Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses

On the basis of results of studies using high doses of estrogens, exposure to estrogen during fetal life is known to inhibit prostate development. However, it is recognized in endocrinology that low concentrations of a hormone can stimulate a tissue, while high concentrations can have the opposite effect. We report here that a 50% increase in free-serum estradiol in male mouse fetuses (released by a maternal Silastic estradiol implant) induced a 40% increase in the number of developing prostatic glands during fetal life; subsequently, in adulthood, the number of prostatic androgen receptors per cell was permanently increased by 2-fold, and the prostate was enlarged by 30% (due to hyperplasia) relative to untreated males. However, as the free serum estradiol concentration in male fetuses was increased from 2- to 8-fold, adult prostate weight decreased relative to males exposed to the 50% increase in estradiol. As a model for fetal exposure to man-made estrogens, pregnant mice were fed diethylstilbestrol (DES) from gestation days 11 to 17. Relative to controls, DES doses of 0.02, 0.2, and 2.0 ng per g of body weight per day increased adult prostate weight, whereas a 200-ng-per-g dose decreased adult prostate weight in male offspring. Our findings suggest that a small increase in estrogen may modulate the action of androgen in regulating prostate differentiation, resulting in a permanent increase in prostatic androgen receptors and prostate size. For both estradiol and DES, prostate weight first increased then decreased with dose, resulting in an inverted-U dose-response relationship.     

The ability of low doses of caffeine to serve as reinforcers in humans: A replication.

Eleven coffee drinkers were given concurrent access to placebo coffee versus coffee to which 25 or 50 mg of caffeine had been added. The 25-mg dose reliably served as a reinforcer in 2 participants and the 50-mg dose served as a reinforcer in 5 participants. When only placebo coffee was available, participants reported more headaches and drowsiness and less stimulation, alertness, and relaxation. The occurrence of headache and drowsiness with placebo coffees predicted subsequent caffeine reinforcement. These results replicate our prior findings that low doses of caffeine can reliably serve as a reinforcer in a subsample of caffeine users and that caffeine withdrawal predicts caffeine reinforcement. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Defects in embryonic hindbrain development and fetal resorption resulting from vitamin A deficiency in the rat are prevented by feeding pharmacological levels of all-trans-retinoic acid

Vitamin A is required for reproduction and normal embryonic development. We have determined that all-trans-retinoic acid (atRA) can support development of the mammalian embryo to parturition in vitamin A-deficient (VAD) rats. At embryonic day (E) 0.5, VAD dams were fed purified diets containing either 12 micrograms of atRA per g of diet (230 micrograms per rat per day) or 250 micrograms of atRA per g of diet (4.5 mg per rat per day) or were fed the purified diet supplemented with a source of retinol (100 units of retinyl palmitate per day). An additional group was fed both 250 micrograms of atRA per g of diet in combination with retinyl palmitate. Embryonic survival to E12.5 was similar for all groups. However, embryonic development in the group fed 12 micrograms of atRA per g of diet was grossly abnormal. The most notable defects were in the region of the hindbrain, which included a loss of posterior cranial nerves (IX, X, XI, and XII) and postotic pharyngeal arches as well as the presence of ectopic otic vesicles and a swollen anterior cardinal vein. All embryonic abnormalities at E12.5 were prevented by feeding pharmacological amounts of atRA (250 micrograms/g diet) or by supplementation with retinyl palmitate. Embryos from VAD dams receiving 12 micrograms of atRA per g of diet were resorbed by E18.5, whereas those in the group fed 250 micrograms of atRA per g of diet survived to parturition but died shortly thereafter. Equivalent results were obtained by using commercial grade atRA or atRA that had been purified to eliminate any potential contamination by neutral retinoids, such as retinol. Thus, 250 micrograms of atRA per g of diet fed to VAD dams (approximately 4.5 mg per rat per day) can prevent the death of embryos at midgestation and prevents the early embryonic abnormalities that arise when VAD dams are fed insufficient amounts of atRA.     

Lyme disease in outdoor workers on Assateague Island: high tick-exposure but low disease risk

Endothelin-1 (ET-1)-converting enzyme (ECE) activity in the human serum lipoprotein fraction was studied using a sensitive enzyme immunoassay and reverse-phase high performance liquid chromatography. The ECE activity of cleaving synthetic human big ET-1 into ET-1 by the serum lipoprotein fraction was about 14-times greater than that by whole serum, and the activity was closely associated with lipoprotein itself. The lipoprotein ECE activity, which was optimal at pH 7.0, was inhibited by EDTA, o-phenanthroline, phosphoramidon, thiorphan, phenylmethanesulfonyl fluoride and chymostatin, but not by cysteine or aspartic proteinase inhibitors, suggesting metalloproteinase- and chymotrypsin-like properties. These results suggest that the serum lipoprotein ECE may be involved in the processing of big ET-1 to ET-1 in the circulatory system.     

Repeat exposure to incremental doses of acetaminophen provides protection against acetaminophen-induced lethality in mice: an explanation for high acetaminophen dosage in humans without hepatic injury

In studies designed to simulate a clinical observation in which an individual became tolerant to normally lethal doses of acetaminophen (APAP), mice were pretreated with increasing doses of APAP for 8 days and challenged on day 9 with normally supralethal doses of APAP. These animals developed minimal hepatotoxicity after a challenge dose with a fourfold increase in LD50 to 1,350 mg/kg. The pretreatment regimen resulted in hepatic changes including: centrilobular localization of 3-(cysteine-S-yl)APAP protein adducts, selective down-regulation of cytochrome P4502E1 (CYP2E1) and CYP1A2 that produced the toxic metabolite, N-acetyl-p-benzoquinone imine, higher levels of reduced glutathione (GSH), centrilobular inflammation, and a fourfold increase in hepatocellular proliferation. The protection against the lethal APAP doses afforded by pretreatment is secondary to these changes and to the associated regional shift in the bioactivation of the APAP challenge dose from centrilobular to periportal regions where CYP2E1 is not found, protective GSH is more abundant, and where cell-proliferative responses are better able to sustain repair. This shift in APAP bioactivation results in less-intense covalent binding that is more diffuse and spread uniformly throughout the hepatic lobe, most likely contributing to protection by delaying the early onset of liver injury that has been generally associated with centrilobular localization of the adducts. Intervention of APAP pretreatment-induced cell division in mice with colchicine left them resistant to a 500-mg/kg (normally lethal) dose of APAP, but unable to survive a 1,000-mg/kg APAP challenge dose. The data demonstrate multiple mechanistic components to the protection afforded by APAP pretreatment. Whereas metabolic and physiological changes not dependent on cell proliferation are adequate to protect against 500 mg/kg APAP, these changes plus a potentiated cell-proliferative response are necessary for protection against the supralethal 1,000-mg/kg APAP dose. Furthermore, the data document an uncoupling of the traditional association between covalent binding and toxicity, and suggest that the assessment of toxicity following repeated or chronic APAP exposure must consider altered drug interactions and parameters besides those historically used to assess acute APAP overdose.     

Determinants of plasma anti-oxidant vitamin levels in a population at high risk for stomach cancer

A high-performance liquid chromatographic method was developed for the determination of a new antiulcer agent, YJA-20379-2, in human plasma and urine. The sample preparation was simple: 2.5-volume of acetonitrile was added to the biological sample to deproteinize. A 50-microliter aliquot of the supernatant was injected onto a C18 reversed-phase column. The mobile phase employed was methanol-0.1M S?rensen phosphate buffer of pH 7.0-H2O (75:2:25, v/v/v), and was run at a flow-rate of 1.0 ml/min. The column effluent was monitored by ultraviolet detector at 295 nm. The retention time for YJA-20379-2 was approximately 7.0 min. The detection limits for YJA-20379-2 in human plasma and urine were both 100 ng/ml. The coefficients of variation of the assay (within-day and between-day) were generally low (below 9.16%) for both the human plasma and urine. No interference from endogenous substances was found.     

Starting low but ending high: A reversal of the anchoring effect in auctions.

Counter to the "start high, end high" effect of anchors in individual judgments and dyadic negotiations, 6 studies using a diverse set of methodologies document how and why, in the social setting of auctions, lower starting prices result in higher final prices. Three processes contribute to this effect. First, lower starting prices reduce barriers to entry, which increase traffic and generate higher final prices. Second, lower starting prices entice bidders to invest time and energy (creating sunk costs) and, consequently, escalate their commitments. Third, the traffic generated by lower starting prices can lead bidders to infer value in the item, thereby explaining previous findings that traffic begets more traffic. The authors show that barriers to entry that limit traffic (e.g., a misspelled brand name) lead to anchoring's normal assimilative effect rather than its reversal. By broadening the understanding of anchors to extended social interactions and open markets, the authors identify when and why starting prices anchor. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of folic acid and combinations of folic acid and vitamin B-12 on plasma homocysteine concentrations in healthy, young women

BACKGROUND: Elevated plasma homocysteine concentrations are considered to be a risk factor for vascular disease and fetal malformations such as neural tube defects. Recent studies have shown that plasma homocysteine can be lowered by folic acid in amounts corresponding to 1-2 times the recommended dietary allowance. Preliminary evidence indicates that vitamin B-12 may be beneficial when included in supplements or in a food-fortification regimen together with folic acid. OBJECTIVE: We aimed to compare the homocysteine-lowering potential of a folic acid supplement with that of 2 supplements containing different doses of vitamin B-12 in addition to folic acid. DESIGN: Female volunteers of childbearing age (n = 150) received a placebo for 4 wk followed by a 4-wk treatment with either 400 microg folic acid, 400 microg folic acid + 6 microg vitamin B-12, or 400 microg folic acid + 400 microg vitamin B-12. RESULTS: Significant reductions (P < 0.001) in plasma homocysteine were observed in all groups receiving vitamin treatment. The effect observed with the combination of folic acid + 400 microg vitamin B-12 (total homocysteine, -18%) was significantly larger than that with a supplement containing folic acid alone (total homocysteine, -11%) (P < 0.05). Folic acid in combination with a low vitamin B-12 dose (6 microg) affected homocysteine as well (-15%). CONCLUSIONS: These results suggest that the addition of vitamin B-12 to folic acid supplements or enriched foods maximizes the reduction of homocysteine and may thus increase the benefits of the proposed measures in the prevention of vascular disease and neural tube defects.     

Midday exposure to bright light changes the circadian organization of plasma melatonin rhythm in humans

With the aim to develop a simple behavioural method for the study of hyperalgesic processes and for the evaluation of anti-hyperalgesic properties of analgesic drugs, the effect of the tail injection of formalin (10% formaldehyde intradermally) on hindpaw nociceptive thresholds to thermal stimulation was evaluated in the rat. The formalin injection in the tail induced a significant reduction of plantar test latencies. The pretreatment with the competitive N-methyl-D-aspartate (NMDA) receptor antagonist CGP 37849 (2.0 mg/kg) completely blocked the hyperalgesic action of the formalin. The analgesic drug paracetamol (25 mg/kg) was able to prevent hyperalgesia. However, this drug was unable to block hyperalgesia when already established. Our results suggest that this method could be used for the evaluation of analgesic drugs in an experimental setting representative of clinical pain.     

Follitropin (FSH) deficiency in an infertile male due to FSHbeta gene mutation. A syndrome of normal puberty and virilization but underdeveloped testicles with azoospermia, low FSH but high lutropin and normal serum testosterone concentrations

Vitamin K deficiency bleeding within the first 24 h of life is caused in most cases by maternal drug intake (e.g. coumarins, anticonvulsants, tuberculostatics) during pregnancy. Haemorrhage is often life-threatening and usually not prevented by vitamin K prophylaxis at birth. We report a case of severe intracranial bleeding at birth secondary to phenobarbital-induced vitamin K deficiency and traumatic delivery. Burr hole trepanations of the skull were performed and the subdural haematoma was evacuated. Despite the severe prognosis, the infant showed an unexpected good recovery. At the age of 3 years, neurological examinations were normal as was the EEG at the age of 9 months. CT showed close to normal intracranial structures. CONCLUSION: This case report stresses the importance of antenatal vitamin K prophylaxis and the consideration of a primary Caesarean section in maternal vitamin K deficiency states and demonstrates the successful management of massive subdural haemorrhage by a limited surgical approach.     

The health status of children up to 14 years old living in an area of long-term post-accident exposure to low doses of ionizing radiation

An assessment is submitted of morbidity rates and physical development of children aged under 14, residing in the territories being monitored after the Chernobyl Power Plant accident. A high level of disharmony in physical development of the children examined was recordable, as was an excess in morbidity of both general and separate classes of disease entities among the pediatric population having been victims of the Chernobyl accident, as compared to that in relatively "clean" areas and in Ukraine as a whole.     

Effects of prenatal exposure to low concentrations of carbon monoxide on sexual behaviour and mesolimbic dopaminergic function in rat offspring

1. Inhalation of low concentrations of carbon monoxide (CO) by pregnant rats (75 and 150 p.p.m. from day 0 to day 20 of gestation) leads to changes in mesolimbic dopaminergic transmission associated with an impairment of sexual behaviour in male offspring. 2. Eighty day old males exposed in utero to CO (150 p.p.m.) exhibited a significant increase in mount/ intromission latency as well as a significant decrease in mount/intromission frequency. A significant decrease in ejaculation frequency was also found in CO (150 p.p.m.)-exposed animals. 3. The acute administration of amphetamine, at a dose (0.5 mg kg(-1) s.c.) stimulating copulatory activity in control rats, failed to reduce mount/intromission latency and did not increase mount frequency in 80-day offspring exposed to CO (150 p.p.m.) during gestation. 4. These behavioural alterations were paralleled by neurochemical changes (in vivo microdialysis) showing that prenatal CO exposure, at concentrations (150 p.p.m.) that did not affect basal extracellular levels of dopamine in the nucleus accumbens, blunted the amphetamine (0.5 mg kg(-1) s.c.)-induced increase in dopamine release in 80-day old male rats. 5. No significant changes in either behavioural or neurochemical parameters were observed in 10-month old rats exposed prenatally to CO. 6. Since the alterations in sexual behaviour and dopaminergic transmission have been produced by prenatal exposure to CO levels resulting in maternal blood carboxyhaemoglobin concentrations equivalent to those maintained by human cigarette smokers, the present data further point out the large risk that the smoking mother poses for her offspring.     

Diet modification alters plasma HDL cholesterol concentrations but not the transport of HDL cholesteryl esters to the liver in the hamster

These studies were undertaken to investigate the mechanism whereby diet modification alters the plasma concentration of high density lipoprotein (HDL) cholesteryl ester and apoA-I and to determine whether diet-induced alterations in circulating HDL levels are associated with changes in the rate of reverse cholesterol transport. Rates of HDL cholesteryl ester and apoA-I transport were measured in hamsters fed a control low-cholesterol, low-fat diet or the same diet supplemented with soluble fiber (psyllium) or with cholesterol and triglyceride (Western-type diet). The Western-type diet increased the plasma concentration of HDL cholesteryl ester by 46% compared to the control diet and by 86% compared to the psyllium-supplemented diet; nevertheless, the absolute rates of HDL cholesteryl ester transport to the liver were identical in the three groups. Diet-induced alterations in circulating HDL cholesteryl ester levels were due to changes in the rate of HDL cholesteryl ester entry into HDL (whole body HDL cholesteryl ester transport) and not to regulation of HDL cholesteryl ester clearance mechanisms. The Western-type diet increased the plasma concentration of HDL apoA-I by 25% compared to the control diet and by 45% relative to the psyllium-supplemented diet. Diet-induced alterations in plasma HDL apoA-I concentrations were also due entirely to changes in the rate of apoA-I entry into HDL (whole body HDL apoA-I transport). These studies demonstrate that the absolute flux of HDL cholesteryl ester to the liver, which reflects the rate of reverse cholesterol transport, remains constant under conditions in which plasma HDL cholesteryl ester concentrations are altered over a nearly 2-fold range by diet modification.     

Tolerance to effects of high doses of ethanol: 1. Lethal effects in mice

Both the alpha- and beta-anomers of 4-methylumbelliferyl-D-glucosaminide were synthesized and shown to be substrates for the lysosomal acetyl-CoA:glucosaminide N-acetyltransferase. Using the beta-anomer, fibroblasts and leukocytes from 11 different Sanfilippo C patients showed < 1% of mean normal N-acetyltransferase activity. Heterozygotes showed intermediate activities. The enzymatic liberation of the fluorochrome from 4-methylumbelliferyl-beta-D-glucosaminide requires the sequential action of the N-acetyltransferase and beta-hexosaminidase. Normal beta-hexosaminidase activity caused complete hydrolysis of the reaction intermediate 4-methylumbelliferyl-beta-D-N-acetylglucosaminide formed by the N-acetyltransferase. In cell extracts with a beta-hexosaminidase deficiency, however, a second incubation in the presence of excess beta-hexosaminidase is needed to avoid underestimation of the N-acetyltransferase activity.     

Respiratory changes due to long-term exposure to urban levels of air pollution: a histopathologic study in humans

STUDY OBJECTIVES: To evaluate the potential associations between long-term exposure to air pollution and histopathologic evidence of damage to the lungs in humans. DESIGN: Lung tissue samples were collected during necropsies of individuals who died due to violent causes, selected on the basis of their exposure background. PATIENTS: The exposed group was composed of individuals who lived in Guarulhos, an area with high mean levels of inhalable particles. The control group was composed of individuals who lived in two cities with economies based on agricultural activities: Ribeir?o Preto and Ourinhos. Interventions: Information about cigarette smoking and occupational exposure was obtained from family members. MEASUREMENTS AND RESULTS: Morphometric evaluation of the main bronchus was conducted to determine the volume ratio of submucosal glands. Histopathologic alterations of the bronchioli were evaluated by scoring the presence of inflammatory reaction, wall thickening, and secretory hyperplasia. The number of spots of carbon deposition was counted along the regions of lymphatic drainage (visceral pleura and axial connective tissue around bronchi and blood vessels). Statistical analysis was done by means of regression models controlled for age, smoking, and occupational exposure. Lungs collected from the high pollution area presented evidence of more histopathologic damage in comparison to those from the clean environments. These effects were observed even after controlling for individual differences in age, sex, and cigarette smoking levels. CONCLUSIONS: These results suggest that long-term exposure to air pollution may contribute to the pathogenesis of airway disease, and that urban levels of air pollution have adverse effects on the respiratory tract.     

Differences in the lipoprotein distribution of free and liposome-associated all-trans-retinoic acid in human, dog, and rat plasma are due to variations in lipoprotein lipid and protein content

The objective of the proposed study was to determine the distribution in plasma lipoprotein of free all-trans retinoic acid (ATRA) and liposomal ATRA (Atragen; composed of dimyristoyl phosphatidylcholine and soybean oil) following incubation in human, rat, and dog plasma. When ATRA and Atragen at concentrations of 1, 5, 10, and 25 micrograms/ml were incubated in human and rat plasma for 5, 60, and 180 min, the majority of the tretinoin was recovered in the lipoprotein-deficient plasma fraction. However, when ATRA and Afragen were incubated in dog plasma, the majority of the tretinoin (> 40%) was recovered in the high-density lipoprotein (HDL) fraction. No differences in the plasma distribution between ATRA and Atragen were found. These data suggest that a significant percentage of tretinoin associates with plasma lipoproteins (primarily the HDL fraction) upon incubation in human, dog, and rat plasma. Differences between the lipoprotein lipid and protein profiles in human plasma and in dog and rat plasma influenced the plasma distribution of ATRA and Atragen. Differences in lipoprotein distribution between ATRA and Atragen were not observed, suggesting that the drug's distribution in plasma in not influenced by its incorporation into these liposomes.     

Clinical significance of erythrosedimentation rate in cancer in relation to cytokine production: correlation with high IL-6 and low IL-2 blood concentrations

Despite its well documented unfavourable prognostic significance in several human diseases, including cancer, the cytokinic mechanisms responsible for an increased erythrosedimentation rate (ESR) still remain to be better analyzed and defined. The recent possibility to measure cytokine concentrations in the blood of patients has allowed us to explore the possible relation between ESR values and endogenous cytokine secretions. This preliminary study was performed to evaluate the relationship between ESR values and serum levels of IL-2 and IL-6, which represent the most important cytokines responsible for the activation and the suppression, respectively, of host anticancer immune reaction. The study included 33 consecutive solid tumor patients, 22 of whom showed distant organ metastases. Abnormally high values of ESR were present in 21 patients, including 18/22 metastatic patients and 3/11 nonmetastatic patients. Patients with elevated values of ESR showed significantly higher mean levels of IL-6 and significantly lower mean concentrations of IL-2 with respect to those found in patients with normal ESR values. These results would show that cancer-related increase in ESR values is associated with low levels of IL-2 and high levels of IL-6. Since IL-2 plays an essential role in the anticancer immunity and IL-6 may suppress the antitumor immune defenses, the evidence of low levels of IL-2 and high values of IL-6 in cancer patients with increased ESR values would explain the unfavourable prognostic significance of high ESR values in human neoplasms.     

Antipyrine: radioimmunoassay in plasma and saliva following administration of a high dose and a low dose

The body's equilibrium is possible thanks to the integration of skeletal structure, vertebrae, ligaments and muscles to form one functional unity. The forces which determine posture are composed of two complementary systems, the ligamentary and the muscular systems, which together determine a dynamic act of balance. The ligaments operate mainly against the visco-hydraulic pressure of the nucleus pulposus and bind the vertebral bodies together, whereas the muscles exhibit an antigravity function and support spinal stability. A mathematical model based on a mixed theory of directed and oriented curves is proposed. Through this model it is possible to develop an exact theory governing the deformation of the ligamentous spine. This theory should be universal in the sense that it can be used to supply the spine in any of its environments.     

Effects of two low-fat diets, high and low in polyunsaturated fatty acids, on plasma lipid peroxides and serum vitamin E levels in free-living hypercholesterolaemic men

Diet enriched with polyunsaturated fat may increase the susceptibility of LDL to oxidation. Therefore the effects of two low-fat diets on plasma lipid peroxides in free-living mildly hypercholesterolaemic men (n = 37) were investigated in a randomized single-blind 28-week study. Composition of the diets were (1) American Heart Association (AHA) type 32/10:8:8 (indicating percentages of energy from total fat/saturated fat:monoenes:polyenes in actual diet); (2) low-fat 30/12:8:3. The subjects kept 3-day dietary records five times during the study to estimate the intake of nutrients. Plasma lipid peroxides were measured photometrically as the thiobarbituric-acid reactive substances (TBARS). Levels of serum vitamin E during the study were also determined. Mean change (+/- SD) in serum low density lipoprotein (LDL) cholesterol was similar in both groups (-0.32 +/- 0.76 vs -0.32 +/- 0.87 mmol/l) (AHA type vs low-fat). Level of TBARS decreased (P < 0.05) during the AHA type diet (-8.4 +/- 37.1%) (mean +/- SD) and increased (P = 0.228) during the low-fat diet (+8.7 +/- 27.0%) from 0 to 6 months. The mean intake of total active tocopherols was greater (14.7 +/- 3.7 mg) during the AHA type diet compared to the low-fat diet (7.8 +/- 2.1 mg). Serum vitamin E to LDL cholesterol ratio increased from 8.9 +/- 2.9 to 9.6 +/- 2.4 nmol/mmol (0 vs 6 months) (P = 0.07) during the AHA type diet and from 8.6 +/- 2.6 to 9.3 +/- 2.4 nmol/mmol (P = 0.159) during the low-fat diet.(ABSTRACT TRUNCATED AT 250 WORDS)