Childhood sexual and physical abuse: age at exposure modulates impact on functional outcome in early psychosis patients.

BACKGROUND: Evidence suggests a relationship between exposure to trauma during childhood and functional impairments in psychotic patients. However, the impact of age at the time of exposure has been understudied in early psychosis (EP) patients. METHOD: Two hundred and twenty-five patients aged 18-35 years were assessed at baseline and after 2, 6, 18, 24, 30 and 36 months of treatment. Patients exposed to sexual and/or physical abuse (SPA) were classified according to age at the time of first exposure (Early SPA: before age 11 years; Late SPA: between ages 12 and 15 years) and then compared to patients who were not exposed to such trauma (Non-SPA). The functional level in the premorbid phase was measured with the Premorbid Adjustment Scale (PAS) and with the Global Assessment of Functioning (GAF) scale and the Social and Occupational Functioning Assessment Scale (SOFAS) during follow-up. RESULTS: There were 24.8% of patients with a documented history of SPA. Late SPA patients were more likely to be female (p = 0.010). Comparison with non-SPA patients revealed that: (1) both Early and Late SPA groups showed poorer premorbid social functioning during early adolescence, and (2) while patients with Early SPA had poorer functional level at follow-up with lower GAF (p = 0.025) and lower SOFAS (p = 0.048) scores, Late SPA patients did not. CONCLUSION: Our results suggest a link between exposure to SPA and the later impairment of social functioning before the onset of the disease. EP patients exposed to SPA before age 12 may present long-lasting functional impairment, while patients exposed at a later age may improve in this regard and have a better functional outcome.

Altered NKG2D function in NK cells induced by chronic exposure to NKG2D ligand-expressing tumor cells.

NKG2D is an activation receptor that allows natural killer (NK) cells to detect diseased host cells. The engagement of NKG2D with corresponding ligand results in surface modulation of the receptor and reduced function upon subsequent receptor engagement. However, it is not clear whether in addition to modulation the NKG2D receptor complex and/or its signaling capacity is preserved. We show here that the prolonged encounter with tumor cell-bound, but not soluble, ligand can completely uncouple the NKG2D receptor from the intracellular mobilization of calcium and the exertion of cell-mediated cytolysis. However, cytolytic effector function is intact since NKG2D ligand-exposed NK cells can be activated via the Ly49D receptor. While NKG2D-dependent cytotoxicity is impaired, prolonged ligand exposure results in constitutive interferon gamma (IFNgamma) production, suggesting sustained signaling. The functional changes are associated with a reduced presence of the relevant signal transducing adaptors DNAX-activating protein of 10 kDa (DAP-10) and killer cell activating receptor-associated protein/DNAX-activating protein of 12 kDa (KARAP/DAP-12). That is likely the consequence of constitutive NKG2D engagement and signaling, since NKG2D function and adaptor expression is restored to normal when the stimulating tumor cells are removed. Thus, the chronic exposure to tumor cells expressing NKG2D ligand alters NKG2D signaling and may facilitate the evasion of tumor cells from NK cell reactions.

Differential effect of long versus short wavelength light exposure on pupillary re-dilation in patients with outer retinal disease.

BACKGROUND: In patients with outer retinal degeneration, a differential pupil response to long wavelength (red) versus short wavelength (blue) light stimulation has been previously observed. The goal of this study was to quantify differences in the pupillary re-dilation following exposure to red versus blue light in patients with outer retinal disease and compare them with patients with optic neuropathy and with healthy subjects. DESIGN: Prospective comparative cohort study. PARTICIPANTS: Twenty-three patients with outer retinal disease, 13 patients with optic neuropathy and 14 normal subjects. METHODS: Subjects were tested using continuous red and blue light stimulation at three intensities (1, 10 and 100 cd/m2) for 13 s per intensity. Pupillary re-dilation dynamics following the brightest intensity was analysed and compared between the three groups. MAIN OUTCOME MEASURES: The parameters of pupil re-dilation used in this study were: time to recover 90% of baseline size; mean pupil size at early and late phases of re-dilation; and differential re-dilation time for blue versus red light. RESULTS: Patients with outer retinal disease showed a pupil that tended to stay smaller after light termination and thus had a longer time to recovery. The differential re-dilation time was significantly greater in patients with outer retinal disease (median = 28.0 s, P < 0.0001) compared with controls and patients with optic neuropathy. CONCLUSIONS: A differential response of pupil re-dilation following red versus blue light stimulation is present in patients with outer retinal disease but is not found in normal eyes or among patients with visual loss from optic neuropathy.

Evaluation of cumulative PCB exposure estimated by a job exposure matrix versus PCB serum concentrations.

Although polychlorinated biphenyls (PCBs) have been banned in many countries for more than three decades, exposures to PCBs continue to be of concern due to their long half-lives and carcinogenic effects. In National Institute for Occupational Safety and Health studies, we are using semiquantitative plant-specific job exposure matrices (JEMs) to estimate historical PCB exposures for workers (n = 24,865) exposed to PCBs from 1938 to 1978 at three capacitor manufacturing plants. A subcohort of these workers (n = 410) employed in two of these plants had serum PCB concentrations measured at up to four times between 1976 and 1989. Our objectives were to evaluate the strength of association between an individual worker's measured serum PCB levels and the same worker's cumulative exposure estimated through 1977 with the (1) JEM and (2) duration of employment, and to calculate the explained variance the JEM provides for serum PCB levels using (3) simple linear regression. Consistent strong and statistically significant associations were observed between the cumulative exposures estimated with the JEM and serum PCB concentrations for all years. The strength of association between duration of employment and serum PCBs was good for highly chlorinated (Aroclor 1254/HPCB) but not less chlorinated (Aroclor 1242/LPCB) PCBs. In the simple regression models, cumulative occupational exposure estimated using the JEMs explained 14-24% of the variance of the Aroclor 1242/LPCB and 22-39% for Aroclor 1254/HPCB serum concentrations. We regard the cumulative exposure estimated with the JEM as a better estimate of PCB body burdens than serum concentrations quantified as Aroclor 1242/LPCB and Aroclor 1254/HPCB.

Pregnancy Outcome Following Maternal Exposure To Statins: A Multicenter Prospective Study

Introduction: Statin use for the treatment of hypercholesterolemia in women of childbearing age is increasingly common. However, published data on pregnancy outcome after exposure to statins are scarce and conflicting. This contribution addresses the safety of exposure to statins during pregnancy.Method: In a multi-center (n = 11) observational, prospective study we compared the outcomes of 249 women exposed during the 1st trimester of pregnancy to simvastatin (n = 124), atorvastatin (n = 67), pravastatin (n = 32), rosuvastatin (n = 18), fluvastatin (n = 7) or cerivastatin (n = 1) with a control group exposed to agents known to be non-teratogenic (n = 249). The data were collected by members of the European Network of Teratology Information Services (ENTIS) during individual risk counseling between 1990 and 2009. Standardized procedures for data collection were used in each center.Results: The difference in the rate of major birth defects between the statin-exposed group and the control group was not statistically significant (4.0% vs. 2.7% OR 1.5; 95% CI 0.5-4.5, P = 0.44). The crude rate of spontaneous abortions (12.8% vs. 7.1%, OR 1.9, 95% CI 1.0-3.6, P = 0.04) was higher in the exposed group. However, after adjustment to maternal age and gestational age at initial contact, the difference became statistically insignificant. The rate of elective pregnancy-termination (8.8% vs. 4.4%, P = 0.05) was higher and the rate of deliveries resulting in live births was significantly lower in the statin exposed group (77.9% vs. 88.4%, P = 0.002). Prematurity was more frequent in exposed pregnancies (16.1% vs. 8.5%; OR 2.1, 95% CI 1.1-3.8, P = 0.02). Nonetheless, gestational age at birth (median 39 weeks, IQR 37-40 vs. 39 weeks, IQR 38-40, P = 0.27) and birth weight (median 3280 g, IQR 2835-3590 vs. 3250 g, IQR 2880-3600, P = 0.95) did not differ between exposed and non-exposed pregnancies.Conclusion: This study did not detect a clear teratogenic effect of statins. Its statistical power however is not sufficient to reverse the recommendation of treatment discontinuation during pregnancy. At most, the results are reassuring in case of inadvertent exposure.

Hand exposure in diagnostic nuclear medicine with 18F- and 99mTc-labelled radiopharmaceuticals - Results of the ORAMED project

Workers performing preparation and administration of radiopharmaceuticals in NM departments are likely to receive high local skin doses to the hands which may even surpass the dose limit of 500 mSv whenever radiation protection standards are insufficient. A large measurement campaign was organised within the framework of the ORAMED project to determine the dose distribution across the hands received during preparation and administration of 18F- and 99mTc-labelled radiopharmaceuticals. The final data, collected over almost 3 years, include 641 measurements from 96 workers in 30 NM departments from 6 European countries. Results have provided levels of reference doses for the considered standard NM diagnostic procedures (mean maximum normalised skin dose of 230 μSv/GBq, 430 μSv/GBq, 930 μSv/GBq and 1200 μSv/GBq for the administration of 99mTc, preparation of 99mTc, administration of 18F and preparation of 18F, respectively). Finger dose was analysed as a function of the potential parameters of influence showing that shielding is the most efficient means of radiation protection to reduce skin dose. An appropriate method for routine monitoring of the extremities is also proposed: the base of the index finger of the non-dominant hand is a suitable position to place the ring dosemeter, with its sensitive part oriented towards the palm side; its reading may be multiplied by a factor of 6 to estimate the maximum local skin dose. Finally, results were compared to earlier published data, which correspond mostly to individual works with a reduced number of workers and measurements.

Surfactant protein-D and exposure to bioaerosols in wastewater and garbage workers.

PURPOSE: Bioaerosols and their constituents, such as endotoxins, are capable of causing an inflammatory reaction at the level of the lung-blood barrier, which becomes more permeable. Thus, it was hypothesized that occupational exposure to bioaerosols can increase leakage of surfactant protein-D (SP-D), a lung-specific protein, into the bloodstream. METHODS: SP-D was determined by ELISA in 316 wastewater workers, 67 garbage collectors, and 395 control subjects. Exposure was assessed with four interview-based indicators and by preliminary endotoxin measurements using the Limulus amoebocyte lysate assay. Influence of exposure on serum SP-D was assessed by multiple linear regression considering smoking, glomerular function, lung diseases, obesity, and other confounders. RESULTS: Overall, mean exposure levels to endotoxins were below 100 EU/m(3). However, special tasks of wastewater workers caused higher endotoxin exposure. SP-D concentration was slightly increased in this occupational group and associated with the occurrence of splashes and contact to raw sewage. No effect was found in garbage collectors. Smoking increased serum SP-D. No clinically relevant correlation between spirometry results and SP-D concentrations appeared. CONCLUSIONS: These results support the hypothesis that inhalation of bioaerosols, even at low concentrations, has a subclinical effect on the lung-blood barrier, the permeability of which increases without associated spirometric changes.

A toxicokinetic model to assess exposure to folpet fungicide from urinary biomarkers

Folpet is one of the most widely employed fungicides in agriculture. It is typically used in the culture of vegetables, fruits and ornamental plants. Once absorbed in the human body, it has been found to be very reactive, especially in acid conditions. According to various in vitro and in vivo experiments in animals, Folpet is first fractioned at the N-S link when in contact with aqueous solutions and thiol groups. From this non-enzymatic process a phthalimide (PI) molecule is formed, which may be used as a biomarker of exposure, along with the short-lived thiophosgene. We have built a human toxicokinetic model to account for the biotransformation of Folpet into PI and its subsequent excretion while accounting for other non-monitored metabolites. The mathematical parameters of the model were determined accordingly from best-fits to the time courses of PI in blood and urine of five volunteers administered orally 1 mg/kg and dermally 10 mg/kg of Folpet. In both cases, the mean elimination half-life of PI from the body (either through faeces, urine or metabolism) was found to be 31.6 h. The average final fractions of administered dose recovered in urine as PI were 0.025% and 0.002%, for oral and dermal administration, respectively after 96 h. According to the model, when orally administered, PI rapidly hydrolyzes to phthalamic and phthalic acids such that only 0.04% of the PI found in the gastrointestinal tract is absorbed into the blood stream. Likewise, after dermal application, model predicts that only 7.4% of the applied Folpet dose crosses the epidermis. In the model, the PI initial metabolite of Folpet is formed in the dermis and further metabolized prior to reaching systemic circulation, such that only 0.125% of PI formed at the site-of-entry reaches systemic blood. Our mathematical model is in accordance with both measures of blood (R2=0.57 for dermal and R2=0.66 for oral) and urine (R2 =0.98 for dermal and R2=0.99 for oral).

A general model to predict individual exposure to solar UV by using ambient irradiance data

Excessive exposure to solar ultraviolet (UV) is the main cause of skin cancer. Specific prevention should be further developed to target overexposed or highly vulnerable populations. A better characterisation of anatomical UV exposure patterns is however needed for specific prevention. To develop a regression model for predicting the UV exposure ratio (ER, ratio between the anatomical dose and the corresponding ground level dose) for each body site without requiring individual measurements. A 3D numeric model (SimUVEx) was used to compute ER for various body sites and postures. A multiple fractional polynomial regression analysis was performed to identify predictors of ER. The regression model used simulation data and its performance was tested on an independent data set. Two input variables were sufficient to explain ER: the cosine of the maximal daily solar zenith angle and the fraction of the sky visible from the body site. The regression model was in good agreement with the simulated data ER (R(2)=0.988). Relative errors up to +20% and -10% were found in daily doses predictions, whereas an average relative error of only 2.4% (-0.03% to 5.4%) was found in yearly dose predictions. The regression model predicts accurately ER and UV doses on the basis of readily available data such as global UV erythemal irradiance measured at ground surface stations or inferred from satellite information. It renders the development of exposure data on a wide temporal and geographical scale possible and opens broad perspectives for epidemiological studies and skin cancer prevention.

In utero exposure to immunosuppressive drugs.

The number of pregnant women receiving immunosuppressants for anti-rejection therapy or autoimmune diseases is increasing. All immunosuppressive drugs cross the placenta, raising questions about the long-term outcome of the children exposed in utero. There is no higher risk of congenital anomalies. However, an increased incidence of prematurity, intrauterine growth retardation (IUGR) and generally low birth weight has been reported, as well as maternal hypertension and preeclampsia. The most frequent neonatal complications are those associated with prematurity and IUGR, as well as adrenal insufficiency with corticosteroids, immunological disturbances with azathioprine and cyclosporine, and hyperkalemia with tacrolimus. The long-term follow-up of infants exposed to immunosuppressants in utero is still limited and experimental studies raise the question whether there could be an increased incidence at adult age of some pathologies including renal insufficiency, hypertension and diabetes.

Evidence for multiple B- and T-cell epitopes in Plasmodium falciparum liver-stage antigen 3.

Liver-stage antigen 3 (LSA-3) is a new vaccine candidate that can induce protection against Plasmodium falciparum sporozoite challenge. Using a series of long synthetic peptides (LSP) encompassing most of the 210-kDa LSA-3 protein, a study of the antigenicity of this protein was carried out in 203 inhabitants from the villages of Dielmo (n = 143) and Ndiop (n = 60) in Senegal (the level of malaria transmission differs in these two villages). Lymphocyte responses to each individual LSA-3 peptide were recorded, some at high prevalences (up to 43%). Antibodies were also detected to each of the 20 peptides, many at high prevalence (up to 84% of responders), and were directed to both nonrepeat and repeat regions. Immune responses to LSA-3 were detectable even in individuals of less than 5 years of age and increased with age and hence exposure to malaria, although they were not directly related to the level of malaria transmission. Thus, several valuable T- and B-cell epitopes were characterized all along the LSA-3 protein, supporting the antigenicity of this P. falciparum vaccine candidate. Finally, antibodies specific for peptide LSP10 located in a nonrepeat region of LSA-3 were found significantly associated with a lower risk of malaria attack over 1 year of daily clinical follow-up in children between the ages of 7 and 15 years, but not in older individuals.