the initiation of treatment (T(0)), at the initiation of treatment (T1), and after 6 months of treatment (T2). In this way, (T(2)-T1) represented cephalometric changes during the treatment period and (T1-T0) represented 6 months of growth changes without treatment. Experimental subjects served as their own control in this study. A grid system consisting of maxillary occlusal plane (OL) and a line perpendicular to OL through sella (OLp) was used for linear measurements. A total of 15 linear and 3 angular cephalometric measurements were made. A multivariate analysis of variance (MANOVA), which used age and treatment time as its factors, was used to determine effect of age and/or treatment on each cephalometric parameter. Results indicated strikingly similar therapeutic response between the younger and older age groups. These data suggest that similar skeletal response can be obtained when maxillary protraction was started either before age 8 (5 to 8 years) or after age 8 years (8 to 12 years).     

Primacy of liver glucosensors in the sympathetic response to progressive hypoglycemia

The impact of hepatic glucose concentration on the sympathetic response to progressive hypoglycemia was examined in chronically cannulated conscious male dogs (n = 6). Graded hypoglycemia was induced via peripheral insulin infusion (30 pmol.kg-1.min-1) with either peripheral (PER) or portal (POR) glucose infusion. Over the 260-min experimental period, arterial glycemia was adjusted from 5.2 +/- 0.1 to 2.5 +/- 0.1 mM in decrements of approximately 0.5 mM every 40 min. Arterial glycemias were not significantly different between PER and POR at any measured level. However, hepatic glycemia was significantly elevated at all times during POR (8.4 +/- 0.8 to 3.4 +/- 0.2 mM) when compared to PER (5.2 +/- 0.2 to 2.5 +/- 0.1 mM). Plasma epinephrine values were significantly greater during PER vs. POR at all arterial glycemias below 4.0 mM. At the lowest level of arterial glycemia studied (2.5 +/- 0.2 mM) the epinephrine response above basal was 3-fold greater for PER (8.7 +/- 1.7 nM) when compared to POR (2.6 +/- 0.6 nM) (P < 0.01). Plasma norepinephrine results were similar for the two protocols, with PER demonstrating a 3-fold greater response above basal when compared to POR at 2.5 mM arterial glycemia (P < 0.05). While the sympathetic response was markedly different between protocols when expressed as a function of arterial glycemia, when expressed as a function of hepatic glycemia this discrepancy was largely eliminated. This latter observation supports the liver as the primary locus for glycemic detection relevant to the sympathoadrenal response when hypoglycemia develops slowly--i.e., over a period of 2-3 h. A comparison of the current findings with our previous observations suggests that the hepatic glucosensors may play a greater role in hypoglycemic counterregulation as the rate of fall in glycemia is less.     

Inhibition by warfarin of prothrombin synthesis and of lipid-saccharide synthesis in rat liver

In vivo and in vitro studies using [3H]glucosamine incorporation into prothrombin and into glycolipids were conducted in rat liver to determine the role of lipid-saccharides in the biosynthesis of prothrombin. In vivo studies demonstrated that 10 mg warfarin/kg inhibited the incorporation of radiolabeled glucosamine into liver prothrombin and glycolipids. This inhibition was similar to the kinetics of inhibition of prothrombin synthesis in the liver. In vitro studies demonstrated a time-dependent increase in the incorporation of radiolabeled glucosamine into lipid-saccharides and prothrombin. This incorporation was inhibited 50% by 5 . 10(-4) M warfarin. Warfarin also inhibited the incorporation of radiolabeled glucosamine into glycolipids in a dose-related manner. In all studies, vitamin K-1 reversed the inhibition of glucosamine incorporation into glycolipids and into prothrombin.