Comparison of the DNA damage response in BEAS-2B and A549 cells exposed to titanium dioxide nanoparticles.

For some decades production of titanium dioxide nanoparticle (TiO2-NP) has been increasing at a considerable rate; concerns as to the toxicity of these particles upon inhalation have been raised. Indeed, TiO2-NPs have been shown to induce significant genotoxicity and to adversely affect both major DNA repair mechanisms: base excision repair (BER) and nucleotide excision repair (NER). The aims of the present study were to (i) compare the genotoxicity of TiO2-NPs and their impact on DNA repair processes on A549 alveolar carcinoma and BEAS-2B normal bronchial lung cell lines and (ii) delve deeper into the mechanisms leading to these effects. To achieve these goals, TiO2-NPs effects on cytotoxicity, genotoxicity, DNA repair activity and DNA repair gene expression were investigated in both cell lines upon exposure to 1-100 µg/mL of anatase/rutile, 21 nm TiO2-NPs. Our results show that TiO2-NPs induce comparable cytotoxic and genotoxic responses in BEAS-2B and A549 cells. Functional response to DNA damage is observed in both cell lines and consists of an overall downregulation in DNA repair processes. When evaluating the relative importance of the two DNA repair pathways, we observed a lower impact on BER compared with NER activities, suggesting that repair of oxidatively generated DNA damage is still triggered in these cells. This response becomes measureable at 4 h of exposure in BEAS-2B but only after 48 h of exposure in A549 cells. The delayed response in A549 cells is due to an initial overall and intense downregulation of the genes encoding DNA repair proteins. This overall downregulation correlates with increased methylation of DNA repair gene promoters and downregulation of NRF2 and BRCA1, which may thus be considered as upstream regulators. These results strengthen the evidence that TiO2-NP induces indirect genotoxicity in lung cells, via modulation of DNA repair processes, and shed some light on the mechanisms behind this effect.

Chemokines mediate ethanol-induced exacerbations of murine cockroach allergen asthma.

Asthma imposes considerable patient and economic burdens, with the most severe cases causing the greatest affliction. Identifying stimuli that worsen asthma severity is an essential step to controlling both disease morbidity and the lessening economic impact. This study provides the first mechanistic investigation into how acute ethanol exposure will increase asthma severity in a murine model of mild cockroach allergen (CRA)-induced asthma. Outbred mice were sensitized to induce mild allergic asthma, with intratracheal CRA exposures on days 0 and 14. On day 21 mice were gavaged with water or 32% ethanol, and the third allergen exposure was given 30 min post-gavage. Asthmatic responses were measured at several time-points up to 42 h after the third allergen challenge. Ethanol-gavaged mice showed increased asthma severity within 90 min post-allergen challenge, with exacerbations lasting for 24 h. Ethanol caused greater airways obstruction, including an eightfold increase in epithelial cell mucin and increased mucus plugs, resulting in a 50% reduction in bronchiole patency. Ethanol gavage also induced significant increases in airways hyperreactivity. While T helper type 1 (Th1) and Th2 cytokines were not altered by ethanol gavage, pulmonary neutrophil and eosinophil recruitment were augmented. This increase was associated with increased chemokine production. Administration 2 h prior to ethanol gavage of a neutralizing antibody cocktail to keratinocyte-derived chemokine, macrophage inflammatory protein-2, eotaxin-1 and eotaxin-2 prevented ethanol-induced eosinophil recruitment and airways hyperreactivity. These data provide evidence that acute alcohol exposure immediately prior to a mild allergen-triggered asthmatic episode will exacerbate asthma severity mediated by increased production of chemokines.

Motor sequence learning in children with recovered and persistent developmental stuttering: preliminary findings.

PURPOSE: Previous studies have associated developmental stuttering with difficulty learning new motor skills. We investigated non-speech motor sequence learning in children with persistent developmental stuttering (CWS), children who have recovered from developmental stuttering (CRS) and typically developing controls (CON). METHODS: Over the course of two days, participants completed the Multi-Finger Sequencing Task, consisting of repeated trials of a10-element sequence, interspersed with trials of random sequences of the same length. We evaluated motor sequence learning using accuracy and response synchrony, a timing measure for evaluation of sequencing timing. We examined error types as well as recognition and recall of the repeated sequences. RESULTS: CWS demonstrated lower performance accuracy than CON and CRS on the first day of the finger tapping experiment but improved to the performance level of CON and CRS on the second day. Response synchrony showed no overall difference among CWS, CRS and CON. Learning scores of repeated sequences did not differ from learning scores of random sequences in CWS, CRS and CON. CON and CRS demonstrated an adaptive strategy to response errors, whereas CWS maintained a high percentage of corrected errors for both days. CONCLUSIONS: Our study examined non-speech sequence learning across CWS, CRS and CON. Our preliminary findings support the idea that developmental stuttering is not associated with sequence learning per se but rather with general fine motor performance difficulties.

Gadolinium-Based Nanoparticles Can Overcome the Radioresistance of Head and Neck Squamous Cell Carcinoma Through the Induction of Autophagy.

Radiation therapy is a mainstay in the therapeutic management of Head and Neck Squamous Cell Carcinoma (HNSCC). Despite significant progress in this field, radioresistance still accounts for most treatment failures. Gadolinium-based nanoparticles (GBNs) have shown great promises as radiosensitizers but the underlying sensitizing mechanism is still largely unknown with regards to the disparities obtained in in vitro studies. In this study, we show that a new formulation of GBNs, AGuIX®, can radiosensitize HNSCC after cell uptake and further accumulation in lysosomes. Although radiation alone triggered late apoptosis and mitochondrial impairment, the pre-treatment with GBNs led to complex DNA damage and a specific increase of autophagic cell death. In addition, a significant radio-enhancement effect was obtained after the pre-conditioning of cells with a glutathione inhibitor before GBNs treatment and radiation exposure. Overall, our results provide additional information on the radio-enhancing properties of GBNs in the management of radioresistant HNSCC.

Age-Dependent Protective Effect of Selenium against UVA Irradiation in Primary Human Keratinocytes and the Associated DNA Repair Signature.

Few studies have focused on the protective role of selenium (Se) against skin aging and photoaging even though selenoproteins are essential for keratinocyte function and skin development. To the best of our knowledge, the impact of Se supplementation on skin cells from elderly and young donors has not been reported. Therefore, the main objective of our study was to evaluate the effects of Se supplementation on skin keratinocytes at baseline and after exposure to ultraviolet A (UVA) irradiation. Low doses of Se (30 nM) were very potently protective against UVA-induced cytotoxicity in young keratinocytes, whereas the protection efficiency of Se in old keratinocytes required higher concentrations (240 nM). Additionally, the DNA repair ability of the old keratinocytes drastically decreased compared with that of the young keratinocytes at baseline and after the UVA exposure. The Se supplementation significantly enhanced the DNA repair of 8-oxoguanine (8oxoG) only in the keratinocytes isolated from young donors. Therefore, aged keratinocytes have an increased vulnerability to oxidative DNA damage, and the Se needs in the elderly should be considered. Strengthening DNA repair activities with Se supplementation may represent a new strategy to combat aging and skin photoaging.

Carcinogenicity of the antineoplastic agent, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, and its metabolites in rats.

Chronic oral administration of the antineoplastic agent, 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (NSC-45388, DTIC), induced predominantly thymic and mammary tumors as demonstrated previously. Male and female Sprague-Dawley and female Buffalo rats were susceptible to the carcinogenicity of DTIC. A 50% incidence of mammary adenocarcinomas was induced in males within 18 weeks. Type of tumor and tumor incidence were dose dependent. Single and multiple intraperitoneal injections of DTIC did not alter organ specificity. DTIC-induced thymic lymphosarcomas and mammary adenocarcinomas were transplantable. Tissue distribution studies revealed no correlation between uptake of DTIC by a given tissue and its susceptibility to carcinogenicity. Metabolites of DTIC were tested for carcinogenic activity. Animals administered 5-diazoimidazole-4-carboxamide orally, intraperitoneally, or intragastrically developed low incidences of thymic, stomach, bladder, or mammary tumors. A low incidence of mammary tumors developed in rats fed 2-azahypoxanthine. A variety of tumors, including several ependymoblastomas, were induced in rats that received 5-aminoimidazole-4-carboxamide orally. 5-(3-Methyl-1-triazeno)imidazole-4-carboxamide (MTIC), when fed or given in single or multiple intraperitoneal injections, induced a high incidence of mammary adenofibromas and a low incidence of uterine leiomyosarcomas. Control rats had low incidences of mammary adenocarcinomas and adenofibromas after 52 weeks. These data show that the carcinogenic properties of DTIC resemble those of carcinogenic N-nitroso compounds, hydrazine, azo, and azoxy-alkanes and aryltriazenes and thus suggest similar mechanism(s) of action. These data also indicate that MTIC is involved in the induction of mammary adenofibromas and uterine leiomyosarcomas by DTIC.

Effects of 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide and its metabolites on Novikoff hepatoma cells.

Studies were undertaken to determine the effects of 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC) and its metabolites on the growth and macromolecular synthesis of Novikoff hepatoma cells in culture. DTIC (3.0 mM) in light decreased the viable cell count by 90% within 96 hr. DTIC protected from light, 2-azahypoxanthine, dimethylamine, and 5-aminoimidazole-4-carboxamide, all at 3.0 mM, reduced the rate of cellular proliferation. 5-Diazoimidazole-4-carboxamide (1.0 mM) and 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (3.0 mM) decreased the viable cell count by 99%. Effects on macromolecular synthesis were determined by the rate of incorporation of the appropriate 3H-labeled precursor. Results after 6 hr are given as percentage of controls. DTIC (1.0 mM) in light inhibited DNA (8%), RNA (41%), and protein (63%) synthesis. DTIC (1.0 mM) protected from light inhibited DNA (12%) and RNA (57%) synthesis. 5-Diazoimidazole-4-carboxamide (0.1 mM) inhibited DNA (1%), RNA (9%), and protein (1%) synthesis. 5-(3-Methyl-1-triazeno)imidazole-4-carboxamide (1.0 mM) inhibited DNA (72%) and protein (65%) synthesis but stimulated RNA (127%) synthesis. 2-Azahypoxanthine (1.0 mM) inhibited DNA (43%), RNA 82%) and protein (28%) synthesis. 5-Aminoimidazole-4-carboxamide (3.0 mM) stimulated DNA (354%) and RNA (266%) synthesis. These data show that DTIC is able to generate several toxic metabolites that may be responsible for its biological effects.

Brain dysmorphology in adults with congenital rubella plus schizophrenialike symptoms.

Brain morphology was quantified with magnetic resonance imaging (MRI) in adult patients with congenital rubella who also had schizophrenialike symptoms. MRIs were compared with those of adult early-onset schizophrenic patients without congenital rubella and age-matched healthy control subjects. The rubella patients had significantly smaller intracranial volumes and shorter stature than the schizophrenic patients or the controls; however, both patient groups had smaller cortical gray matter, but not white matter, volumes than the control group, even when the MRI volumes were corrected for head size and age. In addition, both patient groups showed significant enlargement of the lateral ventricles but not cortical sulci when compared with expected values of normal adults of the same age and head size. Overall, the pattern of dysmorphology was identical in the rubella and the schizophrenic groups. The observations in the rubella group are consistent with a developmental lesion that limits full brain growth, with the small intracranial volume due at least in part to a severe cortical gray matter volume deficit. Thus, the brain dysmorphology of congenital rubella may provide an instance of prenatal viral infection that models the schizophrenic pattern and provides indirect support for a developmental hypothesis of the neuropathogenesis of schizophrenia.

Fulminant neonatal septicemia due to Hemophilus parainfluenzae.

A woman with premature rupture of membranes and chorioamnionitis gave birth to a 0.73-kg infant at 28 weeks' gestation. The infant died of fulminant septicemia caused by Hemophilus parainfluenzae. This organism should be recognized as a potential cause of chorioamnionitis and neonatal septicemia.

Vasectomy and lowering surgeon's risk of liability.

The increased demand for vasectomy as a method of fertility control has resulted in an increase in professional liability suits against those surgeons performing this procedure. In some instances this litigation appears to arise from vague or casual instructions from the surgeon, but an additional causative factor is a misunderstanding on the part of the patient regarding the operative and postoperative periods and his responsibility for utilizing alternative contraceptive methods. I suggest some means for addressing these problems, and comment on the factors to consider when the surgeon finds himself the defendant in a lawsuit on "failed" vasectomy.

Light and ultrastructural study of reactive perforating collagenosis.

In 1967, Mehregan et al described a new and distinct clinicopathologic entity that they called reactive perforating collagenosis (RPC). This rare disease is classified with a group of disorders that involve the transepithelial elimination of histochemically altered dermal tissue. In RPC, minor trauma such as an insect bite, scratch, or pilosebaceous infection alters the collagen fibers in the papillary dermis. The histochemically altered but ultrastructurally intact collagen elicits both a dermal and epithelial response. For the case presented, it is our purpose to demonstrate transepithelial elimination of collagen fibers by ultrastructural study, thereby supporting the recognized histochemical observations.

White matter MR hyperintensities in adult patients with congenital rubella.

PURPOSE: To observe and quantify white matter hyperintensities on MR images in adults with schizophrenialike symptoms who had had congenital rubella, in order to elucidate the neuropathologic sequelae of this perinatal viral infection and to explore the potential relationship of these lesions to schizophrenia. METHODS: Eleven deaf adult patients with documented prenatal rubella virus infection and schizophrenialike symptoms were compared with 19 age-matched patients with early-onset schizophrenia who did not have congenital rubella and with 18 age-matched control subjects. All MR images (obtained at 1.5 T) were evaluated by a neuroradiologist who was blinded to diagnosis and were rated for white matter lesions on a five-point scale: 0 = no lesions; 1 = 1 lesion less than 1 mm in diameter; 2 = 1 to 4 lesions 1 mm or greater; 3 = 5 to 10 lesions; 4 = more than 10 lesions or a single lesion more than 1 cm in diameter. In addition, the white matter hyperintensities were volumed objectively with a manual threshold technique. RESULTS: Ratings of white matter lesions were significantly higher in the rubella patients than in the control subjects: 6 of the 11 patients had ratings greater than 1 compared with 1 of the 18 control subjects and none of the 19 schizophrenic patients. Also, MR images in five rubella patients received ratings at the highest end of the scale of abnormality (3 or 4). The white matter hyperintensities were characterized as bilateral T2 signal hyperintensities in periventricular and subcortical regions, punctate or linear in shape; they were observed predominantly in parietal lobes. CONCLUSION: This quantitative MR study of adult rubella patients disclosed abnormal white matter lesions that may correspond to neurovascular lesions known neuropathologically. They do not appear to be directly related to schizophrenialike symptoms.

A cross-validation of Paulson's discriminant function-derived scales for identifying "at risk" child-abusive parents.

Paulson, Afifi, Chaleff, Liu, & Thomason (1975) developed a series of special subscales from the MMPI for identifying individuals who are at risk for child-abusive behavior. The initial results were highly encouraging, with the scales correctly identifying 93 to 100% of the subjects in their sample. Unfortunately, Paulson et al. (1975) failed to cross-validate their findings before publication. When the six scales were cross-validated on an independent sample from the population of child-abusing parents, significant shrinkage in the accuracy of prediction was found. The use of the special subscales for identifying "at risk" parents in prenatal clinics, pediatric clinics, pediatric clinics and mental health centers as originally suggested by Paulson and his colleagues is seriously questioned.

No benefit of the doubt: intergroup bias in understanding causal explanation.

Conversational conventions predict that receivers weigh later information more heavily than earlier information because they presume that communicators add later information only when it is particularly relevant and important. Drawing on Pettigrew's observation of the ultimate attribution error, the present research predicted that intergroup bias could override this conversational convention when individuals received multiple explanations (one beneficial, one condemning) for acts committed by out-group members vs. in-group members. Specifically, subsequently presented mitigating explanations for negative acts should not temper impressions of out-group members, and subsequently presented crediting explanations for positive acts should not enhance impressions of out-group members. Results supported this pattern, and the discussion considers these findings in light of communication rules, and in-group/out-group definition.

[Hepatic hamartoma in adults. Apropos of a case documented by MRI]. / Hamartome hépatique de l'adulte. A propos d'un cas documenté par IRM.

A mixed hamartoma of the liver in a 39 year old man is reported. Abdominal ultrasound revealed a 4 cm inhomogeneous echogenic mass with acoustic shadowing. MRI T1 weighted images showed a inhomogeneous low intensity mass with lower gadolinium enhancement than normal liver, a moderate low signal intensity on proton density weighted images, and heterogeneous isosignal intensity on T2 weighted images. Peripheric calcifications were found on pathologic examination.

Developing an Elementary School CHD Prevention Program.

In brief: Sixty-three students aged 7 to 12 years (32 boys, 31 girls) were assessed for coronary heart disease (CHD) risk factors, including family history of CHD, blood pressure, VO2 max, serum lipids, body composition, and history of diabetes mellitus and cigarette smoking. Forty-two percent of the children had one risk factor, and 12% and 3% had two and three risk factors, respectively. This information was used to encourage school administrators and faculty to modify the physical education program, teach health and fitness concepts in the classroom, and develop a rehabilitation program for children at risk.