Fetal microchimerism by mode of delivery: a prospective cohort study.

OBJECTIVE: To compare fetal microchimerism (FMc) in pregnancies with uncomplicated vaginal delivery (VD) versus caesarean delivery (CD). DESIGN: Prospective cohort study. SETTING: University of Washington and Fred Hutchinson Cancer Research Center, USA. POPULATION: Women delivering singleton pregnancies without pertinent antenatal complications with uncomplicated deliveries (n = 36). METHODS: We collected maternal predelivery, postdelivery and umbilical cord blood for each mother-baby pair. Following maternal and fetal genotyping, FMc was measured with quantitative polymerase chain reaction assays targeting fetus-specific polymorphisms. Quantification of FMc is expressed as genome equivalents (gEq) of fetal DNA/100 000 total gEq tested. FMc detection was evaluated by logistic regression while controlling for total number of cell equivalents tested and clinically relevant covariates. FMc concentrations were compared using negative binomial regression while controlling for the same covariates and predelivery FMc positivity. MAIN OUTCOME MEASURE: Detection and concentration of FMc by mode of delivery. RESULTS: Twenty-four mother-baby pairs had a VD and 12 had a CD. Postdelivery FMc detection was higher following CD than after VD (58.3% versus 16.7%, P = 0.02). After controlling for covariates, the likelihood of postdelivery FMc detection was almost nine-fold higher after CD than VD (odds ratio 8.8, 95% CI 1.6-47.6; P = 0.01). With respect to postdelivery FMc concentration, the detection rate ratio for CD versus VD in the adjusted negative binomial regression model was 14.7 (95% CI 3.2-66.8; P = 0.001). CONCLUSION: Postdelivery peripheral FMc detection and concentration are significantly higher after CD than after VD. As FMc is associated with long-term maternal health, our findings suggest that the mode of delivery may impact this risk. TWEETABLE ABSTRACT: Greater fetal microchimerism found in maternal blood following caesarean delivery compared with vaginal delivery.

Microchimerism: Defining and redefining the prepregnancy context - A review.

Bidirectional transplacental exchange characterizes human pregnancy. Cells exchanged between mother and fetus can durably persist as microchimerism and may have both short- and long-term consequences for the recipient. The amount, type, and persistence of microchimerism are influenced by obstetric characteristics, pregnancy complications, exposures to infection, and other factors. A reproductive-aged woman enters pregnancy harboring previously acquired microchimeric "grafts," which may influence her preconception health and her subsequent pregnancy outcomes. Many questions remain to be answered about microchimerism with broad-ranging implications. This review will summarize key aspects of this field of research and propose important questions to be addressed moving forward.

Genetic Ablation of CD38 Protects against Western Diet-Induced Exercise Intolerance and Metabolic Inflexibility.

Nicotinamide adenine dinucleotide (NAD+) is a key cofactor required for essential metabolic oxidation-reduction reactions. It also regulates various cellular activities, including gene expression, signaling, DNA repair and calcium homeostasis. Intracellular NAD+ levels are tightly regulated and often respond rapidly to nutritional and environmental changes. Numerous studies indicate that elevating NAD+ may be therapeutically beneficial in the context of numerous diseases. However, the role of NAD+ on skeletal muscle exercise performance is poorly understood. CD38, a multi-functional membrane receptor and enzyme, consumes NAD+ to generate products such as cyclic-ADP-ribose. CD38 knockout mice show elevated tissue and blood NAD+ level. Chronic feeding of high-fat, high-sucrose diet to wild type mice leads to exercise intolerance and reduced metabolic flexibility. Loss of CD38 by genetic mutation protects mice from diet-induced metabolic deficit. These animal model results suggest that elevation of tissue NAD+ through genetic ablation of CD38 can profoundly alter energy homeostasis in animals that are maintained on a calorically-excessive Western diet.

Coinfection by HTLV-I/II is associated with an increased risk of strongyloidiasis and delay in starting antiretroviral therapy for AIDS patients.

OBJECTIVE: To compare the clinical characteristics and outcomes of HIV-1-HTLV-1 coinfected patients, in Bahia, Brazil. METHODS: Retrospective, comparative study. RESULTS: Among a total of 123 consecutive HIV infected patients, 20 men (20.6%) and 6 women (23.1%) had detectable antibodies against HTLV-I/II. The major risk factor associated with coinfection by HTLV was intravenous drug use (57.7% of coinfected patient versus 9.2% of HTLV seronegative patients, p < 0.0001). Coinfected patients had higher absolute lymphocyte counts (1,921 + 762 versus 1,587 + 951, p = 0.03). Both groups of patients had similar means of CD4+ and CD8+ cell counts. However, among patients with AIDS CD4+ cell counts were significantly higher among those coinfected with HTLV-I/II (292 ± 92 cells/mm³, versus 140 ± 177 cells/mm³, p = 0.36). The frequency and type of opportunistic infections were similar for both groups, but strongyloidiasis and encephalopathy were more frequently diagnosed in coinfected patients (p < 0.05). On the other hand, patients coinfected with HTLV-I/II received significantly less antiretroviral therapy than singly infected by HIV-1. CONCLUSION: Coinfection by HTLV-I/II is associated with an increased risk of strongyloidiasis for HIV patients. Higher CD4 count may lead to underestimation of immunodeficiency, and delay to initiate antiretroviral therapy.

Effectiveness of the PPARγ agonist, GW570, in liver fibrosis.

INTRODUCTION: The peroxisome proliferator-activated receptors (PPARs) are well established to be important in modulating the fibrogenic response to liver injury. PPARγ plays a role in hepatic fibrosis, presumably by virtue of its expression in hepatic stellate cells, which are key effectors of fibrosis. In this study, we evaluated whether the potent nonthiozolidinedione PPARγ agonist, GW570, had effects on isolated stellate cells and hepatic fibrosis in vivo. METHODS: Liver fibrosis and stellate cell activation were induced in vivo by either bile duct ligation (BDL) or administration of carbon tetrachloride (CCl(4)). Primary cultures of stellate cells isolated from normal rats were exposed to GW570. The PPARγ agonist was also given to male Sprague-Dawley rats before or during injury to test its ability to ameliorate fibrosis. Fibrosis biomarkers including total collagen, hydroxyproline, collagen I α1 and smooth muscle α actin were measured. RESULTS: GW570 had potent effects on isolated stellate cells, both simulating PPARγ mediated gene transcription, as well as inhibiting collagen I α1 mRNA and protein expression and smooth muscle α actin protein abundance, consistent with suppression of stellate cell activation. In BDL liver injury, a daily dose of 10 mg/kg per day of GW570 inhibited collagen I α1 mRNA, while concentrations of 1 also inhibited fibrosis as measured by hydroxyproline and total collagen content. Lower doses of GW570 (0.1-1.0 mg/kg per day) did not significantly abrogate whole liver collagen or hydroxyproline content in this model. In a CCl(4) model, 0.1-1.0 mg/kg per day GW570 reduced expression of smooth muscle α actin, but did not affect whole liver collagen or hydroxyproline content. Finally, we found that GW570 had anti-inflammatory effects on Kupffer cells as well as in vivo during CCl(4) injury. CONCLUSION: PPARγ receptor agonism with the nonthiozolidinedione, GW570, inhibited stellate cell activation in vitro and in vivo, and abrogated the fibrogenic response to injury in a dose responsive fashion.

Competitive facilitation of drug-resistant Plasmodium falciparum malaria parasites in pregnant women who receive preventive treatment.

Intermittent preventive treatment in pregnancy (IPTp) is used to prevent Plasmodium falciparum malaria. However, parasites resistant to the IPTp drug sulfadoxine-pyrimethamine (SP) have emerged worldwide, and infections with mixed resistant and susceptible parasites are exacerbated by pyrimethamine in mice. In a prospective delivery cohort in Muheza, Tanzania, we examined the effects of SP IPTp on parasite resistance alleles, parasite diversity, level of parasitemia, and inflammation in the placenta. IPTp use was associated with an increased fraction of parasites carrying the resistance allele at DHPS codon 581, an increase in the level of parasitemia, and more intense placental inflammation. The lowest mean level of parasite diversity and highest mean level of parasitemia occurred in women after recent IPTp use. These findings support a model of parasite release and facilitation, whereby the most highly resistant parasites out-compete less fit parasite populations and overgrow under drug pressure. Use of partially effective anti-malarial agents for IPTp may exacerbate malaria infections in the setting of widespread drug resistance.

The Effect of PPARalpha, PPARdelta, PPARgamma, and PPARpan Agonists on Body Weight, Body Mass, and Serum Lipid Profiles in Diet-Induced Obese AKR/J Mice.

Activation of peroxisome proliferator-activated receptor (PPAR) alpha, delta, and gamma subtypes increases expression of genes involved in fatty acid transport and oxidation and alters adiposity in animal models of obesity and type-2 diabetes. PPARpan agonists which activate all three receptor subtypes have antidiabetic activity in animal models without the weight gain associated with selective PPARgamma agonists. Herein we report the effects of selective PPAR agonists (GW9578, a PPARalpha agonist, GW0742, a PPARdelta agonist, GW7845, a PPARgamma agonist), combination of PPARalpha and delta agonists, and PPARpan (PPARalpha/gamma/delta) activators (GW4148 or GW9135) on body weight (BW), body composition, food consumption, fatty acid oxidation, and serum chemistry of diet-induced obese AKR/J mice. PPARalpha or PPARdelta agonist treatment induced a slight decrease in fat mass (FM) while a PPARgamma agonist increased BW and FM commensurate with increased food consumption. The reduction in BW and food intake after cotreatment with PPARalpha and delta agonists appeared to be synergistic. GW4148, a PPARpan agonist, induced a significant and sustained reduction in BW and FM similar to an efficacious dose of rimonabant, an antiobesity compound. GW9135, a PPARpan agonist with weak activity at PPARdelta, induced weight loss initially followed by rebound weight gain reaching vehicle control levels by the end of the experiment. We conclude that PPARalpha and PPARdelta activations are critical to effective weight loss induction. These results suggest that the PPARpan compounds may be expected to maintain the beneficial insulin sensitization effects of a PPARgamma agonist while either maintaining weight or producing weight loss.

Regulation of peroxisome proliferator-activated receptor-gamma in liver fibrosis.

The peroxisome proliferator-activated receptors (PPARs) impart diverse cellular effects in biological systems. Because stellate cell activation during liver injury is associated with declining PPARgamma expression, we hypothesized that its expression is critical in stellate cell-mediated fibrogenesis. We therefore modulated its expression during liver injury in vivo. PPARgamma was depleted in rat livers by using an adenovirus-Cre recombinase system. PPARgamma was overexpressed by using an additional adenoviral vector (AdPPARgamma). Bile duct ligation was utilized to induce stellate cell activation and liver fibrosis in vivo; phenotypic effects (collagen I, smooth muscle alpha-actin, hydroxyproline content, etc.) were measured. PPARgamma mRNA levels decreased fivefold and PPARgamma protein was undetectable in stellate cells after culture-induced activation. During activation in vivo, collagen accumulation, assessed histomorphometrically and by hydroxyproline content, was significantly increased after PPARgamma depletion compared with controls (1.28 +/- 0.14 vs. 1.89 +/- 0.21 mg/g liver tissue, P < 0.03). In isolated stellate cells, AdPPARgamma overexpression resulted in significantly increased adiponectin mRNA expression and decreased collagen I and smooth muscle alpha-actin mRNA expression compared with controls. During in vivo fibrogenesis, rat livers exposed to AdPPARgamma had significantly less fibrosis than controls. Collagen I and smooth muscle alpha-actin mRNA expression were significantly reduced in AdPPARgamma-infected rats compared with controls (P < 0.05, n = 10). PPARgamma-deficient mice exhibited enhanced fibrogenesis after liver injury, whereas PPARgamma receptor overexpression in vivo attenuated stellate cell activation and fibrosis. The data highlight a critical role for PPARgamma during in vivo fibrogenesis and emphasize the importance of the PPARgamma pathway in stellate cells during liver injury.

GI262570, a peroxisome proliferator-activated receptor {gamma} agonist, changes electrolytes and water reabsorption from the distal nephron in rats.

Peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists have been shown to have significant therapeutic benefits such as desirable glycemic control in type 2 diabetic patients; however, these agents may cause fluid retention in susceptible individuals. Since PPARgamma is expressed selectively in distal nephron epithelium, we studied the mechanism of PPARgamma agonist-induced fluid retention using male Sprague-Dawley rats treated with either vehicle or GI262570 (farglitazar), a potent PPARgamma agonist. GI262570 (20 mg/kg/day) induced a plasma volume expansion. The plasma volume expansion was accompanied by a small but significant decrease in plasma potassium concentration. Small but significant increases in plasma sodium and chloride concentrations were also observed. These changes in serum electrolytes suggested an activation of the renal mineralocorticoid response system; however, GI262570-treated rats had lower plasma levels of aldosterone compared with vehicle-treated controls. mRNA levels for a group of genes involved in distal nephron sodium and water absorption are changed in the kidney medulla with GI262570 treatment. In addition, due to a possible rebound effect on epithelial sodium channel (ENaC) activity, a low dose of amiloride did not prevent GI262570-induced fluid retention. On the contrary, the rebound effect after amiloride treatment potentiated GI262570-induced plasma volume expansion. This is at least partially due to a synergistic effect of GI262570 and the rebound from amiloride treatment on ENaCalpha expression. In summary, our current data suggest that GI262570 can increase water and sodium reabsorption in distal nephron by stimulating the ENaC and Na,K-ATPase system. This may be an important mechanism for PPARgamma agonist-induced fluid retention.

Zidovudine: a targeted therapy for endemic Burkitt's lymphoma.

BACKGROUND: Although cyclophosphamide based regimens can produce remission rates approaching 60 to 80% in endemic Burkitts lymphoma, relapses and refractory disease are fairly common in developing countries, due to advanced stage disease and cost-constraints in the implementation of optimal chemotherapeutic protocols. OBJECTIVE: To evaluate an affordable, tolerable and targeted approach to chemotherapy for endemic Burkitt's lymphoma as would be desirable in resource poor settings such as Africa. METHOD: We present data and review pertinent literature that indicates that the antiviral agent Zidovudine specifically targets this tumour through a unique and novel mechanism. DATA SOURCE: Our original studies, publications original and review articles searched in Pubmed indexed for Medline. DATA EXTRACTION: A systematic review to identify studies relating to Zidovudine, EBV+ and Burkitt's lymphoma, indicating antiviral agents zidovudine targeting BL in a unique and novel mechanisms. DATA SYNTHESIS: Our data and a qualitative assessment of the relevant literature was undertaken, given the heterogenicity of the study types making it inappropriate to pool results across studies. CONCLUSION: Our data suggests that the incorporation of Zidovudine into Burkitt's regimens may enhance tumour kill and abbreviate the duration of treatment necessary for this disease. Furthermore, the addition of the widely available and inexpensive agent hydroxyurea, markedly potentiates the tumorcidal activity of Zidovudine in Epstein Barr virus positive Burkitt's lymphomas. We recommend that further clinical studies in patients afflicted with this disease are needed to clearly define this potential use of Zidovudine.

Strategies to overcome myelotoxic therapy for the treatment of Burkitt's and AIDS-related non-Hodgkin's lymphoma.

BACKGROUND: Strategies to circumvent or lessen the myelotoxicity associated with combination chemotherapy may improve the overall outcome of the management of patients particularly in resource poor settings. OBJECTIVES: To develop effective non-myelotoxic therapies for Burkitt's Lymphoma (BL) and AIDS-related non-Hodgkin's lymphoma. DATA SOURCES: Publications, original and review articles, conference abstracts searched mainly on Pubmed indexed for medline. DATA EXTRACTION: A systematic review of the clinical problem of combination chemotherapy. Identification of clinical strategies that circumvent or lessen the myelotoxicity of combination cytotoxic chemotherapy. Length of survival, lack of clinically significant (> grade 3) myelosuppression and weight loss were used as markers of myelotoxicity. DATA SYNTHESIS: Review of published experience with some of these strategies including dose-modification of multi-agent chemotherapy; rationale for targeted therapies, and the preclinical development of a mouse model exploring the role of metronomic scheduling substantiate pragmatism and feasibility of these approaches. CONCLUSION: Myelotoxic death rates using multi-agent induction chemotherapy approach 25% for endemic Burkitt's lymphoma and range between 20% to 60% for AIDS-related malignancy. This is mostly explained by the paucity of supportive care compounded by wasting and inanition attributable to advanced cancer and HIV infection making patients more susceptible to myelosuppressive side effects of cytotoxic chemotherapy. Investigations and alternative approaches that lessen or circumvent myelotoxicity of traditional cytotoxic chemotherapy for the management of Burkitt's lymphoma and AIDS-related non-Hodgkin's lymphoma in the resource-constrained setting are warranted. Pertinent pre-clinical and clinical data are emerging to support the need for abrograting the myelosuppressive effects of traditional cytotoxic chemotherapy. This can be achieved by developing targeted anti-viral and other strategies, such as the use of bryostatin 1 and vincristine, and by developing a preclinical mouse model to frame the clinical rationale for a pilot trial of metronomic therapy for the treatment of Burkitt's and AIDS-related lymphoma. Implementation of these investigational approaches must be encouraged as viable anti-cancer therapeutic strategies particularly in the resource-constrained settings.

Induction of a TRAIL-mediated suicide program by interferon alpha in primary effusion lymphoma.

Gammaherpes viruses are often detected in lymphomas arising in immunocompromised patients. We have found that Azidothymidine (AZT) alone induces apoptosis in Epstein Barr Virus (EBV) positive Burkitt's lymphoma (BL) cells but requires interferon alpha (IFN-alpha) to induce apoptosis in Human Herpes Virus Type 8 (HHV-8) positive Primary Effusion Lymphomas (PEL). Our analysis of a series of AIDS lymphomas revealed that IFN-alpha selectively induced very high levels of the Death Receptor (DR) tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in HHV-8 positive PEL lines and primary tumor cells whereas little or no induction was observed in primary EBV+ AIDS lymphomas and EBV-Burkitt's lines. AZT and IFN-alpha mediated apoptosis in PEL was blocked by stable overexpression of dominant negative Fas Associated Death Domain (FADD), decoy receptor 2 (DcR2), soluble TRAIL receptor fusion proteins (DR-4 and DR-5) and thymidine. Trimeric TRAIL (in place of IFN-alpha) similarly synergized with AZT to induce apoptosis in HHV-8 positive PEL cells. This is the first demonstration that IFN-alpha induces functional TRAIL in a malignancy that can be exploited to effect a suicide program. This novel antiviral approach to Primary Effusion lymphomas is targeted and may represent a highly effective and relatively non-toxic therapy.

Treatment of HIV-associated multicentric Castleman's disease with oral etoposide.

Multicentric Castleman's disease (MCD) is a lymphoproliferative disorder that can be defined based upon both clinical and pathological characteristics. The clinical features of this frequently fatal disease include fever, generalized lymphadenopathy, fatigue, splenomegaly, hepatomegaly, and pancytopenia. Recently, severe forms of this disease have been diagnosed in HIV positive patients. Human herpesvirus type 8 (HHV-8) DNA sequences have been detected in peripheral blood mononuclear cells (PBMCs) of patients with Kaposi's sarcoma and MCD, regardless of HIV infection status. Treatment and outcomes in HIV associated MCD are generally unfavorable. We recently treated two HIV-positive patients diagnosed with aggressive MCD with daily oral etoposide (50 mg). The first patient had relapsed on several occasions despite previous therapy with doxil, paclitaxel, and oral ganciclovir. The second patient was treatment naive. Both patients had HHV-8 detectable by polymerase chain reaction in PBMCs, widespread tumor, and B-type symptoms when therapy was initiated. In both cases remissions (documented by computerized tomography) have been durable, 1.5 and 6 months, respectively, with minimal side effects. Oral etoposide may be a safe, tolerable, and active agent in MCD.

Adipose tissue resistin expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor gamma agonists.

Elevated levels of the hormone resistin, which is secreted by fat cells, are proposed to cause insulin resistance and to serve as a link between obesity and type 2 diabetes. In this report we show that resistin expression is significantly decreased in the white adipose tissue of several different models of obesity including the ob/ob, db/db, tub/tub, and KKA(y) mice compared with their lean counterparts. Furthermore, in response to several different classes of antidiabetic peroxisome proliferator-activated receptor gamma agonists, adipose tissue resistin expression is increased in both ob/ob mice and Zucker diabetic fatty rats. These data demonstrate that experimental obesity in rodents is associated with severely defective resistin expression, and decreases in resistin expression are not required for the antidiabetic actions of peroxisome proliferator-activated receptor gamma agonists.

HHV-8 encoded vIRF-1 represses the interferon antiviral response by blocking IRF-3 recruitment of the CBP/p300 coactivators.

Human herpes virus 8 (HHV-8) has developed unique mechanisms for altering cellular proliferative and apoptotic control pathways by incorporating viral homologs to several cellular regulatory genes into its genome. One of the important pirated genes encoded by the ORF K9 reading frame is a viral homolog of the interferon regulatory factors (IRF), a family of cellular transcription proteins that regulates expression of genes involved in pathogen response, immune modulation and cell proliferation. vIRF-1 has been shown to downregulate the interferon- and IRF-mediated transcriptional activation of ISG and murine IFNA4 gene promoters. In this study we demonstrate that vIRF-1 efficiently inhibited virus-induced expression of endogenous interferon B, CC chemokine RANTES and CXC chemokine IP-10 genes. Co-expression analysis revealed that vIRF-1 selectively blocked IRF-3 but not IRF-7-mediated transactivation. vIRF-1 was able to bind to both IRF-3 and IRF-7 in vivo as detected by coimmunoprecipitation analysis, but did not affect IRF-3 dimerization, nuclear translocation and DNA binding activity. Rather, vIRF-1 interacted with the CBP/p300 coactivators and efficiently inhibited the formation of transcriptionally competent IRF-3-CBP/p300 complexes. These results illustrate that vIRF-1 is able to block the early stages of the IFN response to virus infection by interfering with the activation of IRF-3 responsive, immediate early IFN genes.

Chemotherapy for human immunodeficiency virus-associated non-Hodgkin's lymphoma in combination with highly active antiretroviral therapy.

PURPOSE: This study investigated the efficacy, toxicity, and pharmacokinetic interactions resulting from simultaneous combination chemotherapy and highly active antiretroviral therapy (HAART) for patients with human immunodeficiency virus (HIV)-associated non-Hodgkin's lymphoma (NHL). In addition, the effects on viral load, CD4 counts, and opportunistic infections were examined with the use of combination chemotherapy combined with HAART. PATIENTS AND METHODS: Sixty-five patients with previously untreated and measurable disease at any stage of HIV-associated NHL of intermediate or high grade were entered onto this study at 17 different centers. The first 40 patients entered onto the study received reduced doses of cyclophosphamide and doxorubicin, combined with vincristine and prednisone (modified CHOP [mCHOP]), whereas the subsequent 25 patients entered onto the study received full doses of CHOP combined with granulocyte colony-stimulating factor (G-CSF). All patients also received stavudine, lamivudine, and indinavir. RESULTS: The complete response rates were 30% and 48% among patients who received mCHOP and full-dose CHOP combined with HAART, respectively. Grade 3 or 4 neutropenia occurred in 25% of patients receiving mCHOP and 12% of those receiving full-dose CHOP combined with G-CSF (25% v 12%). There were similar numbers of patients with grade 3 or 4 hyperbilirubinemia (12% and 17%), constipation and abdominal pain (18% and 17%), and transaminase elevation (48% and 52%) on the modified and full-dose arms of the study, respectively. Doxorubicin clearance and indinavir concentration curves were similar among patients on this study and historical controls, whereas cyclophosphamide clearance was 1.5-fold reduced as compared with control values. Human immunodeficiency virus (HIV) load declined from a median baseline value of 29,000 copies/mL to a median minimum value on therapy of 500 copies/mL. CONCLUSION: Either modified-dose or full-dose CHOP chemotherapy for HIV-NHL, delivered with HAART, is effective and tolerable.

Comprehensive messenger ribonucleic acid profiling reveals that peroxisome proliferator-activated receptor gamma activation has coordinate effects on gene expression in multiple insulin-sensitive tissues.

Peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists, including the glitazone class of drugs, are insulin sensitizers that reduce glucose and lipid levels in patients with type 2 diabetes mellitus. To more fully understand the molecular mechanisms underlying their therapeutic actions, we have characterized the effects of the potent, tyrosine-based PPAR gamma ligand GW1929 on serum glucose and lipid parameters and gene expression in Zucker diabetic fatty rats. In time-course studies, GW1929 treatment decreased circulating FFA levels before reducing glucose and triglyceride levels. We used a comprehensive and unbiased messenger RNA profiling technique to identify genes regulated either directly or indirectly by PPAR gamma in epididymal white adipose tissue, interscapular brown adipose tissue, liver, and soleus skeletal muscle. PPAR gamma activation stimulated the expression of a large number of genes involved in lipogenesis and fatty acid metabolism in both white adipose tissue and brown adipose tissue. In muscle, PPAR gamma agonist treatment decreased the expression of pyruvate dehydrogenase kinase 4, which represses oxidative glucose metabolism, and also decreased the expression of genes involved in fatty acid transport and oxidation. These changes suggest a molecular basis for PPAR gamma-mediated increases in glucose utilization in muscle. In liver, PPAR gamma activation coordinately decreased the expression of genes involved in gluconeogenesis. We conclude from these studies that the antidiabetic actions of PPAR gamma agonists are probably the consequence of 1) their effects on FFA levels, and 2), their coordinate effects on gene expression in multiple insulin-sensitive tissues.

Breast cancer and human immunodeficiency virus: a report of 20 cases.

Carcinoma of the breast is the most common malignancy in women in the United States. More than 40% of patients with human immunodeficiency virus (HIV) infection develop cancer during their illness, but breast cancer has seldom been reported. Twenty patients with breast cancer and HIV infection seen at the University of Miami/Jackson Memorial Hospital between January 1988 and August 2000 were retrospectively analyzed. Seventeen patients had a previous or concurrent diagnosis of HIV at the time of the breast cancer diagnosis. Their CD4 count ranged from 13-1126/microL (median, 309/microL). Most patients were premenopausal (16 of 20), with ages ranging from 31-61 years (median, 44 years). All stages of breast cancer were seen: ductal carcinoma in situ (2 patients), stage I (1 patient), stage II (9 patients), stage III (6 patients), and stage IV (2 patients). Ten tumors had estrogen receptors. Four of the 13 patients who underwent axillary lymph node dissection had abnormal lymph node findings, including 2 with follicular hyperplasia and 2 with caseating granulomas. Seven patients received chemotherapy with very poor tolerance. Estrogen receptor-positive patients were treated with tamoxifen. Of the 18 patients who presented with local disease, 7 have died: 2 of breast cancer, 4 of acquired immunodeficiency syndrome, and 1 of cardiac arrest. Nine patients remain free of disease (5 of them > 5 years) and 2 patients are alive with metastatic disease. Breast cancer in the HIV-positive population is similar to that seen in seronegative women. Most of the patients that are long-term survivors were treated with surgery and tamoxifen. The benefits of adjuvant chemotherapy are not clear.

Structure-function relationships in estrogen receptors and the characterization of novel selective estrogen receptor modulators with unique pharmacological profiles.

This article summarizes recent research on the development of estrogen receptor alpha (ER alpha) and estrogen receptor beta (ER beta) subtype-selective ligands based on our understanding of structure-activity relationships in these two estrogen receptors and differences in their ligand binding domains and activation function domains. The use of these ligands should enable greater understanding of the unique biologies mediated by ER alpha versus ER beta and may, as well, provide selective estrogen receptor modulators having unique biological and pharmacological profiles optimal for prevention and treatment of breast cancer, for menopausal hormone replacement, for prevention of osteoporosis, and for potential cardiovascular benefit.