Insulin increases ceramide synthesis in skeletal muscle.

AIMS: The purpose of this study was to determine the effect of insulin on ceramide metabolism in skeletal muscle. METHODS: Skeletal muscle cells were treated with insulin with or without palmitate for various time periods. Lipids (ceramides and TAG) were isolated and gene expression of multiple biosynthetic enzymes were quantified. Additionally, adult male mice received daily insulin injections for 14 days, followed by muscle ceramide analysis. RESULTS: In muscle cells, insulin elicited an increase in ceramides comparable to palmitate alone. This is likely partly due to an insulin-induced increase in expression of multiple enzymes, particularly SPT2, which, when knocked down, prevented the increase in ceramides. In mice, 14 days of insulin injection resulted in increased soleus ceramides, but not TAG. However, insulin injections did significantly increase hepatic TAG compared with vehicle-injected animals. CONCLUSIONS: This study suggests that insulin elicits an anabolic effect on sphingolipid metabolism in skeletal muscle, resulting in increased ceramide accumulation. These findings reveal a potential mechanism of the deleterious consequences of the hyperinsulinemia that accompanies insulin resistance and suggest a possible novel therapeutic target to mitigate its effects.

Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD.

Chronic obstructive pulmonary disease (COPD) is associated with important chronic comorbid diseases, including cardiovascular disease, diabetes and hypertension. The present study analysed data from 20,296 subjects aged > or =45 yrs at baseline in the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS). The sample was stratified based on baseline lung function data, according to modified Global Initiative for Obstructive Lung Disease (GOLD) criteria. Comorbid disease at baseline and death and hospitalisations over a 5-yr follow-up were then searched for. Lung function impairment was found to be associated with more comorbid disease. In logistic regression models adjusting for age, sex, race, smoking, body mass index and education, subjects with GOLD stage 3 or 4 COPD had a higher prevalence of diabetes (odds ratio (OR) 1.5, 95% confidence interval (CI) 1.1-1.9), hypertension (OR 1.6, 95% CI 1.3-1.9) and cardiovascular disease (OR 2.4, 95% CI 1.9-3.0). Comorbid disease was associated with a higher risk of hospitalisation and mortality that was worse in people with impaired lung function. Lung function impairment is associated with a higher risk of comorbid disease, which contributes to a higher risk of adverse outcomes of mortality and hospitalisations.

Automated electrophysiology in drug discovery.

Ion channels play essential roles in nervous system signaling, electrolyte transport, and muscle contraction. As such, ion channels are important therapeutic targets, and the search for compounds that modulate ion channels is accelerating. In order to identify and optimize ion channel modulators, assays are needed that are reliable and provide sufficient throughput for all stages of the drug discovery process. Electrophysiological assays offer the most direct and accurate characterization of channel activity and, by controlling membrane potential, can provide information about drug interactions with different conformational states. However, these assays are technically challenging and notoriously low-throughput. The recent development of several automated electrophysiology platforms has greatly increased the throughput of whole cell electrophysiological recordings, allowing them to play a more central role in ion channel drug discovery. While challenges remain, this new technology will facilitate the pharmaceutical development of ion channel modulators.

Nutritional assessment of pregnant women enrolled in the Special Supplemental Program for Women, Infants, and Children (WIC).

OBJECTIVE: To evaluate nutrient intake from dietary sources for 95 pregnant women enrolled in the Special Supplemental Program for Women, Infants, and Children (WIC). SUBJECTS/SETTING: Women were recruited from Minneapolis and St Paul area WIC clinics between January and June 1999. Based on estimates from the WIC clinics, the study was described to 159 (63%) of the 251 potentially eligible women. Of these 159 women, 107 (67%) completed the in-person interview. Ninety-five (89%) were included in the nutrition analysis. METHODS: Each woman completed a 1-hour in-person interview that included a questionnaire, anthropometric measurements, and a venous blood sample. A shortened Block 98 food frequency questionnaire was used to assess dietary intake. Serum ferritin was measured for 86 women. Means, medians, and standard deviations of dietary intake were explored as well as body mass index distributions. Additionally, the percentage of women consuming less than two thirds of the recommended dietary allowance (RDA) for certain nutrients was calculated. RESULTS: Overall, the women reported consuming only 85% of the RDA for energy. The average percentage of energy from fat was higher than recommended (37% vs 30%). The most notable nutrient shortfall was iron; 90% of the women reported consuming less than 2/3 of the RDA. Additionally, serum ferritin analysis classified 22% of the women with iron-deficiency anemia (<12 mg/L). CONCLUSIONS: Interventions should be designed to decrease fat consumption and increase iron intake among pregnant WIC participants to meet dietary recommendations.

Pet ownership and childhood acute leukemia (USA and Canada).

OBJECTIVES: For more than three decades there has been speculation regarding a possible role of zoonotic diseases in the development of human leukemia. This study investigated the potential relationship between exposure to pets and the development of childhood leukemia. METHODS: Data from 2359 cases of acute leukemia from two large case-control studies were analyzed. Cases were individually matched to population controls on telephone exchange, age, and race. Conditional logistic regression was used to estimate odds ratios (OR) associated with pet ownership. RESULTS: Overall, there was no association between pet ownership (either "any pet", dog, or cat) and childhood acute leukemia (OR(any pet:) = 1.01, 95% CI 0.89-1.2). Additionally, no relationship was found between exposure to an ill pet and childhood leukemia. CONCLUSION: The results of this analysis suggest that pet ownership (healthy or sick) is unrelated to an increased risk of childhood leukemia.

Modulators with convergent cellular actions elicit distinct circuit outputs.

Six neuromodulators [proctolin, Cancer borealis tachykinin-related peptide Ia, crustacean cardioactive peptide (CCAP), red pigment-concentrating hormone, TNRNFLRFamide, and pilocarpine] converge onto the same voltage-dependent inward current in stomatogastric ganglion (STG) neurons of the crab C. borealis. We show here that each of these modulators acts on a distinct subset of pyloric network neurons in the STG. To ask whether the differences in cell targets could account for their differential effects on the pyloric rhythm, we systematically compared the motor patterns produced by proctolin and CCAP. The motor patterns produced in proctolin and CCAP differed quantitatively in a number of ways. Proctolin and CCAP both act on the lateral pyloric neuron and the inferior cardiac neuron. Proctolin additionally acts on the pyloric dilator (PD) neurons, the pyloric (PY) neurons, and the ventricular dilator neuron. Using the dynamic clamp, we introduced an artificial peptide-elicited current into the PD and PY neurons, in the presence of CCAP, and converted the CCAP rhythm into a rhythm that was statistically similar to that seen in proctolin. This suggests that the differences in the network effects of these two modulators can primarily be attributed to the known differential distributions of their receptors onto distinct subsets of neurons, despite the fact that they activate the same current.

The roles of co-transmission in neural network modulation.

Neuromodulation provides considerable flexibility to the output of neural networks. In spite of the extensive literature documenting the presence of modulatory peptide co-transmitters in many neurons, considerably less is known about the specific roles of co-transmission in circuit function. This review describes some of the potential consequences of peptide co-transmission in functional circuits, using specific examples from recent work on the actions of identified peptidergic projection neurons acting on the multifunctional neural network within the crustacean stomatogastric ganglion. This system reveals that co-transmission provides projection neurons with a rich assortment of strategies for eliciting multiple outputs from a multifunctional network.

Prenatal epidemiology of pediatric tumors.

With the exception of a small percentage of cases attributable to hereditary cancer syndromes (eg, familial retinoblastoma) or genetic syndromes (Down syndrome), the etiology of most childhood cancers is unknown. Recent epidemiologic studies have focused on the prenatal period and have investigated potential associations with parental age, cigarette smoking, birth weight of the child, parental occupational exposures, and specific environmental exposures. The following challenges lie ahead for future epidemiologic studies of childhood cancer: 1) improvement of diagnostic classification; 2) improved methods for exposure assessment; 3) evaluation of data from molecular biology to generate biologically derived hypotheses; and 4) incorporation of markers of genetic susceptibility when feasible.

Multiple peptides converge to activate the same voltage-dependent current in a central pattern-generating circuit.

The stomatogastric ganglion of the crab, Cancer borealis, is modulated by >20 different substances, including numerous neuropeptides. One of these peptides, proctolin, activates an inward current that shows strong outward rectification (Golowasch and Marder, 1992). Decreasing the extracellular Ca(2+) concentration linearizes the current-voltage curve of the proctolin-induced current. We used voltage clamp to study the currents evoked by proctolin and five additional modulators [C. borealis tachykinin-related peptide Ia (CabTRP Ia), crustacean cardioactive peptide, red pigment-concentrating hormone, TNRNFLRFamide, and the muscarinic agonist pilocarpine] in stomatogastric ganglion neurons, both in the intact ganglion and in dissociated cell culture. Subtraction currents yielded proctolin-like current-voltage relationships for all six substances, and the current-voltage curves of all six substances showed linearization in low external Ca(2+). The lateral pyloric neuron responded to all six modulators, but the ventricular dilator neuron only responded to a subset of them. Bath application of saturating concentrations of proctolin occluded the response to CabTRP and vice versa. N-(6-Aminohexyl)-5-chloro-1-napthalensulfonamide, a calmodulin inhibitor, increased the amplitude and altered the voltage dependence of the responses elicited by CabTRP and proctolin. Together, these data indicate that all six substances converge onto the same voltage-dependent current, although they activate different receptors. Therefore, differential network responses evoked by these substances may primarily depend on the receptor distribution on network neurons.

GABA and responses to GABA in the stomatogastric ganglion of the crab Cancer borealis.

The multifunctional neural circuits in the crustacean stomatogastric ganglion (STG) are influenced by many small-molecule transmitters and neuropeptides that are co-localized in identified projection neurons to the STG. We describe the pattern of gamma-aminobutyric acid (GABA) immunoreactivity in the stomatogastric nervous system of the crab Cancer borealis and demonstrate biochemically the presence of authentic GABA in C. borealis. No STG somata show GABA immunoreactivity but, within the stomatogastric nervous system, GABA immunoreactivity co-localizes with several neuropeptides in two identified projection neurons, the modulatory proctolin neuron (MPN) and modulatory commissural neuron 1 (MCN1). To determine which actions of these neurons are evoked by GABA, it is necessary to determine the physiological actions of GABA on STG neurons. We therefore characterized the response of each type of STG neuron to focally applied GABA. All STG neurons responded to GABA. In some neurons, GABA evoked a picrotoxin-sensitive depolarizing, excitatory response with a reversal potential of approximately -40 mV. This response was also activated by muscimol. In many STG neurons, GABA evoked inhibitory responses with both K(+)- and Cl(-)-dependent components. Muscimol and beta-guanidinopropionic acid weakly activated the inhibitory responses, but many other drugs, including bicuculline and phaclofen, that act on vertebrate GABA receptors were not effective. In summary, GABA is found in projection neurons to the crab STG and can evoke both excitatory and inhibitory actions on STG neurons.

Seasonal variations in the diagnosis of childhood cancer in the United States.

Seasonal trends in month of diagnosis have been reported for childhood acute lymphoblastic leukaemia (ALL) and non-Hodgkin's lymphoma (NHL). This seasonal variation has been suggested to represent an underlying viral aetiology for these malignancies. Some studies have shown the highest frequency of diagnoses in the summer months, although this has been inconsistent. Data from the Children's Cancer Group and the Pediatric Oncology Group were analysed for seasonal incidence patterns. A total of 20,949 incident cancer cases diagnosed in the USA from 1 January 1989 through 31 December 1991 were available for analyses. Diagnosis-specific malignancies available for evaluation included ALL, acute myeloid leukaemia (AML), Hodgkin's disease, NHL, rhabdomyosarcoma, neuroblastoma, retinoblastoma, osteosarcoma, Wilms' tumour, retinoblastoma, Ewings' sarcoma, central nervous system (CNS) tumours and hepatoblastoma. Overall, there was no statistically significant seasonal variation in the month of diagnosis for all childhood cancers combined. For diagnosis-specific malignancies, there was a statistically significant seasonal variation for ALL (P = 0.01; peak in summer), rhabdomyosarcoma (P = 0.03; spring/summer) and hepatoblastoma (P = 0.01; summer); there was no seasonal variation in the diagnosis of NHL. When cases were restricted to latitudes greater than 40 degrees ('north'), seasonal patterns were apparent only for ALL and hepatoblastoma. Notably, 33% of hepatoblastoma cases were diagnosed in the summer months. In contrast, for latitudes less than 40 degrees ('south'), only CNS tumours demonstrated a seasonal pattern (P = 0.002; winter). Although these data provide modest support for a summer peak in the diagnosis of childhood ALL, any underlying biological mechanisms that account for these seasonal patterns are likely complex and in need of more definitive studies.

Childhood cancer incidence and trends in Minnesota, 1988-1994.

Childhood cancer incidence patterns for Minnesota, obtained from the Minnesota Cancer Surveillance System, were compared with national rates as well as with historic data from eight Minnesota counties. In total, 1,140 neoplasms were diagnosed in children (ages 0 to 14) between 1988 and 1994. Leukemias were the most common diagnosis for boys (30.3%) and girls (29.6%), followed by central nervous system tumors. The average annual age-adjusted incidence rates for all cancer sites were 167.2 and 136.2 per million for boys and girls, respectively. These rates were somewhat higher than national rates. In particular, the incidence rate for astrocytoma in boys was significantly elevated. Childhood cancer incidence, particularly brain tumors, has increased in the eight-county region from 1969 to 1994. This analysis demonstrated the Minnesota's childhood cancer incidence patterns are similar to national patterns.

The age peak in childhood acute lymphoblastic leukemia: exploring the potential relationship with socioeconomic status.

BACKGROUND: White children have a much higher incidence rate of acute lymphoblastic leukemia (ALL) than do African American children. This discrepancy, coupled with the geographic and temporal variations in the incidence of childhood ALL, have led to speculation that factors associated with socioeconomic status (SES) may play an important role in its etiology. Because most of the variation is accounted for by the occurrence of a peak in incidence between the ages of 2 and 5 years, the purpose of this study was to compare the SES of children diagnosed with ALL between the peak ages of 2-5 years with those children diagnosed at other ages (birth-1 year and 6-14 years). METHODS: Patients included 4210 children who were diagnosed with ALL between January 1, 1989 and December 31, 1991 by a member institution of the Children's Cancer Group or the Pediatric Oncology Group. Of these children, 3614 were white and 596 were African American. The SES of a case was defined as the SES of the child's zip code of residence at the time of diagnosis. Five sociodemographic variable categories for each zip code were obtained from the 1990 U.S. Census including per capita income, number of housing units by household income, number of housing units by level of urbanization, number of persons older than 25 years by educational attainment, and number of persons by occupation. Mean values were compared for white children versus African American children, and peak ages (2-5 years) versus nonpeak ages (birth-1 year and 6-14 years) for both whites and African Americans. In addition, Wilcoxon's rank sum tests were performed. RESULTS: There were statistically significant differences between the means in each of the socioeconomic categories when African Americans were compared with whites. However, within race, the means of the SES variables for white children diagnosed during the peak ages (2-5 years) were not significantly different from children diagnosed at other ages (birth-1 year and 6-14 years). Similarly, all but one of the comparisons for African American children yielded nonstatistically significant results. Similar results were obtained from the Wilcoxon's rank sum tests. CONCLUSIONS: The results of this analysis suggest that age differences in childhood ALL incidence may not be solely accounted for by SES differences.

Census statistics through combined use of surveys and registers?

"In this paper we present some results from a study [concerning Norway] on the feasibility of producing census statistics through the combined use of surveys and registers. The main finding is that if one is willing to relax a little on the need for accuracy of statistics for 'small' areas, the large majority of the census statistics can be produced by such a combined use of data sources."