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PubMed1998

[The indices of the thrombocyte serotonin system and of the nerve growth factor system in children with hereditary disorders of neuropsychic development].

Indices of both platelet serotoninergic system and the system of nerve growth factor (NGF) were examined in children with neurofibromatosis (15 patients), polygenic oligophrenia (24 patients) and Rett's syndrome (14 ones). There was an increase of both the level of blood serum autoantibodies (aAB) to NGF and the value of specific binding of 3H-imipramine (Bmax) in platelets of patients with oligophrenia. For this group of patients a significant negative correlation exists between the rate of platelet uptake of serotonin (Vmax value) and the degree of mental retardation (r = -0.425, p < 0.03). Decrease of both Vmax and activity of platelet NGF receptors was revealed in patients with neurofibromatosis. In such patients there was positive correlation between sensitivity of platelet NGF receptors to NGF (during their stimulation by test dose of purified NGF) and the degree of mental retardation (r = 0.697, p < 0.04). In patients with Rett's syndrome a significant increase of activity of platelet NGF receptors to NGF was observed. The conclusion was made on the existence of some general mechanism of intellectual defect development. Autoimmune processes considered to be such mechanism.

Adolescent↗

PubMed1993

Site-directed mutagenesis of human thioredoxin. Identification of cysteine 74 as critical to its function in the "early pregnancy factor" system.

Thioredoxin has been identified as a key component of the "early pregnancy factor" system, a system of components present in pregnancy sera which expresses a lymphocyte modifying activity in an assay known as the rosette inhibition assay. Although thioredoxin alone is inactive, addition of thioredoxin to lymphocytes in combination with nonpregnancy sera or platelet-activating factor results in a positive response. We have changed several amino acids of human thioredoxin by site-directed mutagenesis to investigate the residues required for this cooperative function. Conversion of the two active site residues (cysteines 32 and 35) to serines results in a protein devoid of classical redox activity; however, this protein retained its ability to cooperate with non-pregnancy sera or platelet-activating factor in the rosette inhibition assay. Vertebrate thioredoxins contain an additional conserved pair of cysteine residues in the C-terminal portion of the protein. Changing both to serines resulted in no change in redox activity but completely abolished function in the rosette inhibition assay. Further study revealed this function was solely dependent on cysteine 74 as conversion of only cysteine 74 to serine abolished function, whereas replacement of only cysteine 70 with serine had no effect. The nonfunctional mutants counteracted the action of pregnancy serum in the assay strongly supporting the hypothesis that thioredoxin is an integral part of the early pregnancy factor system with residue cysteine 74 having an important role.

Amino Acid Sequence↗

PubMed2001

Ocular and systemic factors relevant to diabetic keratoepitheliopathy.

PURPOSE: This study examines the contribution of ocular and systemic factors to diabetic keratoepitheliopathy. METHODS: The presence and severity of keratoepitheliopathy was investigated in 114 eyes of patients with diabetes and 59 eyes of patients without diabetes. The ocular factors examined were the status of the lipid layer of the tear fluid assessed with the specular reflection video-recording system, corneal sensitivity using the Cochet-Bonnet method, tear volume by the cotton thread test, tear film stability by tear breakup time, and grade of diabetic retinopathy. The systemic factors examined included patient age, hemoglobin A1c value, and duration of diabetes mellitus. Multivariate regression analysis was performed to assess the factors related to keratoepitheliopathy. RESULTS: The incidence of keratoepitheliopathy was 22.8% and 8.5% in patients with and without diabetes, respectively. Ocular measures, such as nonuniformity of tear lipid layer, corneal sensitivity, and tear breakup time, were significantly worse in patients with diabetes than in patients without diabetes ( p < 0.05). Multivariate regression analysis showed that the status of the tear lipid layer was significantly relevant to diabetic keratoepitheliopathy ( p < 0.05). CONCLUSION: Qualitative abnormalities in tear secretion seem relevant to the development of diabetic keratoepitheliopathy. The tear lipid layer interference pattern may yield useful information for the elucidation of the mechanism and treatment of diabetic keratoepitheliopathy.

Adult↗

PubMed2005

A system factors analysis of "line, tube, and drain" incidents in the intensive care unit.

OBJECTIVE: To analyze the system factors related to "line, tube, and drain" (LTD) incidents in the intensive care unit (ICU). DESIGN: Voluntary, anonymous Web-based patient safety reporting system. SETTING: Eighteen ICUs in the United States. PATIENTS: Incidents reported by ICU staff members during a 12-month period ending June 2003. INTERVENTIONS: None. MEASUREMENTS: Characteristics of the incidents (defined as events that could/did cause harm), patients, and patient harm were described. Separate multivariable logistic regression analyses of contributing, limiting, and preventive system factors for LTD vs. non-LTD incidents were reported. MAIN RESULTS: Of the 114 reported LTD incidents, >60% were considered preventable. One patient death was attributed to an LTD incident. Of patients experiencing LTD incidents, 56% sustained physical injury, and 23% had an anticipated increased hospital stay. Factors contributing to LTD incidents included occurrence in the operating room (odds ratio [OR], 3.50; 95% confidence interval [CI], 1.25-9.83), occurrence on a holiday (OR, 3.65; 95% CI, 1.12-11.9), patient medical complexity (OR, 3.68; 95% CI, 2.28-5.92), and age of 1-9 yrs (OR, 7.95; 95% CI, 3.29-19.2). Factors related to team communication were less likely to limit LTD incidents (OR, 0.28; 95% CI, 0.11-0.68), while clinician knowledge and skills helped prevent LTD incidents (OR, 1.80; 95% CI, 1.09-2.97). CONCLUSIONS: Patients are harmed by preventable LTD incidents. Relative to non-LTD events, these incidents occur more frequently during holidays and in medically complex patients and children. Focusing on these contributing factors and clinician knowledge and skills is important for reducing and preventing these hazardous events.

Adolescent↗

PubMed2000

Quantitation of the mRNA expression of the epidermal growth factor system: selective induction of heparin-binding epidermal growth factor-like growth factor and amphiregulin expression by growth factor stimulation of prostate stromal cells.

The epidermal growth factor (EGF) system is a rapidly expanding system of growth factors involved in many aspects of normal and cancerous growth. We have developed a method for the quantitation of mRNA coding for all six growth factors activating the human EGF receptor (HER-1) and for the quantitation of mRNA for the receptors HER-1 and its preferred dimerization partner, HER-2. The method is based on the generation of specific RNA standards, which are amplified by reverse transcriptase-polymerase chain reaction (RT-PCR) with the sample RNA and a set of calibrators. The resulting calibration curve is used to quantitate the unknown samples, which require only a single RT-PCR reaction. Our method has the advantage that quantitation is based on coamplification of an internal RNA standard, thereby controlling both the PCR and RT reactions. In addition, the RNA standards for all growth factors and receptors are combined in a single RT reaction, which minimizes variation and allows the quantitation of all eight mRNA species with only 0.1 microg RNA. This makes the method suitable for studies in which the supply of material is limited. The developed method has enabled us to demonstrate that prostate stromal cells in primary culture express EGF, heparin-binding EGF (HB-EGF), amphiregulin, betacellulin, and epiregulin as well as the HER-1 and HER-2 receptors, whereas no transforming growth factor-alpha mRNA is found. Furthermore, activation of the EGF system in these cells by stimulation with HB-EGF or EGF in mitogenic doses causes a selective increase in the expression of amphiregulin and HB-EGF mRNA (more than 15-fold and 25-fold, respectively), whereas there is no increase in the expression of mRNA for the other growth factors or receptors. In accord with the increase in amphiregulin mRNA, the amount of amphiregulin peptide released from the cells is also increased. The selective induction of amphiregulin and HB-EGF by growth factor stimulation may represent a mechanism to amplify the initial growth factor signal in prostate stromal cells.

Amphiregulin↗

PubMed1996

Effect of health care system factors on test ordering.

OBJECTIVE: To determine the effect of the emergency department (ED) environment and other health care system factors on test ordering for children with acute abdominal pain. METHODS: We reviewed the encounter records of 1140 consecutive children seen in either the pediatric clinic or ED of an inner-city teaching hospital with a complaint of acute abdominal pain (< 72 hours). In the ED and the clinic, patients were seen by medical students, pediatric residents, and general pediatric faculty members. Measured data on test ordering included the number of tests ordered and the type of tests ordered; specifically examined were the throat culture, urinalysis or urine culture, and chest radiograph. Measured health care system factors included (1) encounter location; (2) resident involvement and level of training; (3) student involvement; and (4) faculty member's years of experience and sex. RESULTS: Of the 1140 children, 117 (10.2%) were seen in the ED, 531 (47.1%) were seen by a resident, 344 (30.2%) were seen by a medical student, and 195 (17.1%) were seen by a faculty member with more than 10 years of clinical pediatric experience. After controlling for initial signs and symptoms in multiple logistic regression, a child treated in the ED was no more likely to have had tests ordered than one who was treated in the clinic. Neither resident involvement nor resident training level affected test ordering. Except for decreasing the likelihood of having a urinalysis or urine culture ordered (odds ratio [OR] = 0.30; 95% confidence interval [CI], 0.15-0.63), student involvement did not affect test ordering. Also, except for decreasing the likelihood of having a throat culture ordered (OR = 0.45; 95% CI, 0.25-0.83), being seen by a pediatrician with more than 10 years of experience did not affect test ordering. Children seen by female physicians were more likely (OR = 2.41; 95% CI, 1.57-3.70) to have at least 1 test ordered. CONCLUSIONS: For children seen for a complaint of acute abdominal pain, we found little evidence that test ordering is affected by encounter location, resident involvement, student involvement, or faculty member experience.

Abdomen, Acute↗

PubMed2003

The insulin-like growth factor system and cancer.

The insulin-like growth factor (IGF) family of ligands, binding proteins and receptors is an important growth factor system involved in both the development of the organism and the maintenance of normal function of many cells of the body. The system also has powerful anti-apoptotic effects. More recently, evidence has accrued to demonstrate that the IGFs play an important role in cancer. Individuals with serum IGF-II levels in the upper quartile of the normal range (and IGF binding protein-3 levels in the lower quartiles) have a relative risk for developing breast, prostate, colon and lung cancer. IGF-II is commonly expressed by tumor cells and may act as an autocrine growth factor; occasionally even reaching target tissues and causing tumor-induced hypoglycemia. The IGF-I receptor is commonly (though not always) overexpressed in many cancers, and many recent studies have identified new signaling pathways emanating from the IGF-I receptor that affect cancer cell proliferation, adhesion, migration and cell death; functions that are critical for cancer cell survival and metastases. In this review, many aspects of the IGF system and its relationship to cancer will be discussed.

Animals↗

PubMed2006

Insulin-induced proliferation of bladder cancer cells is mediated through activation of the epidermal growth factor system.

The mechanism behind the growth-promoting effect of insulin is a subject of debate. Employing RT4 bladder cancer cells, we examined the cross-talk between insulin and the epidermal growth factor system. We found that insulin induced a time- and dose-dependent (25-1000 nmol.L(-1) insulin) increase in mRNA expression of three ligands from the epidermal growth factor system. Times for peak increase and fold increase after incubation with 250 nmol.L(-1) insulin were as follows: heparin-binding epidermal growth factor-like growth factor, 0.5 h, 1.4-fold, P < 0.05; epiregulin, 3 h, 14-fold, P < 0.0001; and amphiregulin, 3 h, 12-fold, P < 0.001. Induction of heparin-binding epidermal growth factor-like growth factor and amphiregulin was verified at the protein level. We demonstrate that incubation of RT4 bladder cancer cells for 24 h with 250 nmol.L(-1) insulin increases proliferation by 43% (P < 0.0001) as compared to untreated cells. At the same time, phosphorylation and thereby activation of the epidermal growth factor receptor (HER1) was observed. Both phosphorylation and insulin-induced proliferation were almost completely inhibited by the HER1 inhibitor Iressa (P < 0.0001). This shows that insulin leads to activation of HER1, and that HER1 plays an essential role in mediating the growth-promoting effect of insulin. Iressa inhibited not only the activation of HER1 caused by insulin but also the insulin-induced increase in the three ligands (heparin-binding epidermal growth factor-like growth factor, epiregulin and amphiregulin). As heparin-binding epidermal growth factor-like growth factor was induced before epiregulin and amphiregulin upon insulin stimulation, we speculated that the insulin-induced heparin-binding epidermal growth factor-like growth factor initiated the activation of HER1, and that this in turn led to increased expression of epiregulin and amphiregulin and thereby to continued activation of HER1. Earlier reports have shown that insulin-like growth factor receptor can activate HER1 via its ligand heparin-binding epidermal growth factor-like growth factor. In accord with this, we found that treatment of RT4 cells with recombinant heparin-binding epidermal growth factor-like growth factor mimicked the effect of insulin, with induction of mRNA for the three ligands. However, the insulin-induced increase in mRNA expression of amphiregulin and epiregulin could not be prevented by the heparin-binding epidermal growth factor-like growth factor inhibitor CRM197, demonstrating that heparin-binding epidermal growth factor-like growth factor is not essential for the insulin-induced increase in the expression of these ligands. In conclusion, we show that insulin-induced growth in RT4 cells requires activated HER1. Furthermore, activation of HER1 is required for the insulin-induced increase in expression of the HER1 ligands heparin-binding epidermal growth factor-like growth factor, amphiregulin and epiregulin.

Cell Proliferation↗

PubMed1991

Alveolar ridge resorption and mandibular atrophy. A review of the role of local and systemic factors.

Loss of alveolar bone from the edentulous jaws is a serious and common clinical problem, especially among the elderly. The retention and stability of dentures are reduced, but little is known about the pathogenesis of this bone loss. The existing data suggest that either local factors, for instance occlusal trauma, or systemic factors such as postmenopausal osteoporosis, contribute to edentulous alveolar bone resorption. This paper reviews the evidence for the aetiology of residual ridge resorption following tooth extraction.

Alveolar Bone Loss↗

PubMed2001

The insulin-like growth factor system in kidney diseases.

The insulin-like growth factor system is intimately involved in renal development, growth, function and the pathophysiology of several disease states. Exogenous IGF-I increases GFR and RPF, perhaps mediated by nitric oxide (NO). In chronic renal failure, IGF-I, the binding proteins and their fragments decrease bioavailability. After transplantation, the levels of bioactive IGF-I increase likely due to better nutrition and increased clearance of the binding proteins and their fragments. In the nephritic syndrome, a similar mechanism may be active, in that the binding proteins and their fragments may inhibit IGF-I action.

Humans↗

PubMedDate not supplied

The short wavelength-sensitive cone electroretinogram in diabetes: relationship to systemic factors.

The short wavelength-sensitive (S-) cone electroretinogram (ERG) is selectively reduced in diabetic patients both with and without retinopathy, but the exact mechanism of the vulnerability of the S-cone system is still unclear. This study examined relationships of the S-cone ERG to systemic factors in diabetes. Cone ERGs to different color flash stimuli were examined in the presence of bright white background illumination in 17 diabetic patients without retinopathy and in 17 diabetics with background retinopathy. Relationships of the amplitude and implicit time of the S-cone ERG to the following systemic factors were statistically analyzed: patients' age, hemoglobin A1 level, method of diabetic control, presence of retinopathy, and presence of nephropathy. The amplitude of the S-cone ERG b-wave was significantly reduced in diabetics treated with insulin and in those associated with nephropathy. No significant correlation was found between the S-cone ERG and patient's age, hemoglobin A1 level and presence or absence of retinopathy. A selective reduction of the S-cone ERG is observed in patients whose metabolic control has been poor for a longer period, suggesting that microvascular changes may play a role in the S-cone ERG impairment.

Adult↗

PubMed2004

Mammography rescreening among women of diverse ethnicities: patient, provider, and health care system factors.

This study identified patient, provider, and health care system factors that influenced mammography rescreening among non-insured, racial/ethnic minority women. Data were collected using a stratified-clustered random sample survey of 1,050 women of five racial/ethnic groups (Latina, Chinese, Filipina, African American, and Caucasian) and 102 primary care clinical sites. Women received screening services through two no-cost screening programs in California. Chi-square tests were used to assess bivariate associations and multiple logistic regressions were used to compute adjusted odds ratios and 95% confidence intervals. Mammography rescreening was associated with living in the United States longer; having higher education levels, better health care access, a history of breast problems, and favorable perceptions of mammography; obtaining regular Pap screening and hormone replacement therapy; having had better communication with clinicians; and attending clinics that conducted in-reach activities. This study suggests that simply removing financial barriers is not enough to improve mammography rescreening among underserved women.

Aged↗

PubMed1995

The insulin-like growth factor system in vascular smooth muscle: interaction with insulin and growth factors.

Vascular smooth muscle cells (SMCs) occur throughout the vascular tree and have important physiological functions. They are also involved in pathological processes such as development and progression of atherosclerotic lesions, restenosis following angioplasty, and in hypertension. This review is focused on the role of the insulin-like growth factor (IGF) system in proliferation, migration, and hypertrophy of vascular SMCs and its interaction with insulin and other growth factors. The IGF-I receptor is highly expressed in SMCs in intact arteries and in cultured SMCs and is activated by binding of IGF-I to the two alpha-subunits. Insulin and IGF-II from the circulation can interact with the IGF-I receptor at higher concentrations. Insulin receptors are few or absent in SMCs and circulating insulin concentrations in vivo are probably too low for a direct action of insulin on the IGF-I receptor in SMCs. Receptor activation initiates a number of signal transduction pathways. Increased phosphatidylinositol turnover and calcium mobilization correlates with actin filament reorganization and stimulation of directed migration of the SMC in a gradient of IGF-I. The effects of IGF-I receptor activation on signal transduction pathways (eg, the MAP kinase cascade) implicated in DNA synthesis and proliferation are weak and this correlates with the meager mitogenic activity of IGF-I in SMC. Several components of the IGF-system in SMC are regulated by growth factors such as platelet-derived growth factor (PDGF)-BB and basic fibroblast growth factor (bFGF).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2004

A system factors analysis of airway events from the Intensive Care Unit Safety Reporting System (ICUSRS).

OBJECTIVE: To evaluate the contributing and limiting factors for airway events reported in the Intensive Care Unit Safety Reporting System (ICUSRS) developed in partnership with the Society of Critical Care Medicine. DESIGN: Analysis of system factors in airway vs. nonairway events reported to a voluntary, anonymous, Web-based patient safety reporting system (the ICUSRS). SETTING: Sixteen adult and two pediatric intensive care units (ICU) across the United States. PATIENTS: Incidents reported during the 12-month period ending June 30, 2003. INTERVENTIONS: None MEASUREMENTS: Descriptive characteristics of incidents (defined as events that could have, or did, cause harm), patients, and patient harm; separate multivariable logistic regression analyses of contributing and limiting factors for airway vs. nonairway events. MAIN RESULTS: There were 78 airway and 763 nonairway events reported. More than half of airway events were considered preventable. One patient death was attributed to an airway event. Physical injury, increased hospital length of stay, and family dissatisfaction occurred in at least 20% of airway events. Important factors contributing to reported airway events (odds ratio (OR), 95% confidence interval (CI)) included patients' medical condition (5.24, 3.07-8.95) and age <1 yr old (4.15, 1.79-9.59). Factors limiting the impact of airway events (OR, 95% CI) included adequate ICU staffing (3.60, 1.71-7.56) and use of skilled assistants (3.20, 1.62-6.32). CONCLUSIONS: Patients are harmed by unintended and preventable incidents involving airway management. Prevention efforts should focus on critically ill infants and patients with complex medical conditions. Managers should ensure appropriate ICU staffing to limit the impact of airway events when they occur.

Adolescent↗

PubMed1983

Local and systemic factors regulating mucosal mast cells.

The contributions of local and systemic factors to the regulation of mucosal mast cells and globule leukocytes have been examined in the rat. Nippostrongylus brasiliensis has been used to provide a potent immunological stimulus for mucosal mast cell hyperplasia and the roles of intestinal and extraintestinal sensitization observed by comparison of the gut mast cell responses to larval and adult worm infestations. Systemic effects of adult worm infestations have been examined in isolated Thiry-Vella loops of intestine. It is concluded that the extraintestinal phase of larval infestation is not obligatory for a gut mast cell response and that mast cell hyperplasia and globule leukocyte formation are not dependent on direct contact with the parasite or its products. The dissemination of the mast cell response and the general significance of the results are discussed.

Animals↗

PubMed1995

Systemic factors in esophageal mucosal protection.

Blood bicarbonate is an important systemic factor in esophageal protection due to its capacity for buffering H+ either in the lumen, at the epithelial surface, within the intercellular space, or within the cell. The ability to buffer within the lumen is in part dependent on submucosal gland secretion, while buffering in the intercellular space depends on bicarbonate diffusion from blood, and intracellular protection depends on the presence of basolateral membrane bicarbonate transport via a mechanism such as the Na(+)-dependent Cl-/HCO3- exchanger.

Animals↗

PubMed2006

Altered muscle development and expression of the insulin-like growth factor system in growth retarded fetal pigs.

We have used a porcine model of spontaneous differential fetal growth to investigate the effects of fetal size on muscle development. We hypothesized that altered muscle development may occur in small fetuses as a consequence of modified expression of selected genes of the insulin-like growth factor system. We examined the development of the Longissimus muscle (m. Longissimus) in small fetuses and their average sized littermates. We collected small for gestational age fetuses and their average sized sibling on days 45, 65 and 100 of gestation (term is 113-116 days). Small fetuses had significantly lower body weight at all three stages of gestation (p<0.05) and significantly reduced secondary to primary muscle fibre ratio in m. Longissimus on day 100 (p<0.05) compared to their littermates. On day 65, the expression of insulin-like growth factor receptor 1 and insulin-like growth factor binding protein 3 were significantly higher (p<0.05) in m. Longissimus of the small fetuses compared with their average sized littermates. On day 100, the expression of insulin-like growth factor receptor 1 remained significantly higher (p=0.001), in addition to significantly higher levels of insulin-like growth factor receptor 2 and insulin-like growth factor binding protein 5 in the small fetuses (p<0.05). No difference in levels of myogenin was observed between the small and average sized littermates. In conclusion, we demonstrate that reduced fetal muscle development is associated with an increased expression of several genes of the insulin-like growth factor system in small fetuses in mid to late gestation.

Animals↗

PubMed2005

The role of the insulin-like growth factor system in colorectal cancer: review of current knowledge.

BACKGROUND: The insulin-like growth factor system, which includes insulin-like growth factors (IGF-I and IGF-II), IGF receptors (IGF-IR and IGF-IIR) and IGF binding proteins (IGFBPs), plays an important role in epithelial growth, anti-apoptosis and mitogenesis. There is a growing body of evidence showing that IGFs control growth and proliferation of several types of cancer. This review introduces the latest information on the biology of the IGF system and its pathophysiological role in the development of colorectal cancer. DISCUSSION: The growth promoting effects of IGF-I and IGF-II on cancer cells are mediated through the IGF-IR, which is a tyrosine kinase and cancer cells with a strong tendency to metastasise have a higher expression of the IGF-IR. Most of the IGFs in circulation are bound to the IGFBPs, which regulate the bioavailability of the IGFs. All IGFBPs inhibit IGF action by high affinity binding, while some of them also potentiate the effects of IGFs. Colon cancer cells produce specific proteases that degrade the IGFBP so that the IGF will be free to act on the cancer cell in an autocrine manner. Therefore, the IGFBPs play a crucial role in the development of the cancer. CONCLUSION: The current knowledge about the link between IGFs and colon cancer is mainly based on in vitro investigations. Further in vivo study is needed to understand the exact role of the IGF system, especially its binding proteins, so that they can be manipulated for the prevention and treatment of colorectal cancer.

Animals↗