Oestradiol enhances plasma growth hormone and insulin-like growth factor-I concentrations and increased the expression of their receptors mRNAs in the liver of ovariectomized cows

Many metabolic hormones, growth hormone (GH), insulin-like growth factor-I (IGF-I) and insulin affect ovarian functions. However, whether ovarian steroid hormones affect metabolic hormones in cattle remains unknown. This study aimed to determine the effect of sex steroids on the plasma profiles of GH, IGF-I and insulin and their receptors in the liver and adipose tissues of dairy cows. Ovariectomized cows (n = 14) were randomly divided into four groups: control group (n = 3) was treated with saline on Day 0; oestradiol (E2) group (n = 3), with saline and 1 mg oestradiol benzoate (EB) on Day 0 and 5, respectively; progesterone (P4) group (n = 4) with two CIDRs (Pfizer Inc., Tokyo, Japan) from Day 0; and E2 + P4 group (n = 4) with two CIDRs on Day 0 that were removed on Day 6 and were immediately injected with 1 mg EB. The animals were euthanized after the experiment, and liver and adipose tissues samples were quantitatively analysed using real-time PCR for the expression of mRNA for the GH (GHR), IGF-I (IGFR-I) and insulin (IR) receptor mRNAs. Oestradiol benzoate significantly increased the number of peaks (p < 0.05), pulse amplitude (p < 0.05) and area under the curve (AUC; p < 0.01) for plasma GH; moreover, it increased plasma IGF-I concentration (p < 0.05), but it had no effect on the plasma insulin profile. P4 significantly decreased the AUC (p < 0.01), compared with the control group, whereas it did not affect the number of peaks and the amplitude of GH pulses. P4 + E2 did not affect the GH pulse profile. E2 increased the mRNA expression of GHR, IGFR-I and IR in the liver (p < 0.05), whereas both P4 and E2 + P4 did not change their expressions. Our results provide evidence that the metabolic and reproductive endocrine axes may regulate each other to ensure optimal reproductive and metabolic function.

The transcription factor encyclopedia

Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field.

Gene expression of tumour necrosis factor and insulin signalling-related factors in subcutaneous adipose tissue during the dry period and in early lactation in dairy cows

Gene expression of adipose factors, which may be part of the mechanisms that underlie insulin sensitivity, were studied in dairy cows around parturition. Subcutaneous fat biopsies and blood samples were taken from 27 dairy cows in week 8 antepartum (a.p.), on day 1 postpartum (p.p.) and in week 5 p.p. In the adipose tissue samples, mRNA was quantified by real-time reverse transcription polymerase chain reaction for tumour necrosis factor alpha (TNFalpha), insulin-independent glucose transporter (GLUT1), insulin-responsive glucose transporter (GLUT4), insulin receptor, insulin receptor substrate 1 (IRS1), insulin receptor substrate 2 (IRS2), regulatory subunit of phosphatidylinositol-3 kinase (p85) and catalytic subunit of phosphatidylinositol-3 kinase. Blood plasma was assayed for concentrations of glucose, beta-hydroxybutyric acid, non-esterified fatty acids (NEFA) and insulin. Plasma parameters followed a pattern typically observed in dairy cows. Gene expression changes were observed, but there were no changes in TNFalpha concentrations, which may indicate its local involvement in catabolic adaptation of adipose tissue. Changes in GLUT4 and GLUT1 mRNA abundance may reflect their involvement in reduced insulin sensitivity and in sparing glucose for milk synthesis in early lactation. Unchanged gene expression of IRS1, IRS2 and p85 over time may imply a lack of their involvement in terms of insulin sensitivity dynamics. Alternatively, it may indicate that post-transcriptional modifications of these factors came into play and may have concealed an involvement.

The role of androgens on hypoxia-inducible factor (HIF)-1α-induced angiogenesis and on the survival of ischemically challenged skin flaps in a rat model

Effects of androgens on angiogenesis are controversial. Hypoxia-inducible factor (HIF)-1α promotes expression of vascular endothelial growth factor (VEGF) that stimulates angiogenesis.

Epidermal growth factor receptor inhibitors plus chemotherapy in non-small-cell lung cancer: biologic rationale for combination strategies

Chemotherapy continues to play an essential role in the treatment of most stages of non-small-cell lung cancer (NSCLC). In fact, within the past 5 years, this role has greatly expanded into adjuvant therapy for early-stage resected disease. Likewise, agents targeting the epidermal growth factor receptor (EGFR), particularly the tyrosine kinase inhibitors gefitinib and erlotinib, have proven to be clinically active in patients with advanced-stage NSCLC. Because of these findings, it is logical to expect that combinations of these 2 classes of antineoplastic agents would prove more efficacious than either one alone. Yet 4 large randomized phase III trials of chemotherapy with or without an EGFR tyrosine kinase inhibitor in unselected patients with advanced-stage NSCLC, altogether totaling > 4000 patients, did not demonstrate improvement in clinical outcomes with the combination. Whether these negative results will be reproduced in ongoing combination studies of chemotherapy plus monoclonal antibodies directed against EGFR remain to be determined. Herein, we review recent preclinical and clinical data addressing this topic and explore the biologic rationale for developing new combination strategies based on patient selection by molecular and clinical factors, or by pharmacodynamic parameters.

ADAMTS-13, von Willebrand factor and related parameters in severe sepsis and septic shock

BACKGROUND: Insufficient control of von Willebrand factor (VWF) multimer size as a result of severely deficient ADAMTS-13 activity results in thrombotic thrombocytopenic purpura associated with microvascluar thrombosis and platelet consumption, features not seldom seen in severe sepsis and septic shock. METHODS: ADAMTS-13 activity and VWF parameters of 40 patients with severe sepsis or septic shock were compared with those of 40 healthy controls of the same age and gender and correlated with clinical findings and sepsis outcome. RESULTS: ADAMTS-13 activity was significantly lower in patients than in healthy controls [median 60% (range 27-160%) vs. 110% (range 63-200%); P < 0.001]. VWF parameters behaved reciprocally and both VWF ristocetin cofactor activity (RCo) and VWF antigen (VWF:Ag) were significantly (P < 0.001) higher in patients compared with controls. Neither ADAMTS-13 activity nor VWF parameters correlated with disease severity, organ dysfunction or outcome. However, a contribution of acute endothelial dysfunction to renal impairment in sepsis is suggested by the significantly higher VWF propeptide and soluble thrombomodulin levels in patients with increased creatinine values as well as by their strong positive correlations (creatinine and VWF propeptide r(s) = 0.484, P < 0.001; creatinine and soluble thrombomodulin r(s) = 0.596, P < 0.001). CONCLUSIONS: VWF parameters are reciprocally correlated with ADAMTS-13 activity in severe sepsis and septic shock but have no prognostic value regarding outcome.

Increased lipopolysaccharide-induced tumour necrosis factor-alpha, interferon-gamma and interleukin-10 production in atopic dermatitis

BACKGROUND: Atopic dermatitis (AD) is based on a genetic predisposition, but environmental factors may trigger skin inflammation. According to the hygiene hypothesis, decreased exposure to microbial products in early childhood does not allow sufficient maturation of the immune system that is associated with an increased risk of atopic sensitization. OBJECTIVES: The effect of lipopolysaccharide (LPS) on the cytokine production of peripheral blood mononuclear cells (PBMC) of AD patients and nonatopic controls was studied. PATIENTS AND METHODS: PBMC were isolated from heparinized blood of 10 patients with AD and 10 nonatopic individuals, suspended in culture medium and stimulated with LPS. Cytokine levels in the supernatants were measured by immunoassays. Results Upon stimulation with LPS, PBMC from AD patients produced significantly higher amounts of tumour necrosis factor-alpha, interferon-gamma and interleukin (IL)-10 compared with control PBMC. LPS stimulation blocked the increased spontaneous production of IL-4 and IL-5 by PBMC from AD patients, but had no effect on IL-13 production. CONCLUSIONS: These results demonstrate that the effects of LPS stimulation depend on both the type of cytokine and the origin of PBMC. Endotoxin exposure is suggested to modulate the disease course of AD.

International registry on factor XIII deficiency: a basis formed mostly on European data

FXIII deficiency is known as one of the rarest blood coagulation disorders. In this study, the phenotypic and in part genotypic data of 104 FXIII-deficient patients recorded from 1993 - 2005 are presented. The most common bleeding symptoms were subcutaneous bleeding (57%) followed by delayed umbilical cord bleeding (56%), muscle hematoma (49%), hemorrhage after surgery (40%), hemarthrosis (36%), and intracerebral bleeding (34%). Prophylactic treatment was initiated in about 70% of all patients. FXIII-B subunit-deficient patients had a milder phenotype than patients with FXIII-A subunit deficiency. The most frequent mutation affecting the F13A gene was a splice site mutation in intron 5 (IVS5-1G>A). This mutation was found in eight (17%) of 46 analyzed families. The haplotype analysis of patients carrying the IVS5-1A allele was consistent with a founder effect. The international registry (http://www.f13-database.de) will provide clinicians and scientists working on FXIII deficiency with a helpful tool to improve patient care and direct future studies towards better understanding and treatment of the disease.

Recurrent ischemic colitis in a patient with leiden factor V mutation and systemic lupus erythematous with antiphospholipid syndrome

Ischemic colitis results from insufficient blood supply to the large intestine and is often associated with hypercoagulable states. The condition comprises a wide range presenting with mild to fulminant forms. Diagnosis remains difficult because these patients may present with non-specific abdominal symptoms. We report a 51- year-old female patient with known Leiden factor V mutation as well as systemic lupus erythematous along with antiphospholipid syndrome suffering from recurrent ischemic colitis. At admission, the patient complained about abdominal pain, diarrhea and rectal bleeding lasting for 24 hours. Laboratory tests showed an increased C-reactive protein (29.5 mg/dl), while the performed abdominal CT-scan revealed only a dilatation of the descending colon along with a thickening of the bowel wall. Laparotomy was performed showing an ischemic colon and massive peritonitis. Histological examination proved the suspected ischemic colitis. Consecutively, an anti-coagulation therapy with coumarin and aspirin 100 was initiated. Up to the time point of a follow up examination no further ischemic events had occurred. This case illustrates well the non-specific clinical presentation of ischemic colitis. A high index of suspicion, recognition of risk factors and a history of non-specific abdominal symptoms should alert the clinicians to the possibility of ischemic disease. Early diagnosis and initiation of anticoagulation therapy or surgical intervention in case of peritonitis are the major goals of therapy.