Thiazolidinediones increase the wingless-type MMTV integration site family (WNT) inhibitor Dickkopf-1 in adipocytes: a link with osteogenesis.

AIMS/HYPOTHESIS: Dickkopf-1 (DKK1) is a secreted inhibitor of canonical wingless-type MMTV integration site family (WNT) signalling; the key pathway for cell fate and development. Inhibition of WNT signalling by DKK1 in precursor cells promotes adipogenesis and inhibits osteogenesis. Previous studies have shown that treatment of type 2 diabetic patients with thiazolidinediones (TZDs) reduces bone density and increases risk of bone fractures, while body fat is increased. METHODS: We examined the effect of TZDs on secretion and DKK1 levels in pre-adipocytes and mature adipose cells and also measured circulating DKK1 levels in 11 patients with type 2 diabetes before and after treatment with the TZD rosiglitazone for 90 days. RESULTS: TZDs added in vitro rapidly increased DKK1 protein levels and secretion in both fully differentiated adipose cells and pre-adipocytes undergoing differentiation. In parallel, beta-catenin levels, a marker of canonical WNT signalling, were reduced. Serum levels of DKK1 were also increased in several of the patients with type 2 diabetes after treatment with rosiglitazone for 90 days. CONCLUSIONS/INTERPRETATION: These results provide a novel mechanism whereby peroxisome proliferator-activated receptor-gamma activation can terminate WNT signalling and promote adipogenesis. Furthermore, they provide an explanation for why TZD treatment can lead to reduced bone formation and increased risk of fractures, since inhibited WNT signalling in progenitor cells promotes adipogenesis while osteogenesis is reduced.

Deflection of the local interstellar dust flow by solar radiation pressure.

Interstellar dust grains intercepted by the dust detectors on the Ulysses and Galileo spacecrafts at heliocentric distances from 2 to 4 astronomical units show a deficit of grains with masses from 1 x 10(-17) to 3 x 10(-16) kilograms relative to grains intercepted outside 4 astronomical units. To divert grains out of the 2- to 4-astronomical unit region, the solar radiation pressure must be 1.4 to 1.8 times the force of solar gravity. These figures are consistent with the optical properties of spherical or elongated grains that consist of astronomical silicates or organic refractory material. Pure graphite grains with diameters of 0.2 to 0.4 micrometer experience a solar radiation pressure force as much as twice the force of solar gravity.

Validation of the use of exogenous gonadotropins (PG600) to increase the efficiency of gilt development programs without affecting lifetime productivity in the breeding herd.

The objective of this study was to validate the use of exogenous gonadotropin (PG600) treatment for stimulating estrus in noncyclic gilts and to compare lifetime productivity of gilts recorded as having natural (NAT) versus PG600-induced (PG600) first estrus in a commercial setting. Prepubertal Camborough gilts ( = 4,489) were delivered to a gilt development unit (GDU) with the goal of delivering known cyclic breeding-eligible females to the sow farm (SF). A boar exposure area (BEAR) was designed to facilitate stimulation and detection of puberty by providing fence line and direct contact (15 min daily) with mature boars over an intensive 28-d period, starting at approximately d 160 (d 0). At d 14, nonpubertal gilts were mixed in new pen groups. At d 23, noncyclic "opportunity" gilts with no record of vulval development and required to meet breeding targets, were eligible for treatment with PG600 to induce puberty. Overall, 77.6% ( = 3,475) of gilts exhibited standing estrus (NAT = 2,654; PG600 = 821) and were eligible for shipping to the SF at approximately 35 d, and 76.6% of gilts that were administered PG600 exhibited the standing reflex within 13 d of treatment. Ultimately, 72.0% of gilts entering the GDU were delivered to the SF as breeding-eligible females. Considering the gilts delivered, a greater proportion of NAT than PG600 gilts were successfully bred ( < 0.001) and had better farrowing rates to first service, and overall farrowing rates (including gilts that returned to estrus and were rebred) were greater for NAT compared to PG600 gilts ( < 0.001) . Farrowing rates at second and third parity were similar between NAT and PG600 gilts; however, at fourth parity, a greater proportion of NAT gilts farrowed. In comparison, considering only gilts served, there was no difference ( > 0.05) in the proportion of NAT and PG600 gilts farrowing a third litter, but a greater proportion of NAT than PG600 gilts farrowed their fourth litter ( < 0.001). There was no difference between NAT and PG600 gilts for litter size at parity 1 through 4 or total pigs born over 4 parities ( > 0.05). A negative correlation ( < 0.0001) was detected between age at puberty and lifetime growth rate at puberty, and growth rate classification affected age and weight at puberty. However, retention rates and total sow productivity to parity 4 were not affected by growth rate classification at puberty.

Gsalpha-mediated regulation of the carnitine carrier in S49 lymphoma cells.

Carnitine is essential for mitochondrial oxidation of long-chain fatty acids. Peripheral cells rely on plasma transport of carnitine which is taken up by an active mechanism in the plasma membrane. This project investigated the plasma membrane bound carnitine carrier in cultured S49 lymphoma cells. We investigated wild-type cells and two mutant cells lines showing deficient activity of adenylyl cyclase, cyc- lacking and H21a containing a deficient Gsalpha. Plasma membranes derived from cyc- cells displayed six times more carnitine binding sites and a 1.35 times faster uptake rate than plasma membranes from wild-type cells. In vitro mixing of plasma membranes from cyc- and wild-type cells transferred a factor reducing the number of expected carnitine binding sites by about 30%. Cyclic AMP could not substitute for wild-type membranes as the inhibitor of carnitine binding to plasma membranes derived from cyc- cells. Cholera toxin induced ADP-ribosylation of Gsalpha causing activation of Gsalpha present in wild-type but not in cyc- cells, further reducing carnitine uptake and carnitine binding to plasma membranes. Our findings thus supported the notion that Gsalpha by a mechanism not involving cyclic AMP inhibited cellular uptake of carnitine by reducing the number of available carnitine binding sites in plasma membranes.

Behavioral symptoms in adult rats after postnatal L-nitro-arginine.

We addressed experimentally the suggestion by Gally et al. [Gally J. A., Read Montague P., Reeke G. N. Jr and Edelman G. M. (1990) Proc. Natl Acad. Sci. U.S.A. 87, 3547-3551] that nitric oxide may play a role in the use-dependent modification of synaptic efficacy in the developing nervous system. In a preliminary control experiment, we treated rat pups from postnatal day 8 to postnatal day 22 with a nitric oxide synthase blocker (L-nitro-arginine) and compared their growth curves and brain weights to those of saline injected control pubs. No significant differences were found after the 14 days of nitric oxide synthase inhibition. In the subsequent experiment, we inhibited nitric oxide synthesis in rat pups from postnatal day 8 to day 29 and assessed their place learning ability and open field behavior as adults. We found an increased speed of habituation of locomotion in an open field in 5-month-old rats that had been treated postnatally with a nitric oxide synthase blocker. There was no difference between treated and non-treated rats with respect to place learning in a water maze. We conclude that perturbation of nitric oxide production during early postnatal development does not preclude normal learning and memory function in the adult.

Glucagon increases cellular uptake and plasma membrane binding of L-carnitine in S49 lymphoma cells.

The carnitine carrier was investigated in S49 lymphoma cells, a murine cell type cultured in suspension culture and used widely in signal transduction studies. Carnitine uptake in S49 lymphoma cells was stimulated almost twofold by pretreatment of intact cells by 0.5 microM glucagon for 4 h. Plasma membranes derived from S49 lymphoma cells bound 556 +/- 81 pmol/mg protein whereas pretreatment by 0.5 microM glucagon for 4 h of cells, before cell harvesting and preparation of plasma membranes, increased the number of carnitine binding sites to 1196 +/- 52 pmol/mg protein. The glucagon pretreatment also altered the carnitine binding characteristics from a two site model to a single binding site. S49 lymphoma cells were further shown to contain 50.9 +/- 2.6 fmol glucagon receptors per 10(6) cells. We conclude that glucagon stimulated cellular uptake of carnitine by a mechanism that at least partially operated through increasing the number of available carnitine binding sites in plasma membranes.

State health expenditure accounts: Minnesota's perspective.

Minnesota's approach to the development and use of State health expenditure accounts (SHEAs) was developed to assist State policymakers with decisions regarding health care reform. The accounts are based on an annual survey of third-party payers and summary Medicaid and Medicare data. Summary data are presented along with a discussion of data collection methodology, estimation, and dissemination. Minnesota's experience demonstrates that the ability of States to conduct detailed analysis of health care spending and to use these estimates to change State policy, inform national policy debate, conduct impact analysis, educate policymakers, and monitor market trends.

The effect of differences in objective and subjective definitions of childhood physical abuse on estimates of its incidence and relationship to psychopathology.

The relationship between objective and subjective definitions of physical abuse and the lifetime prevalence of depression was examined in 280 women attending a family medicine clinic at a large medical center. Based on their responses to a detailed questionnaire regarding discipline and abuse in childhood, 28.2% of these women were objectively defined as abused. Only 11.4% subjectively defined themselves as abused. The proportion of women who experienced depression during their lifetime was highest among those who defined themselves as abused (83%), intermediate among those who met objective criteria for having been physically abused, but did not define themselves as such (56%), and lowest among those who did not meet objective criteria for a history of physical abuse (35%). Similar relationships were found for history of psychotherapy, receipt of psychoactive medication, history of hospitalization for depression, suicide attempts and self-injury.

Acute filariasis in a springhaas.

A 2-yr old Springhaas (Pedetes capensis; Pedetidae, Rodentia) imported into the USA from the Republic of South Africa was severely debilitated as the result of abberant migrations of adult Filaria versterae (Filarioidea: Filariidae) normally confined to the subcutaneous tissues of this host in Africa. Some nematodes invaded the peritoneal and thoracic cavities, the pericardial sac and the lungs. Invasion of the lungs resulted in life-threatening respiratory distress necessitating euthanasia. Filaria versterae is redescribed.

Terbutaline toxicosis in a dog.

A 2-year-old Collie-type dog with lethargy, tachycardia, tachypnea, and muscle tremors was examined 10 hours after the dog had bitten into an inhalation canister containing the beta 2-adrenergic agonist, terbutaline sulfate. Electrocardiographic findings (ventricular premature contractions and paroxysmal ventricular tachycardia) were consistent with excessive adrenergic activity resulting from terbutaline toxicosis. Serum terbutaline concentration was similar to that reported in human beings with terbutaline toxicosis. The dog did not respond to initial treatment with fluids and lidocaine administered IV, but rapid resolution of signs and conversion to normal sinus rhythm was achieved after IV infusion of propranolol.

Methylphenidate toxicosis in a cat.

A 10-year-old cat with restlessness, vocalizing, and circling was examined 13 hours after it was inadvertently given a 5-mg tablet of the CNS stimulant methylphenidate hydrochloride. Physical examination findings (generalized tremors, agitation, mydriasis, tachycardia, tachypnea, and hypertension) were consistent with overstimulation of the CNS and excessive adrenergic activity resulting from methylphenidate toxicosis. Plasma methylphenidate concentration at admission (83 ng/ml) was 5 to 16 times greater than the concentration reported to provide therapeutic effect in human beings. The cat was placed in a dark, padded cage to minimize external stimuli, and supportive care consisting of fluids and diazepam were administered. Clinical signs resolved within 25 hours after ingestion of methylphenidate.

SU-E-T-89: Characterization of Dental Restoration Material for Cs-137 Radiation Dosimetry.

PURPOSE: The purpose of this work is to characterize the radiation-induced thermoluminescence properties of a dental restoration material and to see if the material might be feasible for use in retrospective radiation dosimetry. METHODS: Retrospective, or accidental, dosimetry is the study of using nearby materials to measure radiation received by individuals. In this project we obtained samples of Ivoclar Vivadent e.max CAD material, a glass-ceramic used for making dental restorations such as full or partial crowns. The samples were machined into square chips .32 cm × .32 cm × .089 cm and annealed in the same furnace used by the dentist. The samples were exposed to a Cs-137 source using a PMMA source holder and then read in a Harshaw 3500 TLD reader. The samples were read without nitrogen gas flux using heating rates of 5 degrees C/s or 10 degrees C/s up to a maximum temperature of 400 degrees Celsius. The glow curves were analyzed using Systat PeakFIT peak-fitting software and Microsoft Excel spreadsheets. The authors gratefully thank Dr. Aaron Imdieke and the staff of River City Dental, St. Cloud, MN for the dental restoration materials and the use of their dental furnace. RESULTS: A sample subjected to a radiation exposure of .04 C/kg exhibits a glow curve with a prominent peak at approximately 140 degrees Celsius, which is well-modeled by the first order glow curve deconvolution formula developed by Kitis, Gomez-Ros, and Tuyn. The activation energy corresponding to this peak is approximately 1 eV. The thermoluminescent signal fades with time after exposure. CONCLUSIONS: Ivoclar Vivadent e.max CAD dental restoration material has the potential to be used as a material for retrospective Cs-137 radiation dosimetry. Future work could look at its thermoluminescent dosimetry properties in more detail and also at other dental restoration materials. The authors would like to thank Dr. Aaron Imdieke and the staff of River City Dental, St. Cloud, MN, for the donation of scrap dental restoration materials and the use of their dental furnace.