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PubMed2004

Using our current understanding of dyslexia to support early identification and intervention.

One of the major risk factors for reading disability is difficulty learning to read words in text in an accurate and fluent manner. This is apparent when a child at risk of dyslexia first starts to attempt to read. Dyslexic children struggle to grasp and automate the alphabetic principle (ie, they cannot "sound out" words or use phonemic decoding strategies) and therefore have difficulty deciphering unfamiliar words that they have not encountered before. Even though many of these words are part of the child's oral vocabulary, the child cannot recognize them in printed form. As a result, reading can be extremely laborious and time-consuming, fraught with errors, and altogether an unrewarding, aversive experience. To be an efficient reader, one must be able to rapidly and effortlessly recognize many words by sight, and for a child to acquire this facility requires multiple exposures to these words. The difficulty that dyslexic children have in developing reliable and efficient phonemic decoding ability makes the acquisition of a lexicon of sight words a much slower process than it is for the average reader. Several other factors can affect a child's ability to read, which are reviewed herein. However, early recognition and treatment of deficient phonologic awareness are an extremely important step in the prevention of a reading problem in the child who is at risk of dyslexia.

Child↗

PubMed2003

Tooth bleaching--a critical review of the biological aspects.

Present tooth-bleaching techniques are based upon hydrogen peroxide as the active agent. It is applied directly, or produced in a chemical reaction from sodium perborate or carbamide peroxide. More than 90% immediate success has been reported for intracoronal bleaching of non-vital teeth, and in the period of 1-8 years' observation time, from 10 to 40% of the initially successfully treated teeth needed re-treatment. Cervical root resorption is a possible consequence of internal bleaching and is more frequently observed in teeth treated with the thermo-catalytic procedure. When the external tooth-bleaching technique is used, the first subjective change in tooth color may be observed after 2-4 nights of tooth bleaching, and more than 90% satisfactory results have been reported. Tooth sensitivity is a common side-effect of external tooth bleaching observed in 15%-78% of the patients, but clinical studies addressing the risk of other adverse effects are lacking. Direct contact with hydrogen peroxide induced genotoxic effects in bacteria and cultured cells, whereas the effect was reduced or abolished in the presence of metabolizing enzymes. Several tumor-promoting studies, including the hamster cheek pouch model, indicated that hydrogen peroxide might act as a promoter. Multiple exposures of hydrogen peroxide have resulted in localized effects on the gastric mucosa, decreased food consumption, reduced weight gain, and blood chemistry changes in mice and rats. Our risk assessment revealed that a sufficient safety level was not reached in certain clinical situations of external tooth bleaching, such as bleaching one tooth arch with 35% carbamide peroxide, using several applications per day of 22% carbamide peroxide, and bleaching both arches simultaneously with 22% carbamide peroxide. The recommendation is to avoid using concentrations higher than 10% carbamide peroxide when one performs external bleaching. We advocate a selective use of external tooth bleaching based on high ethical standards and professional judgment.

Animals↗

PubMedDate not supplied

Glycophorin A is a potential biomarker for the mutagenic effects of pesticides.

For individuals with multiple exposures to bone marrow mutagens the glycophorin A (GPA) assay appears to detect the cumulative genotoxic effects of these nonspecific exposures. To determine whether workers exposed to organophosphates and/or carbamate pesticides have more GPA variants compared with controls, this cross-sectional cohort study examined 67 Latino farm workers, most of whom were exposed to organophosphate or carbamate pesticides, and 68 age-, gender-, ethnicity-, and education-matched reference subjects. Of the 27 participants who completed the questionnaire and had the M/N alleleotype required for the GPA assay, the N/N variant frequency was 9.1 x 10(-6) in the ten subjects with more than 1,500 cumulative hours of exposure vs 3.8 x 10(-6) in the six referent subjects with no known pesticide exposure (p = 0.097). A consistent trend with increasing cumulative exposure was found for N/N and O/N allele-loss frequencies when exposures were stratified into three groups. Despite the small sample size due to the alleleotype restriction, these findings support the hypothesis that some pesticides are mutagenic to hematopoietic stem cells.

Adult↗

PubMed2001

A Fas-based suicide switch in human T cells for the treatment of graft-versus-host disease.

Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation. One strategy to treat GVHD is to equip donor T cells with a conditional suicide mechanism that can be triggered when GVHD occurs. The herpes simplex virus thymidine kinase (HSV-tk)/ganciclovir system used clinically has several limitations, including immunogenicity and cell cycle dependence. An alternative switch based on chemically inducible apoptosis was designed and evaluated. A chimeric human protein was expressed comprising an extracellular marker (DeltaLNGFR), the Fas intracellular domain, and 2 copies of an FK506-binding protein (FKBP). Primary human T lymphocytes retrovirally transduced with this construct could be purified to homogeneity using immunomagnetic beads. Genetic integrity of the construct was ensured by redesigning repetitive sequences. Transduced T cells behaved indistinguishably from untransduced cells, retaining the ability to mount a specific antiallogeneic immune response. However, they rapidly underwent apoptosis with the addition of subnanomolar concentrations of AP1903, a bivalent "dimerizer" drug that binds FKBP and induces Fas cross-linking. A single 2-hour treatment eliminated approximately 80% of T cells, and multiple exposures induced further apoptosis. T cells were eliminated regardless of their proliferation state, suggesting that the AP1903/Fas system, which contains only human components, is a promising alternative to HSV-tk for treating GVHD.

Apoptosis↗

PubMed1997

311C90: long-term efficacy and tolerability profile for the acute treatment of migraine. International 311C90 Long-Term Study Group.

311C90 (Zomig; zolmitriptan) is a novel, selective serotonin (5HT)1B/1D receptor agonist with both central and peripheral activity, now in late-stage clinical development for acute oral treatment of migraine. Several studies have demonstrated the tolerability and efficacy of 311C90 in the treatment of a single migraine headache. The objectives of this open-label study were to assess the tolerability and efficacy of repeated doses of 5 mg of 311C90 for acute treatment of multiple attacks for up to 1 year. Patients were allowed to treat as many migraine headaches (mild, moderate, or severe) as desired with an initial dose. A second 5-mg dose could be used to treat recurrence should it develop. Safety assessments included ECG, the frequency, intensity, and duration of adverse experiences, and routine hematology, urinalysis, and clinical chemistry parameters. Efficacy assessments included headache severity at 2 hours (i.e., severe, moderate, mild, or none), the proportion of patients pain-free at 2 hours, the use of a second tablet to treat headache recurrence if it developed, and the consistency of these findings over time. The efficacy profile and the nature/incidence of adverse events reported appear to be consistent with previous 311C90 studies. The dosing regimen was well tolerated during multiple exposures. Notably, headache response rates were consistently good after both initial and repeated exposure (> 80% across 1 to 30 attacks). For 67% of patients who treated at least five attacks, 311C90 was effective 80 to 100% of the time.

Adolescent↗

PubMed1976

Form of developing bends in reactivated sperm flagella.

1. Dark-field, multiple-exposure photographs of reactivated tritonated sea urchin sperm flagella swimming under a variety of conditions were analysed. 2. The length, radius and subtended angle of bends increased during bend development. The pattern of development was essentially the same under all conditions observed. 3. The angles of the two bends nearest the base tend to increase at the same rate, cancelling one another, so that the development of new bends causes little if any net microtubular sliding. 4. The direction of microtubular sliding within a bend is initially in the same direction as that within the preceding bend, and reverses as the bend develops.

Animals↗

PubMed1977

Asymmetric waveforms in echinoderm sperm flagella.

1.Dark-field, multiple-exposure photographs of live spermatozoa of a number of echinoderms were analysed. 2. Bends develop at the base in pairs, as they do in flagella with symmetrical waveforms. However, the angles of these bends do not cancel, so that microtubular sliding-of up to over 50% of that associated with bend propagation-is transferred distally. This sliding implies that (a) microtubules are not rigidly cross-linked within straight regions, and (b) bends can propagate normally in spite of appreciable extrinsic microtubular sliding. 3. Both the sperm head and the asymmetry of the waveform appear to affect the swim path of a spermatozoon.

Animals↗

PubMed1981

Effects of kinins and dipeptidyl carboxypeptidase on the motility of highly washed human sperm.

The influences of bradykinin, kallidin and dipeptidyl carboxypeptidase (kininase II) on the motility of human sperm thoroughly washed with Ficoll were investigated by an objective method with multiple exposure photography technique which recorded stroboscopically the tract of sperm migration. Addition of 0.1--10 ng/ml of bradykinin or kallidin to sperm suspension caused a stimulation of motility. The effect appeared by increase of the velocity of forward motile sperm, whereas the percent of motile sperm was not altered. On the contrary, higher dose of kinins suppressed the motility by decreasing the percent of motile sperm. There was a minor contamination of dipeptidyl carboxypeptidase even in the highly washed sperm suspension. This enzyme was identical with angiotensin I converting enzyme or kininase II and the major enzyme of kinin degrading activity in seminal plasma. Stimulation of sperm motility by kinin was further enhanced in the presence of SQ 14225, a specific inhibitor of dipeptidyl carboxypeptidase, by protection of added kinins from the residual dipeptidyl carboxypeptidase in the sperm suspension. Dipeptidyl carboxypeptidase level in ejaculated human semen was found to correlate to the semen quality, such as sperm density and motility, but it gave no direct influence on sperm motility.

Bradykinin↗

PubMed1984

Effects of angiotensins of the motility of human sperm.

The effects of angiotensins on the motility of highly washed human sperm were examined by multiple exposure photography system. The addition of low doses (0.1-10 ng/ml) of angiotensin II (AT II) stimulated the forward velocity of sperm without increasing the percentage of motility. On the contrary, high concentration (1.0 micrograms/ml) of AT II suppressed the motility. The direct effect of angiotensin I (AT I) on the motility was observed under the presence of SQ 14225, a specific inhibitor of angiotensin I converting enzyme (ACE). At I (0.1-100 ng/ml) gave no influence on the motility, whereas that of high dose (1.0 ug/ml) suppressed the motility in the same manner as the corresponding dose of AT II. The action of AT II on the motility was completely suppressed under the coexistence of saralasin, a specific antagonist against AT II. This fact indicated that the action of AT II on the sperm appeared through the specific receptor on sperm.

Angiotensin I↗

PubMed1984

Lesions induced in rodent pancreas by azaserine and other pancreatic carcinogens.

Focal proliferative changes in the acinar cells of the pancreas of rats have been induced by several systemically administered carcinogens including azaserine, N-nitrosobis(2-oxopropyl)amine, N-nitroso-(2-hydroxypropyl) (2-oxopropyl)amine, and N delta-(N-methyl-N-nitrosocarbamoyl)-L-ornithine (MNCO). Foci, nodules, and adenomas induced by these carcinogens are usually made up of atypical-appearing acinar cells that maintain a high degree of differentiation, but a minority of these lesions exhibit anaplastic cellular changes that suggest the development of malignant potential. Such anaplasia may occupy the whole of smaller lesions or may occur as a secondary focal change within larger nodules or adenomas. Many foci and nodules per pancreas have been induced by single or multiple exposures to these known genotoxic carcinogens, but relatively few of them develop into carcinomas. Azaserine and MNCO have induced acinar cell carcinomas in rats. Those induced by azaserine have exhibited a broad spectrum of histologic variants, including ductlike cystic, and undifferentiated patterns. Higher doses of MNCO have induced a second pattern of change in the pancreatic lobules of rats, which includes cystic and tubular ductlike structures that have been called cystic and tubular ductal complexes. MNCO has also induced focal acinar cell lesions, cystic and tubular ductal complexes, and adenocarcinomas in the pancreas of Syrain golden hamsters. In this species, ductal complexes are much more numerous than are proliferative lesions of acinar cells, and the histologic appearance of the carcinomas is ductlike. Hyperplasia and atypical changes were also seen in the epithelium of the intralobular ducts of hamsters.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1996

Fish models for environmental carcinogenesis: the rainbow trout.

Progress over the past 30 years has revealed many strengths of the rainbow trout as an alternative model for environmental carcinogenesis research. These include low rearing costs, an early life-stage ultrasensitive bioassay, sensitivity to many classes of carcinogen, a well-described tumor pathology, responsiveness to tumor promoters and inhibitors, and a mechanistically informative nonmammalian comparative status. Low-cost husbandry, for example, has permitted statistically challenging tumor study designs with up to 10,000 trout to investigate the quantitative interrelationships among carcinogen dose, anticarcinogen dose, DNA adduct formation, and final tumor outcome. The basic elements of the trout carcinogen bioassay include multiple exposure routes, carcinogen response, husbandry requirements, and pathology. The principal known neoplasms occur in liver (mixed hepatocellular/cholangiocellular adenoma and carcinoma, hepatocellular carcinoma), kidney (nephroblastoma), swim bladder (adenopapilloma), and stomach (adenopapilloma). Trout possess a complex but incompletely characterized array of cytochromes P450, transferases, and other enzymic systems for phase I and phase II procarcinogen metabolism. In general, trout exhibit only limited capacity for DNA repair, especially for removal of bulky DNA adducts. This factor, together with a high capacity for P450 bioactivation and negligible glutathione transferase-mediated detoxication of the epoxide, accounts for the exceptional sensitivity of trout to aflatoxin B1 carcinogenesis. At the gene level, all trout tumors except nephroblastoma exhibit variable and often high incidences of oncogenic Ki-ras gene mutations. Mutations in the trout p53 tumor suppressor gene have yet to be described. There are many aspects of the trout model, especially the lack of complete organ homology, that limit its application as a surrogate for human cancer research. Within these limitations, however, it is apparent that trout and other fish models can serve as highly useful adjuncts to conventional rodent models in the study of environmental carcinogenesis and its modulation. For some problems, fish models can provide wholly unique approaches.

Animals↗

PubMed2002

Additive lithography for fabrication of diffractive optics.

An innovative fabrication technique is introduced that is based on multiple-exposure techniques for micro-optics fabrication. This method utilizes various exposure times and combinations of binary and analog photo masks to sculpture complex photoresist profiles. It also demonstrates the fabrication of analog structures from the multilevel structures thus formed by using resist reflow.

Journal Article↗

PubMed2003

Triply periodic bicontinuous structures through interference lithography: a level-set approach.

Interference lithography holds the promise of fabricating large-area, defect-free photonic structures on the sub-micrometer scale both rapidly and cheaply. There is a need for a procedure to establish a connection between the structures that are formed and the parameters of the interfering beams. There is also a need to produce self-supporting three-dimensional bicontinuous structures. A generic technique correlating parameters of the interfering beams with the symmetry elements present in the resultant structures by a level-set approach is developed. A particular space group is ensured by equating terms of the intensity equation to a representative level surface of the desired space group. Single- and multiple-exposure techniques are discussed. The beam parameters for certain cubic bicontinuous structures relevant to photonic crystals, viz.,the diamond(D), the simple cubic (P), and the chiral gyroid (G) are derived by utilizing either linear or elliptically polarized light.

Journal Article↗

PubMed2005

Estimating the time of last cannabis use from plasma delta9-tetrahydrocannabinol and 11-nor-9-carboxy-delta9-tetrahydrocannabinol concentrations.

BACKGROUND: Knowing the time cannabis was last used is important for determining impairment in accident investigations and clinical evaluations. Two models for predicting time of last cannabis use from single plasma cannabinoid concentrations-model I, using Delta(9)-tetrahydrocannabinol (THC), and model II, using the concentration ratio of 11-nor-9-carboxy-THC (THCCOOH) to THC-were developed and validated from controlled drug administration studies. Objectives of the current study were to extend the validation by use of a large number of plasma samples collected after administration of single and multiple doses of THC and to examine the effectiveness of the models at low plasma cannabinoid concentrations. METHODS: Thirty-eight cannabis users each smoked a 2.64% THC cigarette in the morning, and 30 also smoked a second cigarette in the afternoon. Blood samples (n = 717) were collected at intervals after smoking, and plasma THC and THCCOOH concentrations measured by gas chromatography-mass spectrometry. Predicted times of cannabis smoking, based on each model, were compared with actual smoking times. RESULTS: The most accurate approach applied a combination of models I and II. For all 717 plasma samples, 99% of predicted times of last use were within the 95% confidence interval, 0.9% were overestimated, and none were underestimated. For 289 plasma samples collected after multiple doses, 97% were correct with no underestimates. All time estimates were correct for 76 plasma samples with THC concentrations between 0.5 and 2 mug/L, a concentration range not previously examined. CONCLUSIONS: This study extends the validation of the predictive models of time of last cannabis use to include multiple exposures and low THC concentrations. The models provide an objective and validated method for assessing the contribution of cannabis to accidents or clinical symptoms.

Cannabis↗

PubMed2006

Extracellular-signal regulated kinase 1-dependent metabotropic glutamate receptor 5-induced long-term depression in the bed nucleus of the stria terminalis is disrupted by cocaine administration.

The bed nucleus of the stria terminalis (BNST) is a key component of the CNS stress and reward circuit. Synaptic plasticity in this region could in part underlie the persistent behavioral alterations in generalized anxiety and addiction. Group I metabotropic glutamate receptors (mGluRs) have been implicated in stress, addiction, and synaptic plasticity, but their roles in the BNST are unknown. We find that activation of group I mGluRs in the dorsal BNST induces depression of excitatory synaptic transmission through two distinct mechanisms. First, a combined activation of group I mGluRs (mGluR1 and mGluR5) induces a transient depression that is cannabinoid 1 receptor dependent. Second, as with endocannabinoid-independent group I mGluR long-term depression (LTD) in the adult hippocampus, we find that activation of mGluR5 induces an extracellular signal-regulated kinase (ERK)-dependent LTD. Surprisingly, our data demonstrate that this LTD requires the ERK1 rather than ERK2 isoform, establishing a key role for this isoform in the CNS. Finally, we find that this LTD is dramatically reduced after multiple exposures but not a single exposure to cocaine, suggesting a role for this form of plasticity in the actions of psychostimulants on anxiety and reward circuitries and their emergent control of animal behavior.

Animals↗

PubMed1987

Effects of cryopreservation on the motility characteristics of human spermatozoa.

Ejaculates (164) were obtained from 17 donors serving on an artificial insemination by donor panel. Semen analysis was performed before and after freezing by an integrated microcomputerized system employing the multiple-exposure photography (MEP) method. Sperm count, motility, velocity, motility index (MI; product of the sperm velocity and percentage of motile spermatozoa) and motile density (MD) were determined for each ejaculate. After the initial evaluation the ejaculates were frozen in liquid nitrogen, thawed 24 h later, and assessed for post-thaw motility, velocity, MI and MD. The mean +/- s.e. sperm count and volume for this group of donors was 148 +/- 4 x 10(6)/ml and 3.1 +/- 0.1 ml, respectively. Mean +/- s.e. values obtained from the prefreeze analysis were: motility = 64 +/- 1%, velocity = 30 +/- 0.4 microns/sec, MI = 19 +/- 0.5 microns/sec and MD = 94 +/- 3 x 10(6)/ml. Post-thaw analysis revealed a significant reduction (P less than 0.01) in all values measured. Motility was reduced to 27 +/- 1%, MI was reduced to 5 +/- 0.3 microns/sec, and MD was reduced to 33 +/- 1 x 10(6)/ml. Velocity was the least affected by cryopreservation, being reduced to 21 +/- 0.5 microns/sec (P less than 0.01). Cryopreservation resulted in a marked shift in the frequency distribution of sperm motility and motility index towards subnormal values while in the majority of ejaculates velocity and motile density were maintained in the normal range. Significant differences were noted amongst donors in the percentage change of the various semen measures as a result of cryopreservation. When within-subject coefficients of variation were calculated, velocity was the least variable parameter.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Count↗

PubMed2006

Changes in submaxillary gland gene expression in F344 rats by multiple dosing of theophylline.

Multiple exposure to theophylline, a phosphodiesterase (PDE) inhibitor, induces acinar hypertrophy in the salivary gland. This study examined the effect of theophylline on the gene expression of secretory proteins and phosphodiesterases in the submaxillary gland. Male F344 rats received saline or theophylline (50 mg/kg) intraperitoneally for 4 days. The gene expressions for the secretory protein, cystatin S (CysS), and PDE subfamilies 3A and 4D in the submaxillary gland were quantified using RT-PCR. Theophylline exposure resulted in a sustained increase in mRNA expression for CysS and PDE3A, but PDE4D gene expression was unchanged. Our results suggest that submaxillary hypertrophy is primarily caused by the enhanced transcription of CysS, and that the transcription of each PDE subfamily gene is regulated differently.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2001

Molecular and genetic mechanisms of prostate cancer.

Prostate cancer is the most commonly diagnosed malignancy in American men and is the second leading cause of cancer death in males in the United States. Despite its high incidence, the molecular and genetic events involved in progression of prostate cancer remain poorly understood. In vitro models of human prostate epithelial (HPE) cells provide a practical approach to the analysis of the molecular and genetic mechanisms underlying prostate carcinogenesis. We reported the immortalization of normal adult HPE cells by transfection of the HPV-18 DNA and the subsequent conversion of such nontumorigenic but immortalized cells (HPV-18 C-1) into tumorigenic cells by the introduction of an activated Kras oncogene. Recently, we have demonstrated the malignant transformation of HPV-18 C-1 cells after multiple exposures to the chemical carcinogen N-nitroso-N-methylurea (NMU). Such transformants showed morphological alterations and anchorage-independent growth in soft agar and induced carcinomas when transplanted into nude mice. No TP53 or RAS mutations were observed. Stepwise chromosomal changes in the progression to tumorigenicity were observed. Loss of the p arms of chromosome 8 (p10>pter) and chromosome 10(p10>pter) and gain of the q arm of chromosome 8 (p10>ptr) (the most frequent cytogenetic changes observed directly in prostate cancer patients) were observed only in the tumor outgrowths. These findings provide the first evidence of malignant transformation of HPE cells exposed to a chemical carcinogen.

Animals↗