Cellular mechanisms for developmental toxicity of chlorpyrifos: targeting the adenylyl cyclase signaling cascade

Developmental neurotoxicity caused by chlorpyrifos exposure is generally thought to target cholinesterase but chlorpyrifos may also act on cellular intermediates, such as adenylyl cyclase, that serve global functions in the coordination of cell development. In the current study, neonatal rats were exposed to apparently subtoxic doses of chlorpyrifos (no weight loss, no mortality) either on Postnatal Days 1-4 or on Postnatal Days 11-14, and the effects on components of the adenylyl cyclase cascade were evaluated in brain regions that are enriched (forebrain) or sparse (cerebellum) in cholinergic innervation, as well as in a nonneural tissue (heart). In all three, chlorpyrifos evoked deficits in multiple components of the adenylyl cyclase cascade: expression and activity of adenylyl cyclase itself, functioning of G-proteins that link neurotransmitter and hormone receptors to cyclase activity, and expression of neurotransmitter receptors that act through this cascade. Disruption of signaling function was not restricted to transduction of cholinergic signals but rather extended to adrenergic signals as well. In most cases, the adverse effects were not evident during the immediate period of chlorpyrifos administration, but appeared after a delay of several days. These results suggest that chlorpyrifos can affect cell development by altering the activity and reactivity of the adenylyl cyclase signaling cascade, a major control point for trophic regulation of cell differentiation. The effects are not restricted to cholinergic targets, nor even to the central nervous system. Hence, disruption of cell development by chlorpyrifos is likely to be more widespread than previously thought.     

Eradication of Barrett''s mucosa with argon plasma coagulation and acid suppression: immediate and mid term results

Microcapsules are used for the formulation of drug controlled release and drug targeting dosage forms. Encapsulated hydrophobic drugs are often applied as their solutions in plant oils. The uptake of the oils in the complex coacervate microcapsules can be improved by the addition of surfactants. In this study, soybean, olive and peanut oils were chosen as the representatives of plant oils. The well characterized complex coacervation of gelatin and acacia has been used to produce the microcapsules. The amount of encapsulated oil has been determined gravimetrically. The encapsulation of the oils was high (75-80%). When the surfactants with HLB values from 1.8 to 6.7 were used, the amount of encapsulated oil was high (65-85%). A significant decrease of the oil content in the microcapsules was found when Tween 61 with HLB = 9.6 had been added into the mixture. No oil was found inside the microcapsules from the coacervate emulsion mixture containing Tween 81 (HLB = 10) and Tween 80 (HLB = 15), respectively. The results of the experiment confirm the dependence of hydrophobic substance encapsulation on the HLB published recently for Squalan.     

Depression as a dynamical disease

Mathematical models are helpful in the understanding of diseases through the use of dynamical indicators. A previous study has shown that brain activity can be characterized by a decrease of dynamical complexity in depressive subjects. The present paper confirms and extends these conclusions through the use of recent methodological advances: first episode and recurrent patients strongly differ in their dynamical response to therapeutic interventions. These results emphasize the need for clinical follow-ups to avoid recurrence and the necessity of specific therapeutic intervention in the case of recurrent patients.     

Aortic dissection: a medical perspective

Over the past 3 years, a greater understanding of predisposing factors and the pathology of the aortic wall has yielded more insights into the pathogenesis, as well as into more accurate diagnostic and preventive methods. This update will discuss: (1) the incidence, definition, and recent classification of aortic dissection; (2) epidemiology, medical, and recent surgical series; (3) the pathogenesis and risk factors; (4) clinical features and evolving noninvasive imaging approaches to diagnosis; and (5) management from a medical perspective.     

Red blood cell glutathione status in patients with gastrointestinal malignancies treated with 5-fluorouracil

As an alternative to surgical splenectomy, partial splenic embolization was performed in seven children for hypersplenism manifested by splenomegaly, thrombocytopenia, leukopenia, and erythrocyte hemolysis. Within a few days, platelet and leukocyte counts rose significantly in all patients and were maintained in six of seven patients during a follow-up period of 9 to 69 months. Spleen size and abdominal distention also decreased significantly in all children. There were no infectious complications.     

Multifocal primary neuroblastoma

The purpose of this study is to present three patients with multifocal primary neuroblastoma, to review the literature, and describe the radiographic findings. SUBJECTS AND METHODS: Three children with multifocal neuroblastoma have been identified. The case histories and imaging findings in these patients are reviewed. RESULTS: Two children had synchronous and one child had metachronous multifocal primary neuroblastoma. The primary tumors were both in the abdomen in one patient, both in the chest in another patient, and in the chest and abdomen in the third patient. Evidence for multifocal origin of these tumors, rather than metastatic spread, is presented. CONCLUSION: Multifocal primary neuroblastomas can occur. The tumors maybe synchronous or metachronous. Awareness of this disorder may prevent errors in diagnosis and staging. Although not identified in our patients there is a strong familial incidence of neuroblastomas in those patients with multifocal tumors.     

Outcome of cardiac valve ring abscesses after medical treatment: attempt to identify criteria of favorable prognosis

OBJECTIVES: Identify factors predicting favorable outcome after medical management of valve ring abscesses in order to propose a surveillance schedule for conservative treatment. METHODS: A multicentric study conducted from July 1989 to February 1996 included 28 patients (mean age 64 +/- 16 years, range 26-83) hospitalized for active endocarditis and valve ring abscesses diagnosed at transthoracic or transesophageal echography. Conservative medical therapy was given because of a decision of the medico-surgical team (n = 9), high surgical risk (n = 12), or patient refusal of surgery (n = 7). Outcome was favourable in 18 patients (Group I) and unfavorable in 10 (Group II) due to death (n = 9) or subsequent surgery (n = 1). Univariate and multivariate analysis were used to determine differences between the groups in terms of clinical and laboratory data. RESULTS: Mean follow-up in Group I was 33 +/- 18 months and 15 +/- 10 months in Group II. Univariate analysis showed significant differences between Group I and II respectively for age (59 +/- 18 yr vs 72 +/- 10, p = 0.04), delay to apyrexia after antibiotics (4.3 +/- 2.8 vs 8.3 +/- 2.4 days, p < 0.0008), heart failure (5% vs 70%, p = 0.003), grade III or IV valvular regurgitation (5% vs 60%, p < 0.04), and mean surface area of the abscess (1.5 +/- 1.2 vs 5.4 +/- 6.4 cm2, p < 0.03). Independent factors at multivariate analysis were by decreasing order: lack of heart failure at admission, delay to apyrexia, abscess surface area, and age. Outcome was favorable (mean follow-up 33 +/- 10 months) in all patients with an abscess surface area < 1.5 cm2, no signs of heart failure, no grade III or IV valvular regurgitation, apyrexia after less than 8 days on antibiotics and no staphylococcus positive blood culture. CONCLUSION: Medical management of valve ring abscesses may be indicated in selected patients in care units with rigorous surveillance facilities. Further studies are needed to precisely identify surveillance and treatment criteria.     

In vitro activities of semisynthetic pneumocandin L-733,560 against fluconazole-resistant and -susceptible Candida albicans isolates

Lipopeptide L-733,560 is a water-soluble derivative of pneumocandin B0 that exhibits enhanced anti-Candida activity. We investigated the in vitro activity of L-733,560 compared with those of amphotericin B, flucytosine, and itraconazole, against fluconazole-resistant (n = 44) and fluconazole-susceptible (n = 46) Candida albicans isolates. Tests were performed with a photometer-read broth microdilution method with RPMI-2% glucose and National Committee for Clinical Laboratory Standards reference strains. Except for those of itraconazole, MICs were not significantly different between the two groups of isolates, as expected for agents with different mechanisms of action. L-733,560 was the most active agent against C.albicans, with MICs for 50 and 90% of the strains tested of 0.01 and 0.06 microgram/ml, respectively.     

Congenic rats reveal three independent Copenhagen alleles within the Mcs1 quantitative trait locus that confer resistance to mammary cancer

It has previously been shown that the Copenhagen (COP) rat contains several genetic loci that contribute to its mammary tumor-resistant phenotype after 7,12-dimethylbenz(a)anthracene (DMBA) administration. One of these loci, mammary carcinoma susceptibility 1 (Mcs1), is located on the centromeric end of chromosome 2 and appears to act in a semidominant fashion. To confirm the existence and independent action of this locus and also aid in the identification of the physical location of the Mcs1 gene, congenic lines were generated by transferring the Mcs1 COP allele onto a Wistar Furth (WF) genetic background. Male carriers were genotyped using microsatellite markers spanning 20-30 cM of the Mcs1 locus. One of the congenic lines minimally retained the COP allele at D2Mit29 on the centromeric end of chromosome 2 and extended distally to D2Rat201. Heterozygous Mcs1 carrier rats were interbred, and the female offspring were treated with DMBA. The female rats from the Mcs1 congenic line that carried one or two COP alleles of the Mcs1 region had a significantly reduced (65 and 85%, respectively) tumor development (P < 0.001) compared with rats carrying zero COP alleles at this locus. A WF.COP-D2Mit29/D2Rat201 homozygous congenic strain derived at the N10 generation was treated with DMBA, and the COP homozygous rats developed 1.5 +/- 0.3 carcinomas/rat versus 6.3 +/- 0.5 in WF control rats (P < 0.0001). Fine mapping of this congenic interval using several recombinant lines identified three genetic loci within the Mcs1 congenic region that independently supported a tumor resistance phenotype. These genetic loci have been termed Mcs1a, Mcs1b, and Mcs1c. In rats for which each locus was homozygous for the COP allele, tumor development was reduced by approximately 60% compared with littermate controls. The identification of these independent loci within the Mcs1 COP allele provide a model of the genetic complexity of cancer.