Uptake and virological outcomes of single- versus multi-tablet antiretroviral regimens among treatment-naïve youth in the HIV Research Network.

OBJECTIVES: Several single-tablet regimens (STRs) are now available and are recommended for first-line antiretroviral therapy (ART); however, STR use for youth with HIV (YHIV) has not been systematically studied. We examined the characteristics associated with initiation of STRs versus multi-tablet regimens (MTRs) and the virological outcomes for youth with nonperinatally acquired HIV (nPHIV). METHODS: A retrospective cohort study of nPHIV youth aged 13-24 years initiating ART between 2006 and 2014 at 18 US HIV clinical sites in the HIV Research Network was performed. The outcomes measured were initiation of STRs versus MTRs, virological suppression (VS) at 12 months, and time to VS. Demographic and clinical factors associated with initiation of STR versus MTR ART and VS (< 400 HIV-1 RNA copies/mL) at 12 months after initiation were assessed using multivariable logistic regression. Cox proportional hazards regression was used to assess VS within the first year. RESULTS: Of 987 youth, 67% initiated STRs. Of the 589 who had viral load data at 1 year, 84% of those on STRs versus 67% of those on MTRs achieved VS (P < 0.01). VS was associated with STR use [adjusted odds ratio (AOR) 1.61; 95% confidence interval (CI) 1.01-2.58], white (AOR 2.41; 95% CI 1.13-5.13) or Hispanic (AOR 2.38; 95% CI 1.32-4.27) race/ethnicity, and baseline CD4 count 351-500 cells/µL (AOR 1.94; 95% CI 1.18-3.19) and > 500 cells/µL (AOR 1.76; 95% CI 1.0-3.10). STR use was not associated with a shorter time to VS compared with MTR use [hazard ratio (HR) 1.07; 95% CI 0.90-1.28]. CONCLUSIONS: Use of STR was associated with a greater likelihood of sustained VS 12 months after ART initiation in YHIV.

Glutamine and hyperammonemic crises in patients with urea cycle disorders.

UNLABELLED: Blood ammonia and glutamine levels are used as biomarkers of control in patients with urea cycle disorders (UCDs). This study was undertaken to evaluate glutamine variability and utility as a predictor of hyperammonemic crises (HACs) in UCD patients. METHODS: The relationships between glutamine and ammonia levels and the incidence and timing of HACs were evaluated in over 100 adult and pediatric UCD patients who participated in clinical trials of glycerol phenylbutyrate. RESULTS: The median (range) intra-subject 24-hour coefficient of variation for glutamine was 15% (8-29%) as compared with 56% (28%-154%) for ammonia, and the correlation coefficient between glutamine and concurrent ammonia levels varied from 0.17 to 0.29. Patients with baseline (fasting) glutamine values >900 µmol/L had higher baseline ammonia levels (mean [SD]: 39.6 [26.2]µmol/L) than patients with baseline glutamine ≤ 900 µmol/L (26.6 [18.0]µmol/L). Glutamine values >900 µmol/L during the study were associated with an approximately 2-fold higher HAC risk (odds ratio [OR]=1.98; p=0.173). However, glutamine lost predictive significance (OR=1.47; p=0.439) when concomitant ammonia was taken into account, whereas the predictive value of baseline ammonia ≥ 1.0 upper limit of normal (ULN) was highly statistically significant (OR=4.96; p=0.013). There was no significant effect of glutamine >900 µmol/L on time to first HAC crisis (hazard ratio [HR]=1.14; p=0.813), but there was a significant effect of baseline ammonia ≥ 1.0 ULN (HR=4.62; p=0.0011). CONCLUSIONS: The findings in this UCD population suggest that glutamine is a weaker predictor of HACs than ammonia and that the utility of the predictive value of glutamine will need to take into account concurrent ammonia levels.

Thirty-day hospital readmissions for adults with and without HIV infection.

OBJECTIVES: Risk-adjusted 30-day hospital readmission rate is a commonly used benchmark for hospital quality of care and for Medicare reimbursement. Persons living with HIV (PLWH) may have high readmission rates. This study compared 30-day readmission rates by HIV status in a multi-state sample with planned subgroup comparisons by insurance and diagnostic categories. METHODS: Data for all acute care, nonmilitary hospitalizations in nine states in 2011 were obtained from the Healthcare Costs and Utilization Project. The primary outcome was readmission for any cause within 30 days of hospital discharge. Factors associated with readmission were evaluated using multivariate logistic regression. RESULTS: A total of 5 484 245 persons, including 33 556 (0.6%) PLWH, had a total of 6 441 695 index hospitalizations, including 45 382 (0.7%) among PLWH. Unadjusted readmission rates for hospitalizations of HIV-uninfected persons and PLWH were 11.2% [95% confidence interval (CI) 11.2, 11.2%] and 19.7% (95% CI 19.3, 20.0%), respectively. After adjustment for age, gender, race, insurance, and diagnostic category, HIV infection was associated with 1.50 (95% CI 1.46, 1.54) times higher odds of readmission. Predicted, adjusted readmission rates were higher for PLWH within every insurance category, including Medicaid [12.9% (95% CI 12.8, 13.0%) and 19.1% (95% CI 18.4, 19.7%) for HIV-uninfected persons and PLWH, respectively] and Medicare [13.2% (95% CI 13.1, 13.3%) and 18.0% (95% CI 17.4, 18.7%), respectively], and within every diagnostic category. CONCLUSIONS: HIV infection is associated with significantly increased readmission risk independent of demographics, insurance, and diagnostic category. The 19.7% 30-day readmission rate may serve as a preliminary benchmark for assessing quality of care of PLWH. Policy-makers may consider adjusting for HIV infection when calculating a hospital's expected readmission rate.

Urinary phenylacetylglutamine (U-PAGN) concentration as biomarker for adherence in patients with urea cycle disorders (UCD) treated with glycerol phenylbutyrate.

Urinary phenylacetylglutamine (U-PAGN) concentrations in spot urine samples were analyzed as a dosing biomarker during glycerol phenylbutyrate (GPB) dosing in 68 healthy adults and 66 adult and pediatric patients with urea cycle disorders who participated in GPB clinical trials. Age- and body surface area (BSA)-specific 25th percentile cutoff points for spot U-PAGN concentrations (<~9000 µg/mL for < 2 years old patients, < 7000 µg/mL for > 2 years with BSA ≤ 1.3 m2, and <~5000 µg/mL for > 2 years of age with BSA > 1.3 m2) were determined as an approach to identify patients for whom increased dosing and/or adherence to prescribed dosing should be assessed.

Fluence and polarisation dependence of GaAs based Lateral Photo-Dember terahertz emitters.

We characterise THz output of lateral photo-Dember (LPD) emitters based on semi-insulating (SI), unannealed and annealed low temperature grown (LTG) GaAs. Saturation of THz pulse power with optical fluence is observed, with unannealed LTG GaAs showing highest saturation fluence at 1.1 ± 0.1 mJ cm(-2). SI-GaAs LPD emitters show a flip in signal polarity with optical fluence that is attributed to THz emission from the metal-semiconductor contact. Variation in optical polarisation affects THz pulse power that is attributed to a local optical excitation near the metal contact.

A metamolecule antenna for coplanar waveguides.

We report on a metamolecule antenna, based on a fish-scale design but augmented with two split-ring resonators (SRRs) placed within the fish-scale loops. The properties of the antenna resonator, with and without additional SRRs, were examined using finite element method simulations (COMSOL Multiphysics). The simulation findings were subsequently confirmed experimentally, using a vector network analyser coupled to an antenna-loaded coplanar waveguide (CPW). The addition of SRRs to the fish-scale meta-molecule leads to a demonstrably large increase in microwave-absorption. It is shown that the fish-scale/SRR/CPW combination performs as a microwave antenna. Simulations of the antenna gain and far-field emission are presented and discussed.

Elevated phenylacetic acid levels do not correlate with adverse events in patients with urea cycle disorders or hepatic encephalopathy and can be predicted based on the plasma PAA to PAGN ratio.

BACKGROUND: Phenylacetic acid (PAA) is the active moiety in sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB, HPN-100). Both are approved for treatment of urea cycle disorders (UCDs) - rare genetic disorders characterized by hyperammonemia. PAA is conjugated with glutamine in the liver to form phenylacetyleglutamine (PAGN), which is excreted in urine. PAA plasma levels ≥ 500 µg/dL have been reported to be associated with reversible neurological adverse events (AEs) in cancer patients receiving PAA intravenously. Therefore, we have investigated the relationship between PAA levels and neurological AEs in patients treated with these PAA pro-drugs as well as approaches to identifying patients most likely to experience high PAA levels. METHODS: The relationship between nervous system AEs, PAA levels and the ratio of plasma PAA to PAGN were examined in 4683 blood samples taken serially from: [1] healthy adults [2], UCD patients of ≥ 2 months of age, and [3] patients with cirrhosis and hepatic encephalopathy (HE). The plasma ratio of PAA to PAGN was analyzed with respect to its utility in identifying patients at risk of high PAA values. RESULTS: Only 0.2% (11) of 4683 samples exceeded 500 µg/ml. There was no relationship between neurological AEs and PAA levels in UCD or HE patients, but transient AEs including headache and nausea that correlated with PAA levels were observed in healthy adults. Irrespective of population, a curvilinear relationship was observed between PAA levels and the plasma PAA:PAGN ratio, and a ratio>2.5 (both in µg/mL) in a random blood draw identified patients at risk for PAA levels>500 µg/ml. CONCLUSIONS: The presence of a relationship between PAA levels and reversible AEs in healthy adults but not in UCD or HE patients may reflect intrinsic differences among the populations and/or metabolic adaptation with continued dosing. The plasma PAA:PAGN ratio is a functional measure of the rate of PAA metabolism and represents a useful dosing biomarker.

Investigation of the role of the lateral photo-Dember effect in the generation of terahertz radiation using a metallic mask on a semiconductor.

Pulses of coherent terahertz radiation can be efficiently generated by a lateral diffusion current after ultrafast generation of photo-carriers near a metal interface on the surface of a semiconductor, this is known as the lateral photo-Dember effect. We investigate how the emission depends on the pump spot position, size, power and how it is affected by the application of an applied external bias. We study the role of the metallic mask and how it suppresses emission from the carriers diffusing under it due to a reduction of available radiation states both theoretically and experimentally.

Population pharmacokinetic modeling and dosing simulations of nitrogen-scavenging compounds: disposition of glycerol phenylbutyrate and sodium phenylbutyrate in adult and pediatric patients with urea cycle disorders.

Sodium phenylbutyrate and glycerol phenylbutyrate mediate waste nitrogen excretion in the form of urinary phenylacetylglutamine (PAGN) in patients with urea cycle disorders (UCDs); rare genetic disorders characterized by impaired urea synthesis and hyperammonemia. Sodium phenylbutyrate is approved for UCD treatment; the development of glycerol phenylbutyrate afforded the opportunity to characterize the pharmacokinetics (PK) of both compounds. A population PK model was developed using data from four Phase II/III trials that collectively enrolled patients ages 2 months to 72 years. Dose simulations were performed with particular attention to phenylacetic acid (PAA), which has been associated with adverse events in non-UCD populations. The final model described metabolite levels in plasma and urine for both drugs and was characterized by (a) partial presystemic metabolism of phenylbutyric acid (PBA) to PAA and/or PAGN, (b) slower PBA absorption and greater presystemic conversion with glycerol phenylbutyrate, (c) similar systemic disposition with saturable conversion of PAA to PAGN for both drugs, and (d) body surface area (BSA) as a significant covariate accounting for age-related PK differences. Dose simulations demonstrated similar PAA exposure following mole-equivalent PBA dosing of both drugs and greater PAA exposure in younger patients based on BSA.

Urinary phenylacetylglutamine as dosing biomarker for patients with urea cycle disorders.

UNLABELLED: We have analyzed pharmacokinetic data for glycerol phenylbutyrate (also GT4P or HPN-100) and sodium phenylbutyrate with respect to possible dosing biomarkers in patients with urea cycle disorders (UCD). STUDY DESIGN: These analyses are based on over 3000 urine and plasma data points from 54 adult and 11 pediatric UCD patients (ages 6-17) who participated in three clinical studies comparing ammonia control and pharmacokinetics during steady state treatment with glycerol phenylbutyrate or sodium phenylbutyrate. All patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate or sodium phenylbutyrate in a cross over fashion and underwent 24-hour blood samples and urine sampling for phenylbutyric acid, phenylacetic acid and phenylacetylglutamine. RESULTS: Patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate ranging from 1.5 to 31.8 g/day and of sodium phenylbutyrate ranging from 1.3 to 31.7 g/day. Plasma metabolite levels varied widely, with average fluctuation indices ranging from 1979% to 5690% for phenylbutyric acid, 843% to 3931% for phenylacetic acid, and 881% to 1434% for phenylacetylglutamine. Mean percent recovery of phenylbutyric acid as urinary phenylacetylglutamine was 66.4 and 69.0 for pediatric patients and 68.7 and 71.4 for adult patients on glycerol phenylbutyrate and sodium phenylbutyrate, respectively. The correlation with dose was strongest for urinary phenylacetylglutamine excretion, either as morning spot urine (r = 0.730, p < 0.001) or as total 24-hour excretion (r = 0.791 p<0.001), followed by plasma phenylacetylglutamine AUC(24-hour), plasma phenylacetic acid AUC(24-hour) and phenylbutyric acid AUC(24-hour). Plasma phenylacetic acid levels in adult and pediatric patients did not show a consistent relationship with either urinary phenylacetylglutamine or ammonia control. CONCLUSION: The findings are collectively consistent with substantial yet variable pre-systemic (1st pass) conversion of phenylbutyric acid to phenylacetic acid and/or phenylacetylglutamine. The variability of blood metabolite levels during the day, their weaker correlation with dose, the need for multiple blood samples to capture trough and peak, and the inconsistency between phenylacetic acid and urinary phenylacetylglutamine as a marker of waste nitrogen scavenging limit the utility of plasma levels for therapeutic monitoring. By contrast, 24-hour urinary phenylacetylglutamine and morning spot urine phenylacetylglutamine correlate strongly with dose and appear to be clinically useful non-invasive biomarkers for compliance and therapeutic monitoring.

Cardiac conduction improvement in two heterozygotes for primary carnitine deficiency on L-carnitine supplementation.

Expanded newborn screening (NBS) for free carnitine levels has led to the identification of a larger number of heterozygous infants of undiagnosed mothers affected with systemic primary carnitine deficiency (PCD), which in turn leads to the identification of other undiagnosed heterozygous family members. There is an increasing recognition that individuals heterozygous for mutations of genes involved in fatty acid oxidation (FAO) may become symptomatic under environmental stress (fasting, prolonged exercise and illness). Considering the importance of carnitine in FAO, its role in heart and bowel function and in lipid metabolism, what is still little known is the phenotypic variability, biochemical parameters and clinical course of PCD heterozygotes with consistently low-to-normal levels to low levels of carnitine over a lifetime. We report on three generations of a family--an asymptomatic PCD heterozygous infant identified through NBS that led to the diagnosis of her asymptomatic PCD-affected mother and the heterozygous status of the maternal grandparents who report some cardiac symptoms that overlap with PCD that improved with L-carnitine supplementation.

First Report of Phytophthora sansomeana Causing Wilting and Stunting on Corn in Ohio.

During the spring of 2004, corn seedlings with symptoms of wilting and stunting were observed in corn fields with emergence problems in Madison and Brown counties, Ohio. Phytophthora isolates were recovered from sections of root tissue of diseased seedlings placed on dilute V8 media amended with pentachloronitrobenzene, iprodione, benlate, neomycin sulfate, and chloramphenicol. Colonies were rosaceous on potato dextrose agar, with a growth rate of 5 mm per day. Homothallic isolates with paragynous antheridia were observed on lima bean agar (LBA); oogonia were 35 to 50 µm in diameter. Sporangia were ovoid to obpyriform, nonpapillate, with an average size of 49 × 30 µm. Pathogenicity was tested on corn seeds using a petri dish assay with 3-day-old cultures on LBA and a sand-cornmeal cup test amended with inoculum from 7-day-old cultures on LBA (1). After 1 week in the petri dish assay, the seeds failed to germinate completely and were covered with white, fungal-like, aerial mycelia and the pathogen was recovered from brown discolored radicle roots. In the cup assay, 2-week-old seedlings developed the same symptoms observed in the field; the pathogen was also isolated from brown discolored roots. In both assays, no symptoms developed in the noninoculated controls. Both pathogenicity tests were repeated two times. Genomic DNA was extracted from mycelia of two isolates and the internal transcribed spacer (ITS) region was amplified and sequenced using ITS6/ITS4 primers (2). Both isolates had identical ITS sequences (GenBank Accession No. GQ853880). A BLAST search of the NCBI database showed 100% homology with the sequence of the haplotype isolate of Phytophthora sansomeana (Accession No. EU925375). P. sansomeana is a new species characterized principally by a large oogonial diameter (37 to 45 µm), rapid growth rate (7 to 10 mm/day), and an ITS sequence falling in Cooke's clade 8 (4). Pathogenicity tests, morphological characteristics, and the ITS sequence analysis indicate that P. samsomena is the causal agent of the symptoms observed on corn seedlings. P. sansomeana has been reported as a pathogen of soybean in Indiana, Douglas-fir in Oregon, and weeds in alfalfa fields in New York (4). To our knowledge, this is the first report of P. sansomeana infecting corn in Ohio, albeit other isolates have previously been recovered from soybean in the state. There are four previous reports of Phytophthora spp. affecting corn in the United States and Mexico (3). Crop rotation will have little effect in management of this pathogen since corn and soybean are produced in the same fields continuously throughout the state. References: (1) K. E. Broders et al. Plant. Dis. 91:727, 2007. (2) D. E. L. Cooke et al. Fungal Genet. Biol. 30:17, 2000. (3) D. F. Farr et al. Fungi on Plants and Plant Products in the United States. The American Phytopathological Society, St. Paul, MN. 1989. (4) E. M. Hansen et al. Mycologia 101:129, 2009.

Hospitalization risk following initiation of highly active antiretroviral therapy.

OBJECTIVES: While highly active antiretroviral therapy (HAART) decreases long-term morbidity and mortality, its short-term effect on hospitalization rates is unknown. The primary objective of this study was to determine hospitalization rates over time in the year after HAART initiation for virological responders and nonresponders. METHODS: Hospitalizations among 1327 HAART-naïve subjects in an urban HIV clinic in 1997-2007 were examined before and after HAART initiation. Hospitalization rates were stratified by virological responders (> or =1 log(10) decrease in HIV-1 RNA within 6 months after HAART initiation) and nonresponders. Causes were determined through International Classification of Diseases, 9th Revision (ICD-9) codes and chart review. Multivariate negative binomial regression was used to assess factors associated with hospitalization. RESULTS: During the first 45 days after HAART initiation, the hospitalization rate of responders was similar to their pre-HAART baseline rate [75.1 vs. 78.8/100 person-years (PY)] and to the hospitalization rate of nonresponders during the first 45 days (79.4/100 PY). The hospitalization rate of responders fell significantly between 45 and 90 days after HAART initiation and reached a plateau at approximately 45/100 PY from 91 to 365 days after HAART initiation. Significant decreases were seen in hospitalizations for opportunistic and nonopportunistic infections. CONCLUSIONS: The first substantial clinical benefit from HAART may be realized by 90 days after HAART initiation; providers should keep close vigilance at least until this time.

ProvenCare: quality improvement model for designing highly reliable care in cardiac surgery.

OBJECTIVE: To test whether an integrated delivery system could, through the application of process redesign methodology and reliability science, implement multiple evidence-based medical practices across the continuum of care for a specific surgical intervention and deliver these practices consistently. METHODS: The programme-ProvenCare--had three components: establishing best practices for elective coronary artery bypass graft (CABG) patients; assembling a multidisciplinary team to "hardwire" these best practices into everyday workflow; and implementing the programme with real-time data collection, feedback and focused redesign to reach high reliability. Surgeons reviewed all class I and IIa 2004 ACC/AHA guidelines for CABG surgery and translated them into 19 clinically applicable recommendations. A frontline multidisciplinary team "hardwired" these, resulting in 40 measurable process elements. Feedback of gaps in care was given and the process redesigned as needed. Clinical outcome data on consecutive elective CABG patients seen in the 12 months pre-intervention were then compared with a post-intervention group. RESULTS: Initially, 59% of patients received all 40 elements. At 3 months, compliance reached 100%, fell transiently to 86% and then reached 100% again, and was sustained for the remainder of the study. The overall trend in reliability was significant (p = 0.001). 30-day clinical outcomes showed improved trends in 8/9 measured areas (eg, patient readmissions to ICU decreased from 2.9% to 0.9% and blood products usage decreased from 23.4% to 16.2%). Operative mortality decreased to zero, but only likelihood of discharge was significant (p = 0.033). Frequency and length of readmissions fell, as did mean hospital charges. CONCLUSION: Frontline medical care providers, led by process design specialists, can successfully redesign episodic processes to consistently deliver evidence-based medicine, which may improve patient outcomes and reduce resource use.

High incidence of profound biotinidase deficiency detected in newborn screening blood spots in the Somalian population in Minnesota.

Newborns identified with profound biotinidase deficiency (BTD) by the Minnesota Newborn Screening Program (MN NBS) between 1 October 2004 and 30 May 2008 were all from new immigrant groups. Thirty-three positive cases of BTD were identified out of 264 727 infants screened by the Wolf colorimetric system during the period of this study by MN NBS. Five cases of profound BTD (0.1 to <0.6 nmol/min per ml) and 26 cases of partial BTD (0.9 to 2.3 nmol/min per ml) were later confirmed through measurement of serum biotinidase activity. The incidence of combined partial and profound BTD of 1/8540 and that of profound BTD of 1/52 945 in Minnesota are unusually high in comparison with the reported worldwide numbers of 1/61 067 for combined BTD and 1/137 401 for profound BTD. Four out of the 5 cases of profound BTD ascertained in the MN NBS cohort were of Somali ethnic background, and the remaining case was of Asian (Pakistani/Indian) ethnic background. All four Somali patients have the P497S mutation, with one of the four being homozygous for the mutation. The three compound heterozygotes all have a novel mutation (P142T) and two of them have another change (Y428Y) that has never been described. Within the last two decades, Minnesota has become home to an estimated 40 000 Somali immigrants and their children (<1% of the total Minnesota population). New population demographics prompt careful analysis of case cohorts to identify specific groups at risk for rare inborn errors of metabolism.

Genetic Analysis of Soybean Plant Introductions with Resistance to Phytophthora sojae.

ABSTRACT Phytophthora sojae, which causes Phytophthora root and stem rot of soybean, is a serious disease worldwide and is managed primarily by deploying cultivars with resistance. Thirty-two soybean plant introductions (PIs), all but three of which were from South Korea, were proposed as new sources of single-gene resistance to P. sojae. The objective of this study was to characterize the inheritance of resistance to P. sojae in these PIs. Twenty-two soybean populations from crosses of these PIs and the susceptible cv. Williams were inoculated with P. sojae OH17 (vir 1b, 1d, 2, 3a, 3b, 3c, 4, 5, 6, 7), and OH25 (vir 1a, 1b, 1c, 1k, 7). These isolates were selected because they are virulent on soybeans with all known Rps genes and many Rps gene combinations. Thirteen of the twenty-two populations had consistent segregation responses following inoculations between the two generations. In two PIs, resistance was conferred by two genes to OH17 and three genes to OH25. Resistance to both isolates was conferred by a single gene in PI 398440 although the individual families were not resistant to the same isolates. The data suggest that six of the populations have three-Rps gene combinations as previously proposed, while another four may have either a novel Rps gene or a four-Rps gene combination. Based on this phenotypic analysis, novel and uncharacterized Rps genes may be present in this material. More importantly, these PIs may serve as sources of novel Rps genes that can be used to more effectively manage Phytophthora root and stem rot.

Paris-Trousseau syndrome platelets in a child with Jacobsen's syndrome.

The thrombocytopenia in an infant with clinical features of Jacobsen's syndrome characterized by multiple congenital anomalies, cardiac defects, psychomotor retardation, and deletion of chromosome 11 at 11q23.3 has been evaluated. Study of his platelets in the electron microscope revealed giant alpha granules in his cells identical in appearance to those reported in the family with Paris-Trousseau syndrome. As a result, the Paris-Trousseau syndrome appears to be a variant of the Jacobsen syndrome, and the thrombocytopenia observed in all cases of chromosome 11q23.3 deletion due to dysmegakaryopoieses. Giant alpha granules are frequently observed in normal platelets during long-term storage and may form in Jacobsen and Paris-Trousseau platelets during prolonged residence in the bone marrow.

Metabolic effects of rexinoids: tissue-specific regulation of lipoprotein lipase activity.

Hypertriglyceridemia is a frequent complication accompanying the treatment of patients with either retinoids or rexinoids, [retinoid X receptor (RXR)-selective retinoids]. To investigate the cellular and molecular basis for this observation, we have studied the effects of rexinoids on triglyceride metabolism in both normal and diabetic rodents. Administration of a rexinoid such as LG100268 (LG268) to normal or diabetic rats results in a rapid increase in serum triglyceride levels. LG268 has no effect on hepatic triglyceride production but suppresses post-heparin plasma lipoprotein lipase (LPL) activity suggesting that the hypertriglyceridemia results from diminished peripheral processing of plasma very low density lipoproteins particles. Treatment of diabetic rats with rexinoids suppresses skeletal and cardiac muscle but not adipose tissue LPL activity. This effect is independent of changes in LPL mRNA. In C2C12 myocytes, LG268 suppresses the level of cell surface (i.e., heparin-releasable) LPL activity without altering LPL mRNA. This effect is very rapid (t(1/2) = 2 h) and is blocked by the transcriptional inhibitor actinomycin D. These studies demonstrate that RXR ligands can have dramatic effects on the post-translational processing of LPL and suggest that skeletal muscle may be an important target of rexinoid action. In addition, these data underscore that the metabolic consequences of RXR activation are distinct from either retinoic acid receptor or peroxisome proliferator-activated receptor activation.

Inhibition of growth hormone action in models of inflammation.

Growth hormone (GH) action is attenuated during the hepatic acute-phase response (APR). To understand this attenuation, we asked whether GH and cytokine-signaling pathways intersect during an APR. In hypophysectomized rats treated with lipopolysaccharide (LPS), accumulation of activated signal transducer and transcription activator 5 (Stat5) in hepatic nuclei in response to GH and its binding to a GH response element (GHRE) from the serine protease inhibitor (Spi) 2.1 promoter are diminished in a time-dependent manner. Similarly, accumulation of activated Stat3 in hepatic nuclei in response to LPS and its binding to a high-affinity sis-inducible element (SIE) are also diminished by the simultaneous administration of GH. In functional assays with primary hepatocytes, LPS-stimulated monocyte-conditioned medium (MoCM) inhibits the GH response of Stat5-dependent Spi 2.1 reporter activity but induces Stat3-dependent Spi 2.2 reporter activity, as in an APR. Similar results are obtained when hepatocytes are treated with either tumor necrosis factor-alpha (TNF-alpha) or interleukin (IL)-1beta. TNF-alpha, IL-1beta, and IL-6 also inhibit GH-induced Spi 2.1 mRNA expression in hepatocytes. Thus inhibition of the GH signaling pathway during an APR results in reduced expression of GH-responsive genes.

Hepatic growth hormone signaling in the late gestation fetal rat.

The role of GH in the developing fetus is poorly understood. Several studies have demonstrated a limited role for GH in late fetal life. In fact, few data are available regarding GH signal transduction in the late gestation fetus. We therefore focused on a comparison of hepatic GH signaling in near-term fetal rats [embryonic day 19 (E19)] and adult rats using a combination of in vitro studies employing hepatocytes in primary culture and in vivo studies. We found that GH receptor (GHr) binding was comparable in fetal liver and adult liver. The long isoform of the GHr underwent tyrosine phosphorylation in response to GH stimulation of E19 fetal hepatocytes in a manner similar to that seen in cultured adult hepatocytes. Furthermore, downstream signaling via the Janus kinase-2 tyrosine kinase, STAT1 (signal transducer and activator of transcription), and STAT5 was also intact in both, as demonstrated by the tyrosine phosphorylation of these signaling proteins. To confirm the relevance of these findings to the in vivo situation, GH was directly administered by ip injection to E 19 fetal and adult rats. In both cases, tyrosine phosphorylation of STAT5 was markedly and rapidly induced. Finally, transfection of E19 fetal hepatocytes with GH-responsive reporter elements [Spi2.1(-275/+85)-CAT and 8xGHRE-TKCAT] demonstrated intact transcriptional regulation. Our data indicate that GHr abundance and activity as well as downstream GH signaling are similar in the late gestation fetal rat and in the adult and that these mechanisms appear capable of supporting physiological GH functions in the developing liver.