Risperidone and clozapine for treatment-resistant schizophrenia.
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Antipsychotic Agents↗
Biomedical subjects
A Chatterjee
Publications and source records attributed to A Chatterjee.
Endothelin-1 modulates insulin signaling through phosphatidylinositol 3-kinase pathway in vascular smooth muscle cells.
Diminished insulin action in the vasculature may contribute to the development of cardiovascular diseases in diabetes. We have studied insulin's effects on the phosphatidylinositol (PI) 3-kinase pathway in arterial smooth muscle cells (SMCs) and its inhibition by endothelin (ET)-1, a potent vasoactive hormone reported to be elevated in insulin resistance and other vascular diseases. ET-1 increased the level of serine phosphorylation of insulin receptor beta subunit but increased both tyrosine and serine phosphorylation of insulin receptor substrate (IRS)-2. Pretreatment of cells with ET-1 (10 nmol/l) inhibited insulin-stimulated PI 3-kinase activity associated with IRS-2 by 50-60% and inhibited the association of p85 subunit of PI 3-kinase to IRS-2. The inhibition of insulin-stimulated PI 3-kinase activity by ET-1 was prevented by BQ-123, a selective ET(A) receptor antagonist, but was not affected by pertussis toxin. Treatment of cells with phorbol 12-myristate 13-acetate, an activator of protein kinase C (PKC), reduced both insulin-stimulated PI 3-kinase activity by 57% and the association of IRS-2 to the p85 subunit of PI 3-kinase by 40%, whereas GF109203X, a specific inhibitor of PKC, partially prevented the inhibitory effect of ET-1 on insulin-induced PI 3-kinase activity. These results suggested that ET-1 could interfere with insulin signaling in SMCs by both PKC-dependent and -independent pathways.
Animals↗
Antioxidant activity of active tannoid principles of Emblica officinalis (amla).
The antioxidant activity of tannoid active principles of E. officinalis consisting of emblicanin A (37%), emblicanin B (33%), punigluconin (12%) and pedunculagin (14%), was investigated on the basis of their effects on rat brain frontal cortical and striatal concentrations of the oxidative free radical scavenging enzymes, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX), and lipid peroxidation, in terms of thiobarbituric acid-reactive products. The results were compared with effects induced by deprenyl, a selective monoamine oxidase (MAO) B inhibitor with well documented antioxidant activity. The active tannoids of E. officinalis (EOT), administered in the doses of 5 and 10 mg/kg, i.p., and deprenyl (2 mg/kg, i.p.), induced an increase in both frontal cortical and striatal SOD, CAT and GPX activity, with concomitant decrease in lipid peroxidation in these brain areas when administered once daily for 7 days. Acute single administration of EOT and deprenyl had insignificant effects. The results also indicate that the antioxidant activity of E. officinalis may reside in the tannoids of the fruits of the plant, which have vitamin C-like properties, rather than vitamin C itself.
Animals↗
Chromatin conformation in living cells: support for a zig-zag model of the 30 nm chromatin fiber.
A new method was used to probe the conformation of chromatin in living mammalian cells. The method employs ionizing radiation and is based on the concept that such radiation induces correlated breaks in DNA strands that are in spatial proximity. Human dermal fibroblasts in G0 phase of the cell cycle and Chinese hamster ovary cells in mitosis were irradiated by X-rays or accelerated ions. Following lysis of the cells, DNA fragments induced by correlated breaks were end-labeled and separated according to size on denaturing polyacrylamide gels. A characteristic peak was obtained for a fragment size of 78 bases, which is the size that corresponds to one turn of DNA around the nucleosome. Additional peaks between 175 and 450 bases reflect the relative position of nearest-neighbor nucleosomes. Theoretical calculations that simulate the indirect and direct effect of radiation on DNA demonstrate that the fragment size distributions are closely related to the chromatin structure model used. Comparison of the experimental data with theoretical results support a zig-zag model of the chromatin fiber rather than a simple helical model. Thus, radiation-induced damage analysis can provide information on chromatin structure in the living cell.
Animals↗
Modulation of mitomycin C-induced sister chromatid exchanges and cell cycle delay by buthionine sulfoximine and reduced glutathione in mouse bone marrow cells in vivo.
Mitomycin C (MMC) is a bifunctional alkylating agent and a chemotherapeutic drug, covalently binds to the DNA of cells and produces monoadducts and DNA-DNA, DNA-protein crosslinks, induces damages at chromosomal level and slows down the rate of cell proliferation. Reduced glutathione (GSH), a major non-protein thiol substance plays an important role in detoxification of cells against the toxic effect of exogenous compounds. In order to understand the role of factor which affects MMC sensitivity, we have made an attempt to establish a relationship between MMC-induced DNA damages and the endogenous GSH-status of the cells. MMC was treated to normal and buthionine sulfoximine (BSO; GSH-depleting agent)-treated mice. Exogenous GSH was also added to MMC-treated normal mice. Cells were fixed at 24 h and sister chromatid exchanges (SCEs) and average generation time (AGT) were scored. MMC-induced SCEs and cell cycle delay significantly with respect to control and the frequency of SCEs was increased considerably while MMC treatment combined with either GSH or BSO. The induction of cell cycle delay by MMC was reduced significantly when GSH or BSO was present along with MMC. These observations indicate that the factor responsible for inducing delay in cell cycle after MMC treatment may not be relevant for SCE-induction.
Animals↗
Motor minds and mental models in neglect.
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Brain↗
Weigh(t)ing for awareness.
We wished to learn if weight perception can be extinguished by studying two patients with right hemisphere brain damage. When lifting weights simultaneously, a patient with right frontal damage was not biased in her judgments of which weight was heavier. By contrast, a patient with right parietal damage reported left-sided weights as being lighter than those on the right. Psychophysical power functions revealed that her awareness of increasing weights on the left was dampened compared to the right when lifting weights individually on each side. Strikingly, her awareness of weight changes on the left was completely abolished when she lifted weights in both hands simultaneously. She demonstrated an unusual split in awareness, being motorically aware of and actively engaged with left-sided weights while being unaware of their incremental changes.
Aged↗
Ipsilateral neglect: reversal of bias or exaggerated cross-over phenomenon?
When right brain injury produces contralesional neglect (CN), patients typically misbisect lines to the right. However, others demonstrate so-called "ipsilateral neglect" (IN) with misbisection to the left of midpoint. Paradoxically, most patients with CN also demonstrate a 'cross-over' phenomenon whereby they misbisect short lines to the left. It is not known whether patients with IN actually have a contralesional bias opposite the ipsilesional bias observed with CN, or if their performance reflects an exaggerated cross-over. These alternatives can be distinguished by power function analysis which evaluates the relationship between magnitude of perception and stimulus magnitude. Using line bisection tasks to derive a power function, an IN patient showed a reduced exponent (beta = 0.841), falling outside 95% confidence intervals (CI) for controls but within the CI for CN patients. The IN patient showed a greatly increased constant (K = 7.82), extending outside the CI for both controls and CN patients. The results suggest that the anomalous leftward misbisection with IN is associated with an exaggerated cross-over point and not simply reversal of spatial bias.
Adult↗
Predictability of spherical photorefractive keratectomy for myopia.
OBJECTIVE: This study aimed to examine the effects of purely spherical excimer laser photorefractive keratectomy (PRK) for myopia. DESIGN: Consecutive case series. PARTICIPANTS: A total of 3218 eyes with a mean preoperative mean spherical equivalent (MSE) of -3.75 diopters (D) +/- 1.73 D standard deviation (SD) (range, -1.00 D to -11.88 D) underwent PRK with a Nidek EC-5000 excimer laser. Eyes were divided into groups based on the degree of preoperative myopia in 1 D steps. INTERVENTION: All eyes underwent PRK with a Nidek EC-5000 excimer laser. MAIN OUTCOME MEASURE: Visual and refractive outcome of PRK treatment was measured. RESULTS: After a mean follow-up period of 52.6 weeks (range, 26-150 weeks), the final MSE was -0.07 D (+/-0.68 D) (range, -5.50 D to +4.50 D). Of the 3218 eyes, 2919 (90.7%) were within 1.00 D of emmetropia, and 3038 (94.4%) of eyes had an uncorrected visual acuity of 20/40 or better, with 1886 (58.6%) achieving 20/20 or better visual acuity. Eyes in the lower preoperative myopia groups had a greater chance of attaining 20/40 unaided visual acuity than those in the higher groups (e.g., 98.3% of the -2D group and 53.6% of the -9D group achieved 20/40 unaided visual acuity). Overall, mean postoperative haze was 0.29+/-0.39 SD (scale, 0-3), and 29 eyes (0.9%) lost 0.3 or more logarithm of the minimum angle of resolution (LogMAR) unit of best-corrected visual acuity. CONCLUSIONS: Excimer laser PRK is an effective treatment for myopia of up to -9.00 D. The outcome parameters are less predictable for eyes with greater than -9.00 D of myopia.
Adult↗
Epithelial debridement for secondary hyperopia following myopic excimer laser photorefractive keratectomy.
BACKGROUND: To evaluate epithelial debridement for the treatment of persistent hyperopia in eyes that had photorefractive keratectomy (PRK). SETTING: Optimax Laser Eye Clinics, Manchester, London, Bristol, England. METHODS: Epithelial debridement was performed on 46 eyes to reduce the hypermetropia following excimer laser PRK. RESULTS: Mean age of the patients was 43 years +/- 9.7 (SD). Mean refractive change was -0.51 diopter (D) +/- 0.76 (range +0.75 to -2.50 D). Mean change in best corrected visual acuity (BCVA) was 0.00 Logmar units (range +0.40 to -0.20 units), although 33% of eyes lost one line or more of Logmar BCVA. Mean follow-up after debridement was 61.0 +/- 26.9 weeks (range 26 to 140 weeks). CONCLUSIONS: Epithelial debridement is an unpredictable procedure to treat secondary hyperopia after PRK, producing a small mean change in spherical equivalent with a wide range of results. A significant number of eyes lost one line or more of Logmar BCVA. We therefore do not advocate epithelial debridement after PRK.
Adult↗
Induction of lethal mutations in experimental tumours after single and fractionated irradiations in vivo.
PURPOSE: To investigate the prolonged reduction in cellular viability (lethal mutations) of surviving cells following irradiation of tumours in vivo and to test the effects of fractionation on the expression of lethal mutations. MATERIALS AND METHODS: A mouse mammary carcinoma (CaNT) was treated with single dose or fractionated X-ray treatments in vivo and survival quantified with an in vitro excision assay soon after irradiation and at various times up to 35 days after in vitro propagation of the surviving cells. RESULTS: A dose-dependent reduction in the plating efficiency was observed in cells isolated from irradiated tumours up to 35 days and many cell generations after irradiation. Considerable heterogeneity in plating efficiency was observed in clonal cell lines isolated from individual colonies grown from irradiated tumours. Delayed expression of lethal damage was observed after fractionated irradiation, although recovery of cellular fitness was greater than after irradiation with single doses (reported previously) suggesting that this form of damage is affected by inter-fraction repair. At equi-toxic doses, delayed expression of lethal damage was similar after three compared with two fractions of radiation per day (reported previously). CONCLUSIONS: These effects indicate that conventional excision assays of tumour cell viability under-estimate the total lethal damage caused by irradiation and have implications for modelling of the response of tumours to radiotherapy. The effect of fractionation on expression of this type of damage implies the involvement of repair processes. Therefore the repair proficiency may affect the balance between the immediate and delayed reduction of viability in irradiated cells.
Animals↗
Statistical modelling and phylogenetic analysis of a deaminase domain.
Deamination reactions are catalyzed by a variety of enzymes including those involved in nucleoside/nucleotide metabolism and cytosine to uracil (C-->U) and adenosine to inosine (A-->I) mRNA editing. The active site of the deaminase (DM) domain in these enzymes contains a conserved histidine (or rarely cysteine), two cysteines and a glutamate proposed to act as a proton shuttle during deamination. Here, a statistical model, a hidden Markov model (HMM), of the DM domain has been created which identifies currently known DM domains and suggests new DM domains in viral, bacterial and eucaryotic proteins. However, no DM domains were identified in the currently predicted proteins from the archaeon Methanococcus jannaschii and possible causes for, and a potential means to ameliorate this situation are discussed. In some of the newly identified DM domains, the glutamate is changed to a residue that could not function as a proton shuttle and in one instance (Mus musculus spermatid protein TENR) the cysteines are also changed to lysine and serine. These may be non-competent DM domains able to bind but not act upon their substrate. Phylogenetic analysis using an HMM-generated alignment of DM domains reveals three branches with clear substructure in each branch. The results suggest DM domains that are candidates for yeast, platyhelminth, plant and mammalian C-->U and A-->I mRNA editing enzymes. Some bacterial and eucaryotic DM domains form distinct branches in the phylogenetic tree suggesting the existence of common, novel substrates.
Amino Acid Sequence↗
Influence of buthionine sulfoximine and reduced glutathione on arecoline-induced chromosomal damage and sister chromatid exchange in mouse bone marrow cells in vivo.
Arecoline (ARC), an alkaloid of the betel nut (Areca catechu), is a major ingredient of betel quid. The carcinogenic potentiality as well as its cell transformation ability has already been reported. Reduced glutathione (GSH), a major non-protein thiol substance plays an important role in protection of cells against the toxic effect of exogenous compounds. In order to understand the role of factors which affect ARC sensitivity, we have made an attempt to establish a relationship between ARC-induced DNA damage and the endogenous GSH status of the cells. ARC was administered to untreated and buthionine sulfoximine (BSO) (a GSH-depleting agent)-treated mice. Exogenous GSH was also added to ARC-administered mice. Cells were fixed at 20 h and both chromosome aberrations (CAs) and sister chromatid exchanges (SCEs) were scored. Both CAs and SCEs were significantly induced by ARC and the frequency of both these parameters were increased further when ARC was given to BSO-treated mice. However, GSH reduced the frequency of CAs induced by ARC but failed to do so for SCEs. The data indicate that ARC-induced DNA damage is influenced by endogenous GSH level. The failure of GSH to reduce the frequency of SCEs indicates that the mechanism of induction of CAs and SCEs by ARC are different.
Animals↗
Reversal of resistance against doxorubicin by a newly developed compound, oxalyl bis(N-phenyl)hydroxamic acid in vitro.
A drug-resistant cell line (EAC/Dox) was developed by repeated exposure of Ehrlich ascites carcinoma cells to Doxorubicin (Dox) in vivo in male albino Swiss mice (6-8 weeks old). The weekly i.p. injections of Dox to mice (2 or 4 mg/kg/week for 4 months) gave rise to Dox-resistant cell line EAC/Dox, which displayed typical multidrug resistant (MDR) features of cross-resistance to a number of structurally and functionally unrelated drugs like doxorubicin, vinblastine and cisplatin. Moreover, the EAC/Dox cell line had lower drug accumulation than drug-sensitive (EAC/S) cells. Study of Western blots and immunofluorescence revealed that P-glycoprotein 170 kDa (P-gp) was absent in EAC/Dox cells. The drug resistance appeared to be due to the presence of a higher level of reduced glutathione (GSH) and glutathione S-transferase (GST) in EAC/Dox cells than in drug-sensitive (EAC/S) cells. The two structurally similar hydroxamic acid derivatives, i.e. oxalyl bis(N-phenyl)hydroxamic acid (X1) and succinyl bis(N-phenyl)hydroxamic acid (X2), having very low in vitro toxicity (IC50 value 250 microg/ ml), were investigated for their efficacy to reverse MDR. The compound X1 was able to reverse the effect of MDR and reduce GST in EAC/Dox cells. The compound X2 had no ability to reverse the effect of MDR. Further study on the mechanism of glutathione depletion and the resistance modifying property of X1 on other cell lines is warranted.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Disseminated candidosis in premature twins.
A unique case of disseminated candidosis in premature twins is presented where twin A developed disease soon after birth and died prior to the administration of antifungal therapy. On the other hand, twin B developed infection on the 26th day of birth but survived, though with sequelae (hydrocephalus), since he was promptly and accurately diagnosed and treated.
Candida albicans↗
The simplest walking model: stability, complexity, and scaling.
We demonstrate that an irreducibly simple, uncontrolled, two-dimensional, two-link model, vaguely resembling human legs, can walk down a shallow slope, powered only by gravity. This model is the simplest special case of the passive-dynamic models pioneered by McGeer (1990a). It has two rigid massless legs hinged at the hip, a point-mass at the hip, and infinitesimal point-masses at the feet. The feet have plastic (no-slip, no-bounce) collisions with the slope surface, except during forward swinging, when geometric interference (foot scuffing) is ignored. After nondimensionalizing the governing equations, the model has only one free parameter, the ramp slope gamma. This model shows stable walking modes similar to more elaborate models, but allows some use of analytic methods to study its dynamics. The analytic calculations find initial conditions and stability estimates for period-one gait limit cycles. The model exhibits two period-one gait cycles, one of which is stable when 0 < gamma < 0.015 rad. With increasing gamma, stable cycles of higher periods appear, and the walking-like motions apparently become chaotic through a sequence of period doublings. Scaling laws for the model predict that walking speed is proportional to stance angle, stance angle is proportional to gamma 1/3, and that the gravitational power used is proportional to v4 where v is the velocity along the slope.
Algorithms↗
Serine 257 phosphorylation regulates association of polyomavirus middle T antigen with 14-3-3 proteins.
Polyomavirus middle T antigen (MT) is phosphorylated on serine residues. Partial proteolytic mapping and Edman degradation identified serine 257 as a major site of phosphorylation. This was confirmed by site-directed mutagenesis. Isoelectric focusing of immunoprecipitated MT from transfected 293T cells showed that phosphorylation on wild-type MT occurred at near molar stoichiometry at S257. MT was previously shown to be associated with 14-3-3 proteins, which have been connected to cell cycle regulation and signaling. The association of 14-3-3 proteins with MT depended on the serine 257 phosphorylation site. This has been demonstrated by comparing wild-type and S257A mutant MTs expressed with transfected 293T cells or with Sf9 cells infected with recombinant baculoviruses. The 257 site is not critical for transformation of fibroblasts in vitro, since S257A and S257C mutant MTs retained the ability to form foci or colonies in agar. The tumor profile of a virus expressing S257C MT showed a striking deficiency in the induction of salivary gland tumors. The basis for this defect is uncertain. However, differences in activity for the wild type and mutant MT lacking the 14-3-3 binding site have been observed in transient reporter assays.
14-3-3 Proteins↗
A 44-month clinical-brain MRI follow-up in a patient with B12 deficiency.
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Brain↗