Recent trends in National Institutes of Health funding of surgical research

OBJECTIVE: To compare the amount of National Institutes of Health (NIH) funding provided to departments of surgery with that provided to other major clinical departments, to examine the relationship between peer-review activity and funding success, and to compare trends in participation in the peer-review process between surgeons and representatives from other clinical departments. SUMMARY BACKGROUND DATA: Surgical research has made enormous contributions to human health. This work is fundamentally dependent on fair and unbiased distribution of extramural research funds from the NIH. To date, no published report has examined the relative distribution of extramural support between departments of surgery and other major clinical departments. METHODS: Data regarding funding trends and peer-review activity were obtained from the NIH and compared between departments of surgery and four nonsurgical departments (medicine, psychiatry, pediatrics, neurology). Award data were examined during 1996 to 2001. Participation trends were examined during 1998 to 2000. RESULTS: Success rates of surgical proposals were significantly lower than nonsurgical proposals. Differentials in success rates were greatest for proposals assigned to the National Cancer Institute, although relative underfunding for surgical research spanned all major institutes. Awards for surgical grants averaged 5% to 27% less than nonsurgical grants). Surgeons exhibited 35% to 65% less peer-review activity relative to nonsurgeons when normalized to grant submission activity. Overall, surgeons participated on sections where they made up a relatively smaller proportion of total review members compared to nonsurgeons. CONCLUSIONS: Surgical grant proposals are less likely to be funded and carry significantly smaller awards compared to nonsurgical proposals. Relatively fewer surgeons participate in the review process, and those who do are more likely to be in the minority within study sections. Multiple strategies are needed to address these trends and level the playing field for surgical research.     

A soy protein diet alters hepatic lipid metabolism gene expression and reduces serum lipids and renal fibrogenic cytokines in rats with chronic nephrotic syndrome

Nephrotic syndrome (NS) is characterized by the presence of proteinuria and hyperlipidemia. However, ingestion of soy protein has a hypolipidemic effect. The present study was designed to determine whether the ingestion of a 20% soy protein diet regulates the expression of hepatic sterol regulatory element binding protein (SREBP)-1, fatty acid synthase (FAS), malic enzyme, beta-hydroxy-beta-methylglutaryl-CoA (HMG-CoA) reductase (r) and synthase (s), and LDL receptor (r), and to assess whether soy protein improves lipid and renal abnormalities in rats with chronic NS. Male Wistar rats were injected with vehicle or with puromycin aminonucleoside to induce NS and were fed either 20% casein or soy protein diets for 64 d. NS rats fed 20% soy protein had improved creatinine clearance and reduced proteinuria, hypercholesterolemia, hypertriglyceridemia, as well as VLDL-triglycerides and LDL cholesterol compared with NS rats fed the 20% casein diet. In addition, the soy protein diet decreased the incidence of glomerular sclerosis, and proinflammatory cytokines in kidney. Ingestion of the soy protein diet by control rats reduced the gene expression of SREBP-1, malic enzyme, FAS and increased HMG-CoAr, HMG-CoAs and LDLr. However, NS rats fed either casein or soy protein diets had low insulin concentrations with reductions in SREBP-1, FAS and malic enzyme expression compared with control rats fed the casein diet. NS rats fed the soy diet also had lower HMG-CoAr and LDLr mRNA levels than NS rats fed casein. In conclusion, the beneficial effects of soy protein on lipid metabolism are modulated in part by SREBP-1. However, in NS rats, the benefit may be through a direct effect of this protein on kidney rather than mediated by changes in expression of hepatic lipid metabolism genes.     

Multimodal neuroimaging studies and neurodevelopment and neurodegeneration hypotheses of schizophrenia

The interpretation of the huge number of results in schizophrenia research using neuroimaging is uncertain. However, the simultaneous use of complimentary data obtained with these techniques may yield more relevant information in this regard. In this paper we present a series of studies performed by our group in two schizophrenic samples with the use of structural (magnetic resonance imaging, MRI), functional [glucose positron emission tomography (PET) and N-acetyl-aspartate (NAA) magnetic resonance spectrocopy] and neurophysiological techniques (the P300 event-related potential). Transversal and longitudinal measurements were performed.The integrated vision of the results so obtained allows us to propose the hypothesis of a neurodevelopmentally determined state of prefrontal disinihibition, in which the degree of atrophy would directly relate to the metabolic rate. This state would already be present in the first stages of illness and could have neurotoxic consequences in the long term. This would explain the findings of an association between sulcal cerebrospinal fluid (CSF) and illness duration and decreased NAA levels in chronic but not in recent-onset cases. The prefrotnal disinhibition would overstimulate the limbic system and the hippocampus would become overactivated, the metabolic rate at this level being inversely related to P300 amplitude. Clozapine showed a more selective and intense action on that hyperactive metabolic tone than haloperidol.     

Intracranial aneurysms associated with unsuspected aortic coarctation

Intracranial aneurysms (IAs) are found more often in patients with aortic coarctation (AC) than in the general population and aneurysm rupture occurs much earlier in the lives of these patients when there is coexistent AC. The diagnosis of AC is frequently made only after a serious cerebrovascular complication has developed. The aim of this paper is to call attention to AC in patients presenting with aneurysmal subarachnoid hemorrhage. The literature is reviewed, the key clinical features are highlighted, and the proposed pathogenesis of this association is discussed. The authors present clinical information and imaging data obtained in three young patients with ruptured IAs that were associated with initially unnoticed AC. Abnormal results of cardiovascular examinations led the authors to consider an underlying AC, which was later confirmed by aortography. These aneurysms were successfully treated prior to correction of the ACs. The diagnosis of AC should be considered in adolescent and young adult patients presenting with IAs.     

Development of a physiologically based pharmacokinetic model for deltamethrin in the adult male Sprague-Dawley rat.

Deltamethrin (DLT) is a type II pyrethroid insecticide widely used in agriculture and public health. DLT is a potent neurotoxin that is primarily cleared from the body by metabolism. To better understand the dosimetry of DLT in the central nervous system, a physiologically based pharmacokinetic (PBPK) model for DLT was constructed for the adult, male Sprague-Dawley rat that employed both flow-limited (brain, gastrointestinal [GI] tract, liver, and rapidly perfused tissues) and diffusion-limited (fat, blood/plasma, and slowly perfused tissues) rate equations. The blood was divided into plasma and erythrocytes. Cytochrome P450-mediated metabolism was accounted for in the liver and carboxylesterase (CaE)-mediated metabolism in plasma and liver. Serial blood, brain, and fat samples were taken for DLT analysis for up to 48 h after adult rats received 2 or 10 mg DLT/kg po. Hepatic biotransformation accounted for approximately 78% of these administered doses. Plasma CaEs accounted for biotransformation of approximately 8% of each dosage. Refined PBPK model forecasts compared favorably to the 2- and 10-mg/kg po blood, plasma, brain, and fat DLT profiles, as well as profiles subsequently obtained from adult rats given 1 mg/kg iv. DLT kinetic profiles extracted from published reports of oral and iv experiments were also used for verification of the model's simulations. There was generally good agreement in most instances between predicted and the limited amount of empirical data. It became clear from our modeling efforts that there is considerably more to be learned about processes that govern GI absorption and exsorption, transport, binding, brain uptake and egress, fat deposition, and systemic elimination of DLT and other pyrethroids. The current model can serve as a foundation for construction of models for other pyrethroids and can be improved as more definitive information on DLT kinetic processes becomes available.     

In vitro assessment of immunocompetence in patients with malignant melanoma

Ninety-four patients with malignant melanoma and 96 healthy controls were tested for lymphocyte proliferative capacity in a microblastogenesis assay. Each lymphocyte sample was assayed for incorporation of (³H)thymidine after stimulation with PHA, PWM, Con A (two doses), PPD, and allogeneic lymphocytes (MLC). MLC was the only assay that revealed a substantial and significant difference between the melanoma patients and controls. Almost all assays showed lower values in patients with more advanced disease. However, it was not possible to accurately predict clinical outcome from data obtained from in vitro immunocompetence tests. These results indicate the relatively limited clinical usefulness of assays of lymphocyte proliferative capacity in melanoma patients.     

Antimycobacterial agents from selected Mexican medicinal plants

As part of the ICBG program Bioactive Agents from Dryland Biodiversity of Latin America, the present investigation was undertaken to explore the possible antimycobacterial potential of compounds derived from selected Mexican medicinal plants. Bioassay-guided fractionation of the crude extracts of Rumex hymenosepalus (Polygonaceae), Larrea divaricata (Zygophyllaceae), Phoradendron robinsonii (Loranthaceae) and Amphipteryngium adstringens (Julianiaceae) led to the isolation of several antimycobacterial compounds. Four stilbenoids, two flavan-3-ols and three anthraquinones were isolated from R. hymenosepalus. Two flavonols and nordihydroguaiaretic acid were obtained from L. divaricata. Sakuranetin was the antimycobacterial agent isolated from P. robinsonii. Two known triterpenoids and the novel natural product 3-dodecyl-1,8-dihydroxy-2-naphthoic acid were obtained from A. adstringens. In general, the isolates were identified by spectral means. The antimycobacterial activity of the secondary compounds isolated from the analysed species, as well as that of nine pure compounds previously isolated in our laboratories, was investigated; the MIC values ranged from 16 to 128 microg mL-1. Among the tested compounds, the glycolipids, sesquiterpenoids and triterpenoids showed the best antimycobacterial activity. The antimycobacterial property of the glycolipids is reported for the first time. Although the tested compounds showed moderate antimycobacterial activity, their presence in the analysed species provides the rationale for their traditional use in the treatment of tuberculosis.     

Pesticide exposure alters follicle-stimulating hormone levels in Mexican agricultural workers

Organophosphorous pesticides (OPs) are suspected of altering reproductive function by reducing brain acetylcholinesterase activity and monoamine levels, thus impairing hypothalamic and/or pituitary endocrine functions and gonadal processes. Our objective was to evaluate in a longitudinal study the association between OP exposure and serum levels of pituitary and sex hormones. Urinary OP metabolite levels were measured by gas-liquid chromatography, and serum pituitary and sex hormone levels by enzymatic immunoassay and radioimmunoassay in 64 men. A total of 147 urine and blood samples were analyzed for each parameter. More than 80% of the participants had at least one OP metabolite in their urine samples. The most frequent metabolite found was diethylthiophosphate (DETP; 55%), followed by diethylphosphate (DEP; 46%), dimethylthiophosphate (DMTP; 32%), and dimethyldithiophosphate (DMDTP; 31%). However, the metabolites detected at higher concentrations were DMTP, DEP, DMDTP, and dimethylphosphate. There was a high proportion of individuals with follicle-stimulating hormone (FSH) concentrations outside the range of normality (48%). The average FSH serum levels were higher during the heavy pesticide spraying season. However, a multivariate analysis of data collected in all periods showed that serum FSH levels were negatively associated with urinary concentrations of both DMTP and DMDTP, whereas luteinizing hormone (LH) was negatively associated with DMTP. We observed no significant associations between estradiol or testosterone serum levels with OP metabolites. The hormonal disruption in agricultural workers presented here, together with results from experimental animal studies, suggests that OP exposure disrupts the hypothalamic-pituitary endocrine function and also indicates that FSH and LH are the hormones most affected.