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PubMed2001

Ataxia telangiectasia mutated (ATM) kinase and ATM and Rad3 related kinase mediate phosphorylation of Brca1 at distinct and overlapping sites. In vivo assessment using phospho-specific antibodies.

Recent studies have provided evidence that breast cancer susceptibility gene products (Brca1 and Brca2) suppress cancer, at least in part, by participating in DNA damage signaling and DNA repair. Brca1 is hyperphosphorylated in response to DNA damage and co-localizes with Rad51, a protein involved in homologous-recombination, and Nbs1.Mre11.Rad50, a complex required for both homologous-recombination and nonhomologous end joining repair of damaged DNA. Here, we report that there is a qualitative difference in the phosphorylation states of Brca1 between ionizing radiation (IR) and UV radiation. Brca1 is phosphorylated at Ser-1423 and Ser-1524 after IR and UV; however, Ser-1387 is specifically phosphorylated after IR, and Ser-1457 is predominantly phosphorylated after UV. These results suggest that different types of DNA-damaging agents might signal to Brca1 in different ways. We also provide evidence that the rapid phosphorylation of Brca1 at Ser-1423 and Ser-1524 after IR (but not after UV) is largely ataxia telangiectasia mutated (ATM) kinase-dependent. The overexpression of catalytically inactive ATM and Rad3 related (ATR) kinase inhibited the UV-induced phosphorylation of Brca1 at these sites, indicating that ATR controls Brca1 phosphorylation in vivo after the exposure of cells to UV light. Moreover, ATR associates with Brca1; ATR and Brca1 foci co-localize both in cells synchronized in S phase and after exposure of cells to DNA-damaging agents. ATR can itself phosphorylate the region of Brca1 phosphorylated by ATM (Ser-Gln cluster in the C terminus of Brca1, amino acids 1241-1530). However, there are additional uncharacterized ATR phosphorylation site(s) between residues 521 and 757 of Brca1. Taken together, our results support a model in which ATM and ATR act in parallel but somewhat overlapping pathways of DNA damage signaling but respond primarily to different types of DNA lesion.

Ataxia Telangiectasia↗
PubMed2003

Ataxia-telangiectasia-mutated (ATM) and NBS1-dependent phosphorylation of Chk1 on Ser-317 in response to ionizing radiation.

In mammals, the ATM (ataxia-telangiectasia-mutated) and ATR (ATM and Rad3-related) protein kinases function as critical regulators of the cellular DNA damage response. The checkpoint functions of ATR and ATM are mediated, in part, by a pair of checkpoint effector kinases termed Chk1 and Chk2. In mammalian cells, evidence has been presented that Chk1 is devoted to the ATR signaling pathway and is modified by ATR in response to replication inhibition and UV-induced damage, whereas Chk2 functions primarily through ATM in response to ionizing radiation (IR), suggesting that Chk2 and Chk1 might have evolved to channel the DNA damage signal from ATM and ATR, respectively. We demonstrate here that the ATR-Chk1 and ATM-Chk2 pathways are not parallel branches of the DNA damage response pathway but instead show a high degree of cross-talk and connectivity. ATM does in fact signal to Chk1 in response to IR. Phosphorylation of Chk1 on Ser-317 in response to IR is ATM-dependent. We also show that functional NBS1 is required for phosphorylation of Chk1, indicating that NBS1 might facilitate the access of Chk1 to ATM at the sites of DNA damage. Abrogation of Chk1 expression by RNA interference resulted in defects in IR-induced S and G(2)/M phase checkpoints; however, the overexpression of phosphorylation site mutant (S317A, S345A or S317A/S345A double mutant) Chk1 failed to interfere with these checkpoints. Surprisingly, the kinase-dead Chk1 (D130A) also failed to abrogate the S and G(2) checkpoint through any obvious dominant negative effect toward endogenous Chk1. Therefore, further studies will be required to assess the contribution made by phosphorylation events to Chk1 regulation. Overall, the data presented in the study challenge the model in which Chk1 only functions downstream from ATR and indicate that ATM does signal to Chk1. In addition, this study also demonstrates that Chk1 is essential for IR-induced inhibition of DNA synthesis and the G(2)/M checkpoint.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2004

STAR: an algorithm to Search for Tandem Approximate Repeats.

MOTIVATION: Tandem repeats consist in approximate and adjacent repetitions of a DNA motif. Such repeats account for large portions of eukaryotic genomes and have also been found in other life kingdoms. Owing to their polymorphism, tandem repeats have proven useful in genome cartography, forensic and population studies, etc. Nevertheless, they are not systematically detected nor annotated in genome projects. Partially because of this lack of data, their evolution is still poorly understood. RESULTS: In this work, we design an exact algorithm to locate approximate tandem repeats (ATR) of a motif in a DNA sequence. Given a motif and a DNA sequence, our method named STAR, identifies all segments of the sequence that correspond to significant approximate tandem repetitions of the motif. In our model, an Exact Tandem Repeat (ETR) comes from the tandem duplication of the motif and an ATR derives from an ETR by a series of point mutations. An ATR can then be encoded as a number of duplications of the motif together with a list of mutations. Consequently, any sequence that is not an ATR cannot be encoded efficiently by this description, while a true ATR can. Our method uses the minimum description length criterion to identify which sequence segments are ATR. Our optimization procedure guarantees that STAR finds a combination of ATR that minimizes this criterion. AVAILABILITY: for use at http://atgc.lirmm.fr/star

Algorithms↗
PubMed2000

The effects of atrazine on female wistar rats: an evaluation of the protocol for assessing pubertal development and thyroid function.

The effects of atrazine (ATR), a chlorotriazine herbicide, on the onset of puberty were evaluated in Wistar rats. Female rats were dosed by oral gavage from postnatal day(s) (PND) 22 through PND 41 with 0, 12.5, 25, 50, 100, or 200 mg ATR/kg. Vaginal opening (VO) was significantly delayed 3.4, 4.5, or greater than 6.8 days by 50, 100, and 200 mg/kg, respectively. VO had not occurred in 4 of 15 females in the 200 mg/kg group by the time of necropsies (PND 41). Body weight (bw) at necropsy was reduced in the 200 mg/kg group by 11.6%, but was not different from the control (0) in the 50 and 100 mg/kg groups. To examine the influence of reduced bw on pubertal development, a group of pair-fed controls was included whose daily food intake was dependent upon the amount consumed by their counterpart in the 200 mg/kg group. Although necropsy bw was reduced to the same extent as the ATR females, VO in the pair-fed controls was not significantly delayed. Adrenal, kidney, pituitary, ovary, and uterine weights were reduced by 200 mg/kg ATR. Serum T(3), T(4), and TSH were unaltered by ATR, which was consistent with no histopathologic/morphologic changes in the thyroid. Estrous cyclicity was monitored in a second group of females from VO to PND 149. The number of females displaying regular 4- or 5-day estrous cycles during the first 15-day interval after VO was lower in the 100 and 200 mg/kg ATR and pair-fed controls. Irregular cycles were characterized by extended periods of diestrus. By the end of the second 15-day interval (PND 57-71), no effects on estrous cyclicity were observed. These data show that ATR can delay the onset of puberty and alter estrous cyclicity in the female Wistar rat ( NOAEL of 25 mg/kg). Reduced food consumption and bw did not account for the delay in VO, because this effect was not observed in the pair-fed controls. In addition, the effect on estrous cyclicity was observed in the 100 mg/kg ATR group where no significant reduction in bw was observed.

Animals↗
PubMed1998

Effects of four anticholinesterase-anticholinergic combinations and tracheal extubation on QTc interval of the ECG, heart rate and arterial pressure.

BACKGROUND: Imbalance in cardiac sympathetic tone causes prolongation of the QTc interval of the ECG. On the other hand, impairment of the parasympathetic control of the heart rate caused by anticholinesterase-anticholinergic combinations might also affect the cardiac sympathetic tone and hence the QTc interval of the ECG. The main purpose of the present study was to compare the effects of four anticholinesterase-anticholinergic combinations used for the antagonism of the neuromuscular block on the QTc interval of the ECG, heart rate and arterial pressure. METHODS: Eighty-four ASA class I-II patients with a mean age of 32 to 37 yr undergoing otolaryngological surgery were randomly allocated to one of the following groups: neostigmine 40 microg/kg+glycopyrronium 8 microg/kg (Ne-Glyc), neostigmine 40 microg/kg+atropine 20 microg/kg (Ne-Atr), edrophonium 200 microg/kg+atropine 300 microg (Edr-Atr (1)), edrophonium 500 microg/kg+atropine 7 microg/kg (Edr-Atr (2)). QTc interval and heart rate were measured by a signal processing method based on an IBM/PC/xT-compatible microcomputer and arterial pressure with a sphygmomanometer at 1-min intervals up to 10 min after the injection of the drugs and immediately and 2 min after extubation. The ECG, lead II, was continuously recorded. Neuromuscular block was measured by a Datex relaxograph. RESULTS: In all groups, the most pronounced increase in both QTc interval, heart rate and arterial pressure occurred 1 min after the study drugs and immediately after extubation. In all groups, the mean QTc intervals at 1 and 2 min after the study drugs and after extubation were longer than the upper limit of the normal range (440 ms). Junctional rhythm occurred in 1 to 3 patients in all other groups with the exception of the Edr-Atr(1) group in which no cardiac arrhythmias occurred. At 1 min, the heart rate in the Ne-Atr group was at a significantly higher level than that in the Ne-Glyc group. From 3 to 6 min, the heart rate in the Edr-Atr(2) group and at 3 min in the Edr-Atr(1) group was at a lower level than the heart rate in the Ne-Glyc group. CONCLUSIONS: On the basis of the present results, anticholinesterase-anticholinergic combinations should be avoided in patients having a long QT interval syndrome or a prolonged QT interval from other causes. In addition, the cardiovascular stimulation caused by tracheal extubation should also be avoided in these patients.

Adult↗
PubMed2006

Acute transfusion reactions in the pediatric intensive care unit.

BACKGROUND: Acute transfusion reactions (ATRs) are probably underdiagnosed in critically ill children because associated symptoms can frequently be attributed to the patient's underlying disease. This study was undertaken to determine the incidence, type, imputability, and severity of ATRs observed in a tertiary care pediatric intensive care unit (PICU). STUDY DESIGN AND METHODS: All transfusions of labile blood product administered to consecutive patients admitted to our PICU, between February 2002 and February 2004, were prospectively recorded. For each transfusion, the bedside nurse recorded the patient's status before, during, and up to 4 hours after the transfusion, as well as the presence of any new sign or symptom suggesting an ATR. Three independent experts retrospectively reviewed all transfusion event reports and hospital charts. The presence, type, imputability, and severity of ATRs were adjudicated by consensus of two of three experts (Delphi method), with predefined criteria. RESULTS: A total of 2509 transfusions were administered to 305 patients during the study. Forty transfusion events (1.6%) were confirmed to be ATRs by expert consensus: 24 febrile nonhemolytic, 6 minor allergic, 4 isolated hypotension, 3 bacterial contamination, 1 major allergic (anaphylactic shock), 1 TRALI, and 1 hemolytic reaction. Imputability of ATRs was probable or possible in 35 cases (88%). ATRs led to an immediate vital threat in 15 percent of cases. CONCLUSION: Improved surveillance of transfusions given to PICU patients and better knowledge of these reactions by health care professionals should improve the safety of transfusions in the PICU.

Acute Disease↗
PubMed2006

Acid tolerance of Streptococcus macedonicus as assessed by flow cytometry and single-cell sorting.

An in situ flow cytometric viability assay employing carboxyfluorescein diacetate and propidium iodide was used to identify Streptococcus macedonicus acid tolerance phenotypes. The logarithmic-phase acid tolerance response (L-ATR) was evident when cells were (i) left to autoacidify unbuffered medium, (ii) transiently exposed to nonlethal acidic pH, or (iii) systematically grown under suboptimal acidic conditions (acid habituation). Stationary-phase ATR was also detected; this phenotype was gradually degenerated while cells resided at this phase. Single-cell analysis of S. macedonicus during induction of L-ATR revealed heterogeneity in both the ability and the rate of tolerance acquisition within clonal populations. L-ATR was found to be partially dependent on de novo protein synthesis and compositional changes of the cell envelope. Interestingly, acid-habituated cells were interlaced in lengthier chains and exhibited an irregular pattern of active peptidoglycan biosynthesis sites when probed with BODIPY FL vancomycin. L-ATR caused cells to retain their membrane potential after lethal challenge, as judged by ratiometric analysis with oxonol [DiBAC(4)(3)]. Furthermore, F-ATPase was important during the induction of L-ATR, but in the case of a fully launched response, inhibition of F-ATPase affected acid resistance only partially. Activities of both F-ATPase and the glucose-specific phosphoenolpyruvate-dependent phosphotransferase system were increased after L-ATR induction, distinguishing S. macedonicus from oral streptococci. Finally, the in situ viability assessment was compared to medium-based recovery after single-cell sorting, revealing that the culturability of subpopulations with identical fluorescence characteristics is dependent on the treatments imposed to the cells prior to acid challenge.

Adaptation, Physiological↗
PubMed1994

A low-pH-inducible, stationary-phase acid tolerance response in Salmonella typhimurium.

Acid is an important environmental condition encountered by Salmonella typhimurium during its pathogenesis. Our studies have shown that the organism can actively adapt to survive potentially lethal acid exposures by way of at least three possibly overlapping systems. The first is a two-stage system induced in response to low pH by logarithmic-phase cells called the log-phase acid tolerance response (ATR). It involves a major molecular realignment of the cell including the induction of over 40 proteins. The present data reveal that two additional systems of acid resistance occur in stationary-phase cells. One is a pH-dependent system distinct from log-phase ATR called stationary-phase ATR. It was shown to provide a higher level of acid resistance than log-phase ATR but involved the synthesis of fewer proteins. Maximum induction of stationary-phase ATR occurred at pH 4.3. A third system of acid resistance is not induced by low pH but appears to be part of a general stress resistance induced by stationary phase. This last system requires the alternative sigma factor, RpoS. Regulation of log-phase ATR and stationary-phase ATR remains RpoS independent. Although the three systems are for the most part distinct from each other, together they afford maximum acid resistance for S. typhimurium.

Bacterial Proteins↗
PubMed2001

The ToxR-mediated organic acid tolerance response of Vibrio cholerae requires OmpU.

It was previously demonstrated that the intestinal pathogen Vibrio cholerae could undergo an adaptive stress response known as the acid tolerance response (ATR). The ATR is subdivided into two branches, inorganic ATR and organic ATR. The transcriptional regulator ToxR, while not involved in inorganic ATR, is required for organic ATR in a ToxT-independent manner. Herein, we investigate the effect of organic acid stress on global protein synthesis in V. cholerae and show by two-dimensional gel electrophoresis that the stress response alters the expression of more than 100 polypeptide species. The expression of more than 20 polypeptide species is altered in a toxR strain compared to the wild type. Despite this, ectopic expression of the porin OmpU from an inducible promoter is shown to be sufficient to bypass the toxR organic ATR defect. Characterization of the effect of organic acid stress on ompU and ompT transcription reveals that while ompU transcription remains virtually unaffected, ompT transcription is repressed in a ToxR-independent manner. These transcript levels are similarly reflected in the extent of accumulation of OmpU and OmpT. Possible roles for OmpU in organic acid resistance are discussed.

Adhesins, Bacterial↗
PubMed1989

Atropine-induced cutaneous vasodilation decreases esophageal temperature during exercise.

Four healthy adult males volunteered for this study, which followed informed-consent procedures administered by our local Human Use Committee. Esophageal (Tes) and mean skin (Tsk, eight site) temperatures, forearm sweating rate (ms), metabolism (M), heart rate (HR), and forearm blood flow (FBF) were measured at rest and during forearm blood flow (FBF) were measured at rest and during exercise [55% oxygen consumption (Vo2) peak] during control experiments and after 2 mg im atropine (ATR). Experiments were randomized and separated by at least 72 h. ATR increased heart rate at rest by 15 beats/min and during exercise by 24 beats/min. ATR decreased whole body sweating by 57%. All eight local skin temperatures were higher in ATR than in control. Tsk was 32.6 degrees C in ATR and 31.0 degrees C in control (P less than 0.01). During exercise, ATR increased vasodilation of the forearm compared with control. The slope of FBF to Tes increased over 300% in ATR experiments compared with control (P less than 0.05). The higher sensible heat flux from this vasodilation decreased Tes during exercise, which further decreased sweating. Skin blood flow remained elevated as Tes decreased, suggesting that local vasodilatory factors promoted atropine-induced cutaneous vasodilation.

Adult↗
PubMed1993

Anorectal tightening reflex: role in fecal incontinence.

The present study describes the clinical significance of the anorectal tightening reflex (ATR) in normal and incontinent subjects. It was examined in 16 healthy volunteers and 11 subjects incontinent to flatus and fluid stools; 5 of the latter had in addition fecal soiling. The rectum was distended by a condom inflated with carbon dioxide, while the rectal and rectal neck (RN) (anal canal) pressures were measured, and the external (EAS) and internal anal sphincter (IAS) EMG activity was recorded. The rectum was inflated at two rates: slow and rapid. In normal subjects, the RN pressure increased upon slow rectal inflation; the IAS EMG was augmented. Pudendal nerve block and phentolamine administration revealed that this pressure increase is due to increased IAS tone which tightens the RN against the slow rectal filling by the time adaptive reaction occurs. Rapid rectal filling evoked Gower's rectoinhibitory reflex. Thus, while increased IAS tone in the ATR protects against involuntary incontinence upon 'slow' rectal filling, the increased EAS tone of Gower's reflex protects in the case of 'rapid' filling. Of the 11 incontinent patients, the 5 with fecal soiling did not show ATR, and investigative results pointed to the IAS as being responsible for incontinence. The other 6 patients had normal ATR but nonresponsive EAS on rapid filling. Findings suggest that the ATR plays a role in maintaining continence during slow rectal distension and that a disordered ATR due to IAS dysfunction leads to fecal incontinence. Thus ATR may be useful as an investigative tool in anorectal disorders.

Adult↗
PubMed2004

Vitamin A activation of transforming growth factor-beta1 enhances porcine ileum wound healing in vitro.

Treatment with transforming growth factor-beta(1) (TGF-beta(1)) has been shown to be effective in accelerating skin wound healing. Another approach to gain the beneficial effects of TGF-beta(1) on wound healing could be the activation of tissue stores of latent TGF-beta(1) with agents such as vitamin A. The aims of this study were to determine whether 1) vitamin A is effective in enhancing intestinal wound healing in vitro and 2) activation of TGF-beta(1) is increased during wound healing with vitamin A treatment. We used the intraluminal chemical induction model of necrotizing enterocolitis (NEC), which was adapted to the 1-wk-old piglet. Injured (NEC) and noninjured full-thickness ileum explants harvested from the piglets were cultured for 24 and 48 h in serum-free medium supplemented with all-trans retinol (ATR; 0, 2, 5, and 10 microM). All concentrations of ATR improved recovery of normal ileal wall cytoarchitecture of NEC explants, with maximal recovery observed with 2 microM ATR after 24 h of culture. Further recovery after 48 h was observed with 5 and 10 microM ATR but did not achieve the degree of healing observed with 2 microM ATR. There were no observable adverse effects of ATR on noninjured ileal explant morphology. Active TGF-beta(1) was identified only in the NEC explants incubated with ATR. The results of this study demonstrate that administration of vitamin A accelerates recovery of normal intestinal wall cytoarchitecture of injured ileum in vitro, without adversely affecting noninjured ileum. The increased activation of latent TGF-beta(1) may, in part, be responsible for the accelerated healing of injured ileum observed with vitamin A administration.

Animals↗
PubMed1994

Factors affecting mammary tumor incidence in chlorotriazine-treated female rats: hormonal properties, dosage, and animal strain.

Chlorotriazines are widely used in agriculture as broadleaf herbicides. The compounds specifically inhibit photosynthesis, and, as such, display little interaction with animal systems. However, a 24-month feeding study with atrazine (ATR) revealed a significant dose-related increase of mammary tumors in female Sprague-Dawley (SD) rats. Because numerous studies indicated that ATR had a low mutagenic and oncogenic potential, it was decided to test a hypothesis that the herbicide possessed endocrine activity. Among tests for estrogenic action, oral dosing of ATR up to 300 mg/kg did not stimulate uterine weight of ovariectomized rats. However, ATR administration did reduce estrogen-stimulated uterine weight gain. Further evidence of inhibition came from measures of [3H]-thymidine incorporation into uterine DNA of ATR-treated immature rats. Again, no intrinsic estrogenic activity was observed up to a 300-mg/kg dose. In vitro, ATR competed poorly against estradiol binding to cytosolic receptors, with an approximate IC50 of 10(-5) M. Atrazine administration to SD and Fischer-344 (F-344) rats for 12 months, up to 400 ppm in food, was correlated with significant alterations of estrous cycling activity; but there was a divergent strain response. SD rats showed an increased number of days in vaginal estrus, increased plasma estradiol, and decreased plasma progesterone by 9 to 12 months of treatment. F-344 rats did not demonstrate treatment-related affects. A study of ultrastructure in the hypothalamic arcuate nucleus of female SD rats that were fed diaminochlorotriazine (DACT), an ATR metabolite, suggested that age-associated glial pathology was enhanced by treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Light-induced damage to the retina: role of rhodopsin chromophore revisited.

The presence of the regenerable visual pigment rhodopsin has been shown to be primarily responsible for the acute photodamage to the retina. The photoexcitation of rhodopsin leads to isomerization of its chromophore 11-cis-retinal to all-trans-retinal (ATR). ATR is a potent photosensitizer and its role in mediating photodamage has been suspected for over two decades. However, there was lack of experimental evidence that free ATR exists in the retina in sufficient concentrations to impose a risk of photosensitized damage. Identification in the retina of a retinal dimer and a pyridinium bisretinoid, so called A2E, and determination of its biosynthetic pathway indicate that substantial amounts of ATR do accumulate in the retina. Both light damage and A2E accumulation are facilitated under conditions where efficient retinoid cycle operates. Efficient retinoid cycle leads to rapid regeneration of rhodopsin, which may result in ATR release from the opsin "exit site" before its enzymatic reduction to all-trans-retinol. Here we discuss photodamage to the retina where ATR could play a role as the main toxic and/or phototoxic agent. Moreover, we discuss secondary products of (photo)toxic properties accumulating within retinal lipofuscin as a result of ATR accumulation.

Humans↗
PubMedDate not supplied

The effect of five forage species on transport and transformation of atrazine and isoxaflutole (balance) in lysimeter leachate.

A field lysimeter study with bare ground and five different ground covers was established to evaluate the effect of forage grasses on the fate and transport of two herbicides in leachate. The herbicides were atrazine (ATR; 2-chloro-4-ethylamino-6-isopropylamino-1,3,5-triazine) and isoxaflutole [IXF; 5-cyclopropyl-4-(2-methylsulfonyl-4-trifluormethyl-benzoyl)isoxazole], which has the commercial name Balance (Aventis Crop Science, Strasbourg, France). The ground covers included orchardgrass (Dactylis glomerata L.), smooth bromegrass (Bromus inermis Leyss.), tall fescue (Festuca arundinacea Schreb.), timothy (Phleum pratense L.), and switchgrass (Panicum virgatum L.). The results suggested that the total IXF (parent + metabolites) showed higher mobility than ATR and its metabolites. Differences in the timing of transport reflected the rapid degradation of IXF to the more soluble, stable, and biologically active diketonitrile (DKN) metabolite in the system. Although grass treatments did not promote the hydrolysis of DKN, they significantly reduced its transport in the leachate through enhanced evapotranspiration. Grass treatments significantly enhanced ATR degradation in the leachates and soils, especially through N dealkylation, but they did not reduce total ATR transported in the leachate. Leachate from the orchardgrass lysimeters contained the highest proportion of ATR metabolites (64.2%). Timothy and smooth bromegrass treatments also displayed a significant increase in ATR metabolites in leachate. Grass-treated lysimeters showed higher microbial biomass carbon than bare ground. For ATR treatments, the proportion of metabolites in the leachate strongly correlated with the elevated soil microbial biomass carbon in forage treatments. In contrast, DKN degradation was poorly correlated with soil microbial biomass carbon, suggesting that DKN degradation is an abiotic process.

Atrazine↗
PubMed2006

Microcephalin: a causal link between impaired damage response signalling and microcephaly.

Seckel Syndrome (SS) and Primary Microcephaly (MCPH) are disorders exhibiting marked microcephaly with a head circumference less than three standard deviations below the mean. ATR-Seckel Syndrome is conferred by mutations in ataxia and telangiectasia and Rad3 related (ATR), a kinase that activates a DNA damage signalling response. Cell lines from additional SS patients, who are normal for ATR, show defective ATR signalling, suggesting that they carry mutations in other components of the ATR pathway. Primary Microcephaly is distinct from SS since patients display solely microcephaly without accompanying marked growth delay. MCPH1, the first Primary Microcephaly causative gene identified, encodes three BRCT domains, similar to other damage response proteins. Recent studies employing MCPH1 siRNA or exploiting cell lines from MCPH1 patients have shown that MCPH1 functions in the ATR-dependent DNA damage response pathway. Additionally, MCPH1 has a function in the regulation of mitotic entry that is ATR-independent and confers a characteristic phenotype of premature chromosome condensation. Recent studies will be reviewed and their relationship to the aetiology of microcephaly discussed.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2000

Is pseudophakic astigmatism a desirable goal?

PURPOSE: To determine whether pseudophakic astigmatism is a desirable goal, and if so, which one is better: against-the-rule (ATR) or with-the-rule (WTR). METHOD: Eyes were included only if they had an uncorrected vision > or = 6/18 and N/18. Three groups, of 40 patients each were evaluated: group 1, pseudophakes with neutral astigmatism; group 2, with ATR and group 3, with WTR astigmatism Unaided distance and near visual acuity was recorded. Statistical analysis was performed using the chi-square test for independence. RESULTS: Unaided distance vision of > or = 6/7.5 was achieved in 19 eyes (47.5%) of group 1 (neutral), 12 eyes (30%) in group 2 (ATR), and 5 eyes (12.5%) in group 3 (WTR) (p = 0.0133, significant). Unaided near vision of > or = N/9 was achieved in 17 eyes (42.5%) in group 1 (neutral), 34 eyes (85%) in group 2 (ATR), and 10 eyes (25%) in group 3 (WTR) (P < 0.001, significant). Group 1 (neutral) fared the best for unaided distance visual acuity. Group 2 (ATR) was better than in group 3 (WTR) for distant vision. Group 2 (ATR) fared the best for unaided near vision. CONCLUSION: ATR astigmatism could be a desirable goal after cataract extraction in selected populations because the largest proportion of these cases achieved good unaided near vision with acceptable distant vision.

Astigmatism↗
PubMed2000

Learning deficits induced by 4 belladonna alkaloids are preferentially attenuated by tacrine.

AIM: To examine the antagonism of tacrine on the amnesic effects of scopolamine (Sco), anisodine (AT3), atropine (Atr), and anisodamine (Ani). METHODS: Cognitive functions and locomotor activities were determined using two sessions of step-through and open-field tests, respectively. Mice were injected with one of the belladonna alkaloids (0.05-50 mumol.kg-1, i.p.) and tacrine (50 mumol.kg-1, s.c.) 30 min before the first session. RESULTS: Tacrine completely blocked the avoidance-learning deficit caused by Sco 0.5 mumol.kg-1, AT3 and Atr 5 mumol.kg-1, or Ani 50 mumol.kg-1. But tacrine partly antagonized the learning deficit induced by Sco 5-50 mumol.kg-1 or Atr and AT3 50 mumol.kg-1. The avoidance-memory deficit caused by Sco 0.05-5 mumol.kg-1 or Atr 5 mumol.kg-1 was completely or partly attenuated by tacrine, which did not antagonize the memory deficit elicited by Sco and Atr 50 mumol.kg-1, AT3 5 and 50 mumol.kg-1, and Ani 50 mumol.kg-1. During the acquisition, the locomotor activity of the mice was inhibited by tacrine. This reduction was completely antagonized by Sco 0.5-50 mumol.kg-1, AT3 5-50 mumol.kg-1, Atr 5-50 mumol.kg-1, and only partly antagonized by AT3 and Atr 0.5 mumol.kg-1 or Ani 50 mumol.kg-1. CONCLUSION: Compared with the avoidance-memory deficit, the avoidance-learning deficit caused by belladonna alkaloids is more preferentially attenuated by tacrine.

Animals↗