Decrease in bladder cell micronucleus prevalence after intervention to lower the concentration of arsenic in drinking water

Epidemiological studies performed in Taiwan, Argentina, and Chile suggest that ingestion of arsenic (As) may cause bladder cancer. Because of these findings, we previously investigated the relationship between As ingestion and genetic damage to the urothelium in two cross-sectional biomarker studies, one in Nevada and one in Chile. In both studies, we found that increased levels of micronucleated cells (MNCs) in exfoliated bladder cells were associated with elevated concentrations of As in drinking water, suggesting that As induces genetic damage to bladder cells. To further investigate this relationship, we conducted an intervention study in a subset of highly exposed men (n = 34) from the cross-sectional study in Chile. Subjects whose usual source of water contained about 600 micrograms/liter As were supplied with water lower in As (45 micrograms/liter) for 8 weeks, allowing ample opportunity for renewal and exfoliation of bladder epithelial cells. Mean urinary As levels decreased during the intervention from 742 to 225 micrograms/liter. Bladder MNC prevalence also decreased from 2.63 MNCs/1000 cells preintervention to 1.79 MNCs/1000 cells postintervention (P < 0.05). When the analysis was limited to individuals previously having subcytotoxic urinary As levels (< 700 micrograms/liter), the change between pre- and postintervention MNC was more pronounced: the level decreased from 3.54 to 1.47 MNCs/1000 cells, respectively (P = 0.002). Among smokers, MNC prevalences decreased from 4.45 MNCs/1000 cells preintervention to 1.44 MNCs/1000 cells postintervention (P = 0.002). Among nonsmokers, the decrease was much smaller: 2.04 MNCs/1000 cells preintervention to 1.90 MNCs/1000 cells postintervention (P = 0.25), suggesting that smoker's bladder cells could be more susceptible to genotoxic damage caused by As. The reduction in bladder MNC prevalence with reduction in As intake provides further evidence that As is genotoxic to bladder cells.     

Toxicity and allergy to local anesthesia

Considering the amount of local anesthetic administered on a daily basis, dental professionals must be familiar with the factors that influence the dose and type of local anesthetic that induces a toxic or allergic reaction. In addition to the route and rate of administration, the patient's physical condition and health may also influence the dose of local anesthetic that could be safely administered. This article reviews the different causes of local anesthesia toxicity and allergy. With prevention and early recognition of the warning signs, poor prognosis can be avoided.     

A randomized, controlled trial of intravenous clodronate in patients with metastatic bone disease and pain

The present study analyses cell loss and proliferation which account for the decrease in the number of germ cell populations in the senile male Octodon degus. This is a good model to study ageing in wild animals, since it has recently been incorporated as a laboratory animal but still has a high degree of genetic heterogeneity, thus representing a situation found in natural systems. The cell loss from pachytene spermatocytes to round spermatids is estimated by cell counts in the cross section of seminiferous tubules. DNA testicular synthesis is measured by scintillation counting and the index of labelling of spermatogonia by radioautography of testes comparing sexually mature young animals and senile animals. Other determinations in both groups are testis weight, thickness of the albuginea and tubular wall, daily sperm production, percentage of depleted seminiferous tubules and nuclear cell diameters of germ cells. The results suggest a decrease in the number of cell population in the senile animals resulting from an increase in physiological cell loss coupled with a decreased proliferative spermatogonial activity. There is also a decreased yield of meiosis in terms of round spermatid production. Lowered testosterone levels both in plasma and testicular parenchymal fluid are found in senile animals. All these senescent changes reflect an altered remodelling activity of the seminiferous epithelium and presumably also of Leydig cells.     

Genetic variation in the interleukin 10 gene promoter and systemic lupus erythematosus

OBJECTIVE: To investigate interleukin 10 (IL-10) gene promoter polymorphisms in systemic lupus erythematosus (SLE) and its clinical subsets. METHODS: DNA from 76 Caucasian patients with SLE and 119 controls as genotyped for 3 defined dimorphic polymorphisms (G or A at position -1082, C or T at position -819, C or A at position -592) in the promoter region of the IL-10 gene, using the polymerase chain reaction to amplify the IL-10 gene promoter and oligonucleotide probes specific for each allelic sequence. The frequency of genotypes was compared between patients with SLE and controls, and between clinical subsets of patients with the disease. RESULTS: There was no significant change in the allele frequency of the three IL-10 gene promoter dimorphic polymorphisms in the SLE group compared with controls. However, when subgrouped according to autoantibody status and clinical features, IL-10 -1082*G, -819*C, and -592*C alleles were increased in patients possessing Ro autoantibodies and those with renal involvement. These alleles are in preferential allelic association, namely GCC, ACC, and ATA haplotypes, and the GCC haplotype was increased in these patient subgroups. CONCLUSION: Polymorphisms within the IL-10 gene promoter that are associated with high IL-10 levels may be important in the development of certain clinical features in SLE.     

Mitosis in the human embryo: the vital role of the sperm centrosome (centriole)

The pattern of sperm centrosomal (centriolar) inheritance, centrosomal replication and perpetuation during mitosis of the human embryo is reviewed with a series of electron micrographs. Embryonic cleavage involves repeated mitoses, a convenient sequence to study centriolar behaviour during cell division. After the paternal inheritance of centrioles in the human was reported (Sathananthan et al., 1991a), there has been an upsurge of centrosomal research in mammals, which largely follow the human pattern. The human egg has an inactive non-functional centrosome. The paternal centrosome contains a prominent centriole (proximal) associated with pericentriolar material which is transmitted to the embryo at fertilization and persists during sperm incorporation. Centriolar duplication occurs at the pronuclear stage (interphase) and the centrosome initially organizes a sperm aster when male and female pronuclei breakdown (prometaphase). The astral centrosome containing diplosomes (two typical centrioles) splits and relocates at opposite poles of a bipolar spindle to establish bipolarization, a prerequisite to normal cell division. Single or double centrioles occupy pivotal positions on spindle poles and paternal and maternal chromosomes organize on the equator of a metaphase spindle, at syngamy. Bipolarization occurs in all monospermic and in most dispermic ova. Dispermic embryos occasionally form two sperm asters initially and produce tripolar spindles (tripolarization). Anaphase and telophase follows producing two or three cells respectively, completing the first cell cycle. Descendants of the sperm centriole were found at every stage of perimplantation embryo development and were traced from fertilization through cleavage (first four cell cycles) to the morula and hatching blastocyst stage. Centrioles were associated with nuclei at interphase, when they were often replicating and occupied pivotal positions on spindle poles during mitosis. Sperm remnants were associated with centrioles and were found at most stages of cleavage. Centrioles were found in trophoblast, embryoblast and endoderm cells in hatching blastocysts. Pericentriolar, centrosomal material nucleated astral and spindle microtubules. Abnormal nuclear configurations observed in embryos reflect mitotic aberrations. The bovine embryo closely resembles the human embryo in centriolar behaviour during mitosis. It is concluded that the sperm centrosome is the functional active centrosome in humans and is likely the ancestor of centrioles within centrosomes in foetal and adult somatic cells. The role of the sperm centrosome in embryogenesis and male infertility is discussed, since it is of clinical importance in assisted reproduction.     

Galvanic vestibular stimulation in humans: effects on otolith function in roll

All autopsy reports from 1990-1994 inclusive of the Department of Pathology, University of Hong Kong and the Wales Institute of Forensic Medicine were examined and cases of death due to massive pulmonary embolism were noted. The incidence of this condition was calculated and found to be insignificantly lower in the Hong Kong series than the Welsh series by statistical analysis, both in the crude incidence in all autopsies and when correcting for different case mixes in the two locations. The majority of cases in both locations were in the over-60 age group. The study helps refute the longstanding belief among Hong Kong physicians that fatal massive pulmonary embolism is rare in Hong Kong (with approximately 98% Chinese population) in comparison with a predominantly Caucasian population.     

Preclinical and phase I clinical studies with the nonclassical antifolate thymidylate synthase inhibitor nolatrexed dihydrochloride given by prolonged administration in patients with solid tumors

PURPOSE: A phase I, multicenter trial of the thymidylate synthase (TS) inhibitor THYMITAQ (nolatrexed dihydrochloride; Agouron Pharmaceuticals, Inc, San Diego, CA) given by 5-day continuous infusion was performed to establish the maximum-tolerated dose (MTD) and to investigate pharmacokinetics, pharmacodynamics, and antitumor effects. METHODS: In vitro and in vivo preclinical studies demonstrated increased activity with prolonged nolatrexed exposure. In 32 patients, nolatrexed was given as a 5-day infusion at 96 to 1,040 mg/m2/d for 5 days. Pharmacokinetics were determined from high-performance liquid chromatography (HPLC) analyses of plasma and urine. In addition to studying toxicity, plasma deoxyuridine (UdR) elevations were measured as a marker of TS inhibition. RESULTS: The MTD was 904 mg/m2/d for 5 days and the recommended phase II dose is 800 mg/m2/d for 5 days. The dose-limiting toxicity was neutropenia with clinically significant thrombocytopenia and mucositis. These antiproliferative toxicities of nolatrexed were predictable and reversible. A partial response that lasted 3 months occurred in a patient with metastatic colorectal cancer. Pharmacokinetics were nonlinear, with the median plasma clearance (CI) decreasing from 151 mL/min/m2 (range, 124 to 211) at 96 mg/m2/d for 5 days to 49 mL/min/m2 (range, 30 to 84) at 768 mg/ m2/d for 5 days. The half-life (t1/2) was 173 minutes (range, 43 to 784) and 18% (range, 9% to 35%) of the dose was excreted unchanged in the urine. Plasma UdR increased, but returned to pretreatment levels after the end of infusion. Hematologic toxicity was significantly related to nolatrexed plasma concentrations and dose. CONCLUSION: Nolatrexed can be safely administered to patients at a dose of 800 mg/m2/d over 5 days by continuous intravenous infusion and this schedule is associated with antitumor effects. The phase II evaluation of nolatrexed is ongoing.     

Relations among self-reported depressive symptoms in clinic-referred children versus adolescents.

Although there is consensus regarding the existence of childhood depression, disagreement remains as to whether symptoms are developmentally isomorphic. Previous studies focused on developmental differences in symptom levels; analyses of relations among symptoms may be more appropriate, however. Here both approaches were used to compare the Children's Depression Inventory responses from 1,030 clinic-referred children and adolescents. Four of 9 symptom categories showed significant developmental differences in their correlations with total score. Externalizing behavior and guilt were more strongly related to depression in children than adolescents; affective symptoms and concerns about the future showed the reverse pattern. Results illustrate the importance of considering relations among symptoms as well as differences in symptom levels when evaluating theoretical claims about developmental differences in the nature of clinical syndromes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Planning robotic trajectories for thermal spray shape deposition

Thermal spray shape deposition is a new process for fabricating net-shape parts by incremental material buildup of cross-sectional layers. This article presents an approach for spraying thin, flat layers using a robotic thermal spray system. Asymmetries of the spray distribution are first corrected by tilting the spray torch based on a computer model of the measured spray distribution. The path of the torch is then found using heuristics that are based on the estimated standard deviation of the corrected distribution. For example, thick arc-sprayed coatings of approximately 4.0 mm thickness have been deposited using this method, with the resulting standard deviation from the mean thickness ranging from 20.0 to 30.0 μm. To demonstrate the shape deposition process, a prototype turbine blade shape was built using these optimized trajectories.     

Heuristic configuration of single hidden-layer feed-forward neural networks

For optimum statistical classification and generalization with single hidden-layer neural network models, two tasks must be performed: (a) learning the best set of weights for a network of k hidden units and (b) determining k, the best complexity fit. We contrast two approaches to construction of neural network classifiers: (a) standard back-propagation as applied to a series of single hidden-layer feed-forward nerual networks with differing number of hidden units and (b) a heuristic cascade-correlation approach that quickly and dynamically configures the hidden units in a network and learns the best set of weights for it. Four real-world applications are considered. On these examples, the back-propagation approach yielded somewhat better results, but with far greater computation times. The best complexity fit, k, for both approaches were quite similar. This suggests a hybrid approach to constructing single hidden-layer feed-forward neural network classifiers in which the number of hidden units is determined by cascade-correlation and the weights are learned by back-propagation.