Sensory evoked potentials in patients with Rett syndrome through the lens of animal studies: Systematic review

ObjectiveSystematically review the abnormalities in event related potential (ERP) recorded in Rett Syndrome (RTT) patients and animals in search of translational biomarkers of deficits related to the particular neurophysiological processes of known genetic origin (MECP2 mutations).MethodsPubmed, ISI Web of Knowledge and BIORXIV were searched for the relevant articles according to PRISMA standards.ResultsERP components are generally delayed across all sensory modalities both in RTT patients and its animal model, while findings on ERPs amplitude strongly depend on stimulus properties and presentation rate. Studies on RTT animal models uncovered the abnormalities in the excitatory and inhibitory transmission as critical mechanisms underlying the ERPs changes, but showed that even similar ERP alterations in auditory and visual domains have a diverse neural basis. A range of novel approaches has been developed in animal studies bringing along the meaningful neurophysiological interpretation of ERP measures in RTT patients.ConclusionsWhile there is a clear evidence for sensory ERPs abnormalities in RTT, to further advance the field there is a need in a large-scale ERP studies with the functionally-relevant experimental paradigms.SignificanceThe review provides insights into domain-specific neural basis of the ERP abnormalities and promotes clinical application of the ERP measures as the non-invasive functional biomarkers of RTT pathophysiology.     

Sequence-dependent Termination of Mammalian DNA Polymerase Reaction by a New Platinum Compound, (–)-(R)-2-Aminomethylpyrrolidine(1,1-cyclobutane-dicarboxylato)-2-platinum(II) Monohydrate

We examined the mechanisms of the inhibition of DNA synthesis by a new platinum compound, (-)-( R )-2-aminomethylpyrrolidine(1,1-cyclobutane-dicarboxylato)-2-platinum(II) monohydrate (DWA-2114R), a derivative of the antitumor drug cis- diamminedichloroplatinum(II) (CDDP), using prokaryotic and eukaryotic DNA polymerases. Preincubating activated DNA with CDDP or DWA-2114R reduced its template activity for prokaryotic and eukaryotic DNA polymerases in a dose-dependent manner. DWA2114R required six times greater drug concentration and two times longer incubation time to show the same decrease of the template activity compared to CDDP. Treatment of primed pUC118 ssDNA templates with the two drugs followed by second-strand synthesis by prokaryotic and eukaryotic DNA polymerases revealed that DWA2114R bound to DNA in a similar manner to CDDP and these adducts blocked DNA elongation by DNA polymerases of eukaryotes as well as of prokaryotes. With these two drugs, the elongations by E. coli DNA polymerase I (Klenow fragment), T7 DNA polymerase and calf thymus DNA polymerase α were strongly arrested at guanine-guanine sequences (GG). Stop bands were also observed at adenine-guanine sequences (AG) guanine-adenine-guanine sequences (GAG) and mono-guanine sequence (G). Calf testis DNA polymerase β was also arrested efficiently at AG, GAG and G, but much more weakly at GG. This pattern was common to DWA2114R and CDDP.     

Thrombotic Micro‐Angiopathy with Sirolimus‐Based Immunosuppression: Potentiation of Calcineurin‐Inhibitor‐Induced Endothelial Damage?

Thrombotic microangiopathy is a rare but important finding in the context of organ transplantation. Acute renal insufficiency in the setting of hemolysis and thrombocytopenia, a triad that constitutes 'hemolytic uremic syndrome', can be associated with, or triggered by, conditions such as verocytotoxin-producing Escherichia coli, viral infections, malignant hypertension, scleroderma, allograft rejection, lupus erythematosus, pregnancy, and medications including mitomycin C, calcineurin inhibitors, and oral contraceptives. After renal transplantation, it can occur, as either a de novo episode, or recurrent disease. Calcineurin inhibitors have long been associated with post-transplantation thrombotic microangiopathy. Sirolimus has been used as a primary immunosuppressant in patients transplanted with a history of earlier hemolytic-uremic syndrome, and also as rescue therapy in patients with calcineurin-inhibitor-associated thrombotic microangiopathy. We describe four cases where there was significant thrombotic microangiopathy in the context of contemporaneous or contiguous calcineurin inhibitor and sirolimus usage. As the intrarenal cyclosporin concentration is thought to be significantly elevated when cyclosporin and sirolimus are used together, this may explain these findings, and mandates caution in their co-administration.     

Synaptic organization of cortico-cortical connections from the primary visual cortex to the posteromedial lateral suprasylvian visual area in the cat

The synaptic organization of the projection from the cat striate visual cortex to the posteromedial lateral suprasylvian cortical area (PMLS) was examined. The anterograde tracer Phaseolus vulgaris leucoagglutinin (PHA-L) was iontophorectically delivered into area 17, and anterogradely labeled fibers were revealed in PMLS by means of an immunocytochemical detection method. Most axons and presumptive terminal swellings were found in layers III and IV. The neuronal elements (n = 190) that were postsynaptic to anterogradely labeled boutons were quantitatively analyzed. All anterogradely labeled cortico-cortical boutons (n = 182) established type 1 synapses. The results show that 83% of the postsynaptic targets were dendritic spines, probably belonging to pyramidal cells. Dendritic shafts constituted 17% of the targets. The dendritic shafts postsynaptic to cortico-cortical boutons were studied for the presence of gamma-aminobutyric acid (GABA) with a postembedding immunogold method. Most dendritic shafts (85%) that were tested were found to be GABA-positive, demonstrating that they originate from local inhibitory neurons. Taking into account that most postsynaptic targets were spines and extending the results of the immunocytochemical testing to the total population of postsynaptic dendrites, it was calculated that at least 14% of targets originated from GABA-positive cells. Thus cortico-cortical axons establish direct monosynpatic connections mainly with pyramidal and to a lesser extent with GABAergic nonpyramidal neurons in area PMLS, providing both feedforward excitation and feedforward inhibition to a visual associational area known to be involved in the processing of motion information. The results are consistent with previously demonstrated deficits in physiological properties of neurons in PMLS following removal of cortico-cortical afferents.     

The effect of fluconazole and ketoconazole on the metabolism of sulphamethoxazole

1 Cytochrome P450-mediated bioactivation of sulphamethoxazole to a hydroxylamine has been implicated in the hypersensitivity reactions associated with co-trimoxazole administration. Inhibiting the formation of the hydroxylamine may be one method of preventing the high frequency of toxicity which is observed in HIV-infected patients. Therefore, in this study, we have investigated the ability of fluconazole and ketoconazole, known cytochrome P450 inhibitors, to inhibit the formation of sulphamethoxazole hydroxylamine.
2 Ten healthy male volunteers were given co-trimoxazole (800  mg sulphamethoxazole and 160  mg trimethoprim) alone or 1  h after either fluconazole (150  mg) or ketoconazole (200  mg) in a randomized fashion with a washout period of at least 1 week between each phase. Urine was collected for 24  h, and sulphamethoxazole and its metabolites were quantified by electrospray LC-MS.
3 Ketoconazole had no effect on the urinary recovery of sulphamethoxazole or any of its metabolites. In contrast, fluconazole significantly ( P <0.001) inhibited the formation of sulphamethoxazole hydroxylamine by 50.0±15.1%. Fluconazole also inhibited the oxidation of sulphamethoxazole to the 5-methylhydroxy and 5-methylhydroxy acetate metabolites by 69.9±15.8% and 64.0±12.0%, respectively, but had no effect on the amount of sulphamethoxazole, N₄-acetyl sulphamethoxazole, or sulphamethoxazole N₁-glucuronide excreted in urine.
4 The potential clinical benefit of using fluconazole to prevent hypersensitivity to co-trimoxazole in patients with AIDS needs to be assessed in a prospective study using both metabolite formation and the clinical occurrence of adverse reactions as end-points.     

THE INTERACTION BETWEEN ENALAPRILAT AND SELECTED α-ADRENOCEPTOR ANTAGONISTS IN ISOLATED RAT TAIL ARTERIES

1. Isolated perfused rat tail artery preparations were used to investigate the effects of the angiotensin converting enzyme inhibitor enalaprilat on the actions of a series of α-adrenoceptor antagonists. The agonist used was phenylephrine. 2. Enalaprilat (1 μmol/L) potentiated the competitive α₁-adrenoceptor antagonist actions of phentolamine (10–100 nmol/L) and yohimbine (0.3–3.0 μmol/L) as well as the non-competitive antagonist action of phenoxybenzamine (50–100 pmol/L). 3. The competitive α₁-adrenoceptor antagonist action of prazosin (1–10 nmol/L) was not affected by enalaprilat. 4. For the competitive α₁-adrenoceptor antagonists, including prazosin, there appeared to be an inverse relationship between antagonist potency and the extent of potentiation by enalaprilat. 5. The results support the hypothesis and angiotensin II modulates vascular smooth muscle α₁-adrenoceptor function.     

Competition for sucrose-pellets in triads of male wistar rats: effects of acute and subchronic chloridazepoxide

Within triads of male Wistar rats, some animals almost completely abstain from competition for palatable sucrose pellets (so-called poor-performing rats), whereas other rats consistently win the competition (so-called high-performing rats). Subchronic (5 mg/kg; 5 consecutive days), but not acute (0.1–20 mg/kg), treatment with chlordiazepoxide temporarily helped poor-performing rats to behave more competitively. This finding, considered together with parallel studies (using high-performing rats), suggested that chloridazepoxide's beneficial effect was only demonstrable when the poor-performing rats had become tolerant to the drug's initial sedative effect.     

Proliferation of DU145 prostate cancer cells is inhibited by suppressing insulin-like growth factor binding protein-2

BACKGROUND: Insulin-like growth factor binding protein-2 (IGFBP-2) is expressed by all human prostate cancer cell lines and dramatically increases in the serum of prostate cancer patients. However, the role of IGFBP-2 in prostatic tumorigenesis is not known. The aim of the present study was to investigate the effects of IGFBP-2 on the proliferation of DU145 human prostate cancer cells in culture. METHODS: Using cell proliferation assays, we examined the effects of exogenously administered and endogenously modulated levels of IGFBP-2 on the proliferation of DU145 cells. RESULT: Cell growth was stimulated by exogenously administered IGFBP-2, but significantly retarded (P < 0.05) by its neutralizing antibody. Overexpression of IGFBP-2 by transfection also stimulated cell growth, which was significantly (P < 0.05) inhibited in transfectants expressing antisense mRNA to IGFBP-2. Furthermore, the proliferation of IGFBP-2 overexpressing cells was significantly dampened by exogenously administered IGFBP-2 antibody. CONCLUSIONS: IGFBP-2 is an autocrine growth factor for DU145 human prostate cancer cells and cell proliferation can be significantly retarded by neutralizing or inhibiting its synthesis. These findings provide a strong rationale for targeting IGFBP-2 in the testing of novel strategies to treat prostate cancer.     

牡蛎功能短肽的制备及ACE抑制活性

以新鲜无壳牡蛎为原料,采用酶水解的方法制备牡蛎短肽,经SephadexG 15分离,并用HPLC测定其相对分子质量分布,通过HPLC法定量马尿酸测定各组分的ACE(血管紧张素转化酶)抑制活性。结果表明,牡蛎水解液中相对分子质量较大和较小部分的ACE抑制活性偏低,只有相对分子质量在一定范围内的短肽,对ACE具有较好的抑制作用,质量浓度为0.4mg/mL的牡蛎功能短肽的ACE抑制率为51.4%.     

Effect of etodolac on the prostaglandin concentrations in the kidney of the normal rat

The effect of acute and subchronic dosing with etodolac on the renal PGE₂ and 6-keto-PGF_1α concentrations in the normal rat were studied. Etodolac and other nonsteroidal antiinflammatory drugs (NSAIDs) were administered orally, at equieffective antiinflammatory doses, to normal rats either as a single dose or as seven daily doses. Whole kidney prostaglandin (PG) concentrations were measured. In the acute study, etodolac (3 mg/kg) did not significantly lower the PGE₂ levels for up to 4 hr postdosing. In contrast, naproxen (3 mg/kg) and piroxicam (0.5 mg/kg) significantly decreased the PGE₂ levels to about 20% and 60% of control, respectively. Similar reductions in 6-keto-PGF_1α concentrations were observed. In the subchronic study, etodolac (3 mg/kg/day) did not lower either PGF₂ or 6-keto-PGF_1α concentrations whereas naproxen (3 mg/kg/day), piroxicam (0.5 mg/kg/day), indomethacin (1 mg/kg/day), and aspirin (300 mg/kg/day) significantlydecreased both PGs. In both studies, the effect of etodolac was significantly different from that of the NSAIDs. It is concluded that etodolac possesses only a very weak capacity to lower renal PGs, and therefore is unlikely to cause any renal complications related to PG biosynthesis inhibition.