On the need of a sampling strategy in biological monitoring: The example of hexane exposure

Ambient and biological monitoring of hexane exposure were repeatedly carried out in 14 female shoe makers. Airborne hexane (Ci-H) was measured in 4-h samples collected by a diffusive method. Urinary spot samples were collected before, during (at noon), and at the end of a work shift. 2,5-Hexanedione (2,5HD) in urine collected at noon was poorly related to morning Ci-H. End-of-shift 2,5HD were also poorly related to afternoon air samples. The correlation was still relatively low when end-of-shift 2,5HD was related to 8-h TWA Ci-H (r= 0.44; P<0.01 on=" a=" linear=" scale,=" and=">r-0.58, P< 0.01=" on=" a=" log-log=" scale).=" end-of-shift=" 2,5hd=" levels=" estimated=" on=" the=" basis=" of=" pre-shift=" values=" using=" a=" mathematical=" model=" were=" much=" higher=" (2.3=" times=" on=" average)=" than=" those=" experimentally=" measured=" during=" the=" study=" period.=" owing=" to=" its=" relatively=" long=" half-time,=" 2,5hd=" seems=" to=" be=" influenced=" not=" only=" by=" current=" exposure,=" but=" also=" by=" hexane=" absorbed=" during=" the=" day(s)=" preceding=" sampling.=" the=" lack=" of=" a=" sampling=" strategy=" may=" account=" not=" only=" for=" inconsistencies=" between=" environmental=" and=" biological=" data,=" but=" also=" for=" a=" possible=" misuse=" of=" biological=" monitoring=" when=" utilized=" for=" risk=" assessment.=" despite=" sometimes=" poor=" correlations=" with=" ci-h,=" 2,5hd=" may=" still=" be=" preferred=" to=" other=" indicators=" as=" a=" marker=" of=" effective=" internal=" dose.=" a=" sampling=" strategy=" should=" ensure=" that=" measured=" values=" are=" representative=" of=" the=" individual=" risk=" for=" adverse=">     

Color-doppler velocimetry of uterine arteries in pregnant and nonpregnant patients during multiovulation induction for IVF

Objectives To evaluate uterine artery resistance during multiovulation induction in relation to the implantation rate in patients attendingin vitro fertilization (IVF) cycles.Patients Multiovulation induction for IVF was monitored by daily determination of the pulsatility index (PI) of the uterine arteries, obtained by a transvaginal probe (6.5 MHz) implemented with color-flow imaging. Doppler data were obtained from 5 days before hCG administration to the day of follicular aspiration. One IVF cycle was monitored in 70 patients. In 17 patients, 41 IVF cycles were monitored until a successful attempt occurred.Results In the 70 patients studied during one IVF attempt, the PI of the uterine arteries significantly varied (P < 0.001) in the different phases of the cycle. In the 24 patients who conceived, a significantly lower PI (P < 0.03) was found throughout the cycle. This result was mainly due to a highly significant difference of PI values observed the day after hCG administration (P < 0.005). In the 17 patients who conceived after 1 to 4 negativein vitro fertilizations, no significant difference in PI was observed in the uterine artery resistance in cycles in which implantation was or was not successful.Conclusions Uterine artery resistance varies significantly during phases of the induction therapy. Uterine artery resistance is lower throughout the course of multiovulation induction in patients with higher pregnancy rates. The PI on the day after hCG administration was the best index of pregnancy rate. Low uterine artery resistance was present even in negative attempts in patients who eventually achieved a successful implantation. PI values 3 can be considered a favorable prognostic factor for future IVF cycles.Presented at the 49th Annual Meeting of the American Fertility Society, Montreal, 1993 and the 50th Annual Meeting of the American Fertility Society, November 5–10, 1994, San Antonio, Texas.     

Pregnancies in an 18-Year Follow-up after Biliopancreatic Diversion

Background: 239 pregnancies occurred in 1136 women who had undergone biliopancreatic diversion (BPD). Methods: There were 73 abortions, and 14 pregnancies are presently in their course. The 152 term pregnancies (six twins) occurred in 129 women 2-173 months (mean 42.7) after BPD. Mean age and current excess weight were 31.4 years (20-42) and 29.1% (-6.9-78.2), and mean excess weight loss was 72.9% (30.4-110.5). Results: Mean weight gain during pregnancy was 6.2 kg (-21-25). In 32 patients (21%), parenteral nutritional support was needed. In all the other patients (79%), the usual supplementations were given. Of the newborns, 122 were delivered at term (84.7%) with a mean weight of 2842.4 g (1760-4600 g) and a mean length of 48.5 cm (43-59 cm), while the 22 preterm babies (15.3%) weighed 2151.1 g (1400-3850 g) and had a length of 44.6 cm (33-56 cm). Forty infants (27.8%) were small for gestational age but 17 of them weighed more than 2500 g. Eleven twins (one abortion at 26th week) were also delivered, with a mean weight of 2088.6 g (1200-3100 g) and a mean length of 45.6 cm (35-50 cm). Delivery was spontaneous in 85 instances (56%), while vacuum extractor was used in one, and 66 cesarean sections were performed. There were two birth malformations, one infant died after surgery for meconium obstruction and two died from unknown causes. Of the 129 women, 35 had been infertile before BPD. Conclusions: Disappearance of infertility and decrease of pregnancy risk are to be considered among the beneficial effects of weight reduction following BPD.     

Immunological changes among workers occupationally exposed to styrene

The functional status of the immune system was investigated in a group of 71 workers exposed to styrene and in 65 control subjects, recruited according to the same selection criteria and comparable as to sex, age, and confounding variables. Air and biological monitoring were used to characterize styrene exposure (median of the main urinary metabolites in the next-morning spot samples: 106 mg/g creatinine). Phenotypic analysis of peripheral blood lymphocytes (PBL) by automated flow cytometry revealed a reduced proportion of T lymphocyte subsets (CD3⁺, CD4⁺ and CD4⁺45⁺), with no changes in CD8⁺, and a higher proportion of B lymphocytes (CD19⁺) among styrene-exposed workers. The exposed workers showed a higher proportion of activation markers, namely DR and interleukin-2 receptors (CD25). Immunoglobulin subclasses were comparable in the two groups. An increased prevalence of abnormally low values was apparent for CD2⁺, CD3⁺, CD4⁺, CD4⁺45⁺ and CD11b subsets among workers exposed to styrene, whereas CD19⁺, DR⁺ and CD25⁺ showed an increased prevalence of abnormally high values. Natural killer-related phenotypes (CD56⁺, CD56+16⁺, and CD56⁺16^–) were more expressed among styrene workers, with average increase of 30%. However, the frequency distribution of the lytic activity of natural killer cells against K-562 target cells was shifted towards lower values in the exposed workers as compared to control subjects. Dose-response relationships between indices of internal dose and prevalence of abnormal values were detectable for T lymphocyte subsets, NK phenotypes, and activation markers. These findings suggest that moderate exposure to styrene is associated with an altered distribution of lymphocyte subsets. The decreased proportion of T lymphocytes, mainly of T helper-inducer cells, could hamper regulatory functions, thus suggesting a negative modulation by styrene exposure. Since a proper balance between immunocycte subsets is important for immunological responses, such changes should be regarded as adverse effects.     

Prognostic factors in fetal hydronephrosis: a multivariate analysis

With the increasing use of obstetric echography fetal hydronephrosis has been reported more frequently. The purpose of this study was to identify prognostic factors associated with adverse outcome, such as renal failure and death, in fetal hydronephrosis. One hundred and forty-eight children with fetal hydronephrosis were admitted, submitted to a systematic protocol, and prospectively followed. Prognostic factors associated with fetal echography and clinical and laboratory findings on admission were studied. The median follow-up was 39 months. The analysis was conducted in two steps. In a univariate analysis, variables associated with adverse outcome were identified by the Kaplan-Meier method. The variables that were significantly associated with adverse outcome were then included in a multivariate analysis. This analysis, using the multivariate Cox’s model, was performed to identify variables that were independently associated with a worse prognosis. Only variables that remained independently associated with adverse outcome were included in the final model. After final adjustment by Cox’s multivariate model, three variables were identified as independent predictors of adverse outcome: oligohydramnios, prematurity, and glomerular filtration rate lower than 20 ml/min. Thus, in the presence of oligohydramnios, prematurity, and abnormal renal function, the medical team must plan appropriate follow-up for infants at health centers prepared to investigate and treat uropathies in newborns. Received: 24 August 1998 / Revised: 7 December 1998 / Accepted: 11 December 1998     

p53 Accumulation Is a Prognostic Factor in Intestinal-Type Gastric Carcinoma but Not in the Diffuse Type

Background: The prognostic value of p53 nuclear accumulation in gastric cancer is still unclear, as shown by the discordant results still reported in the literature. In this study, we evaluated the correlation between p53 accumulation and long-term survival of patients resected for intestinal and diffuse-type gastric cancer.Methods: Eighty-three patients with carcinoma of the intestinal type and 53 patients with carcinoma of the diffuse type were included in the study. Immunohistochemical staining of the paraffin sections was performed by using monoclonal antibody DO1; cases were considered positive when nuclear immunostaining was observed in 10% or more of the tumor cells. Prognostic significance of different variables was investigated by univariate and multivariate analysis.Results: p53 positivity was found in 51.8% of intestinal-type and 50.9% of diffuse-type cases. No significant correlation between the rate of p53 overexpression and age, sex, tumor location, tumor size, depth of invasion, lymph node involvement, distant metastases, and surgical radicality was found in the two groups of patients. A statistically significant difference in survival rate was observed between p53-negative and p53-positive cases in the intestinal type (P < .05), confirmed by multivariate analysis (P < .005; relative risk = 3.09). On the contrary, no correlation with survival was found in diffuse-type cases according to p53 overexpression.Conclusions: These results suggest that the immunohistochemical detection of p53 accumulation is a useful indicator of poor prognosis in the intestinal but not in the diffuse type of gastric cancer, and are indicative of distinct molecular pathways and pattern of progression in the two histotypes.     

Molecular mechanisms of tolerance to and withdrawal of GABAA receptor modulators

Here, we summarize recent data pertaining to the effects of GABA_A receptor modulators on the receptor gene expression in order to elucidate the molecular mechanisms behind tolerance and dependence induced by these drugs. Drug selectivity and intrinsic activity seems to be important to evidence at the molecular level the GABA_A receptor tolerance. On the contrary, we suggested that all drug tested are equally potentially prone to induce dependence. Our results demonstrate that long-lasting exposure of GABA_A receptors to endogenous steroids, benzodiazepines and ethanol, as well as their withdrawal, induce marked effects on receptor structure and function. These results suggest the possible synergic action between endogenous steroids and these drugs in modulating the functional activity of specific neuronal populations. We report here that endogenous steroids may play a crucial role in the action of ethanol on dopaminergic neurons.     

In vivo assessment of antiangiogenic activity of SU6668 in an experimental colon carcinoma model.

PURPOSE: The purpose of this research was to assess in vivo by dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) the antiangiogenic effect of SU6668, an oral, small molecule inhibitor of the angiogenic receptor tyrosine kinases vascular endothelial growth factor receptor 2 (Flk-1/KDR), platelet-derived growth factor receptor, and fibroblast growth factor receptor 1. EXPERIMENTAL DESIGN: A s.c. tumor model of HT29 human colon carcinoma in athymic mice was used. DCE-MRI with a macromolecular contrast agent was used to measure transendothelial permeability and fractional plasma volume, accepted surrogate markers of tumor angiogenesis. CD31 immunohistochemical staining was used for assessing microvessels density and vessels area. Experiments were performed after 24 h, and 3, 7, and 14 days of treatment. RESULTS: DCE-MRI clearly detected the early effect (after 24 h of treatment) of SU6668 on tumor vasculature as a 51% and 26% decrease in the average vessel permeability measured in the tumor rim and core (respectively). A substantial decrease was also observed in average fractional plasma volume in the rim (59%) and core (35%) of the tumor. Histological results confirmed magnetic resonance imaging findings. After 3, 7, and 14 days of treatment, postcontrast magnetic resonant images presented a thin strip of strongly enhanced tissue at the tumor periphery; histology examination showed that this hyperenhanced ring corresponded to strongly vascularized tissue adjacent but external to the tumor. Histology also revealed a strong decrease in the thickness of peripheral viable tissue, with a greatly reduced vessel count. SU6668 greatly inhibited tumor growth, with 60% inhibition at 14 days of treatment. CONCLUSIONS: DCE-MRI detected in vivo the antiangiogenic efficacy of SU6668.