Apoptosis of hypothalamic neurosecretory cells in stress mice at different stages of ontogenesis

The aim of the present work was to identify the role of cycloferon in the apoptosis of cells in the neurosecretory centers of the hypothalamus in young and old mice in conditions of immobilization stress. Apoptotic cells were identified by staining with ethidium bromide. The optical density of the detection product of the antiapoptotic protein Bcl-2 was also studied in cells of the supraoptic and paraventricular (PVN) nuclei. Cycloferon was found to decrease the level of apoptosis in the neurosecretory centers of the hypothalamus via a Bcl-2-independent pathway. Administration of cycloferon before stress had no effect on the number of apoptotic cells, except in the PVN of old mice, where apoptosis was inhibited. __________ Translated from Morfologiya, Vol. 127, No. 3, pp. 27–29, May–June, 2005.     

Population Pharmacokinetic Measures,Their Estimation and Selection of Sampling Times

In pharmacokinetic (PK) studies, including bioavailability assessment, various population PK measures, such as area under the curve (AUC), maximal concentration (C _max ) and time to maximal concentration (T _max ) are estimated. In this paper we compare a model-based approach, where parameters of a compartmental model are estimated and the explicit formulae for PK measures are used, and a model-independent approach, where numerical integration algorithms are used for AUC and sample estimates for C _max and T _max . Since regulatory agencies usually require the model-independent estimation of PK measures, we focus on the empirical approach while using the model-based approach and corresponding measures as a benchmark. We show how to “split” a single sampling grid into two or more subsets, which substantially reduces the number of samples taken for each patient, but often has little effect on the precision of estimation of PK measures in terms of mean squared error (MSE). We give explicit formulae for the MSE of the empirical estimator of AUC for a simple example and discuss how costs may be taken into account.     

Antibody responses against B-cell epitopes of the hypervariable region 1 of hepatitis C virus in self-limiting and chronic human hepatitis C followed-up using consensus peptides.

A rare collection of serum samples from patients with hepatitis C virus (HCV) infection followed up from the onset of clinical symptoms was acquired. RNA corresponding to the hypervariable region 1 (HVR1) of E2 protein of HCV isolated from nine patients was reverse-transcribed, amplified, sequenced, and HVR1 amino acid sequences were deduced. These sequences and a selection of HVR1 amino acid sequences of matching HCV genotypes from protein and translated DNA sequence databanks were used to create the HVR1 amino acid consensus. The degenerated peptides mimicking N- and C-termini of the consensus were synthesized. Most (76%) of 17 patients followed up for the period from 1 week to a minimum of 7 months from the onset of acute symptoms developed antibodies reacting with peptides representing N- and/or C- termini of HVR1. Antibody recognition of the consensus HVR1 peptides indicates that the variability of HVR1 sequence on the protein level is limited with certain conserved structure(s) being untouched. A tendency was observed for a slower development of anti-HVR1 antibody response in patients developing chronic HCV, as compared to those with self-limiting HCV infection.     

Determination of the number of active centers and of the propagation rate constant for ethylene polymerization on supported Ni-containing catalysts by using 14CO

Ethylene polymerization on supported Ni-containing catalysts was studied using ¹⁴CO as the inhibitor and as a label for determining the number of active centers (AC). The polymerization rate decreases sharply after introducing a mole ratio ¹⁴CO/Ni = 0.5 ÷ 1 and recovers after the removal of ¹⁴CO. The number of labels in the polymer and in the liquid phase (hexane) increases with the amount of ¹⁴CO introduced and with ¹⁴CO contact time (τ_co). In the absence of ethylene the number of labels in the polymer does not increase with τ_co and the number of labels in the liquid phase is essentially less than in the presence of ethylene. The rate of the label accumulation in the polymer during short contact times (τ_co = 5 min) is essentially higher than that during the following periods of time (τ_co = 5–135 min). Fast label accumulation occurs through first ¹⁴CO molecule insertion into the Ni-polymer bond, and the slower one through copolymerization of ¹⁴CO with ethylene, i.e. when the second and more ¹⁴CO molecules insert into the polymer chain. Catalyst activity and the number of AC (in the range of 1.5 to 6% of Ni content) decrease with polymerization time. For both catalysts the values of the propagation rate constant are maximum at short polymerization time (5 to 15 min) and equal to (3 ± 0.8) · 10³ L/(mol · s) at 65°C.     

Endoscopic mucosal resection of non-ampullary sporadic duodenal adenomas: a retrospective analysis with long-term follow-up

Objective: We investigate the efficiency of endoscopic mucosal resection (EMR) of non-ampullary sporadic duodenal adenomas (NASDA) in a retrospective analysis with long-term follow-up.

Methods: Consecutive patients undergoing EMR of NASDA between May 2002 and December 2016 were retrospectively identified from an electronic database. Endoscopic follow-up was scheduled after 3, 6 and 12 months for the first year, then yearly for up to five years.

Results: EMR of 75 NASDA was performed in 68 patients (56% en-bloc, 44% piecemeal). Retroperitoneal perforations occurred in 3/68 (4.4%) patients, were treated by surgical (n?=?2) or percutaneous (n?=?1) drainage; delayed bleeding was reported in 13/75 (17.3%) resections and was successfully managed by endoscopy (n?=?12) or radiologic embolization (n?=?1). There was no procedure-related mortality. Follow-up was available in 61/68 patients (89.7%) after a median time of 59 months from resection. Residual and recurrent adenoma were diagnosed in 9 (14.5%) and 6 (10.9%) cases, respectively; all but one were successfully retreated endoscopically.

Conclusions: EMR for NASDA is effective with a favorable long-term outcome. Local recurrences can be retreated endoscopically. A recall system, patient’s compliance to endoscopic follow-up are mandatory to detect recurrences and their prompt treatment.     

Structural study of compounds modelling elementary polymer units, 2. Molecular and crystal structures of bis[(3-pentafluorophenoxy)phenyl] 4,4′-oxydibenzoate and octafluorobiphenyl-4,4′-diylbis(oxy-1,3-phenylene) dibenzoate

This paper discusses the synthesis and X-ray studied of bis[(3-pentafluorophenoxy)phenyl] 4,4′-oxydibenzoate ( 10 ) and octafluorobiphenyl-4,4′-diylbis(oxy-1,3-phenylene) dibenzoate ( 11 ). These compounds are differently chosen models of the elementary unit of a polyarylate based on fluorinated bisphenols and aromatic dicarboxylic acids. Structures of 10 and 11 provide data on the conformational flexibility and the predominant was of arrangement of polyarylate chains.     

Selective cyclooxygenase-2 silencing mediated by engineered E. coli and RNA interference induces anti-tumour effects in human colon cancer cells

Background:

Cyclooxygenase-2 (COX-2) overexpression is strongly associated with colorectal tumourigenesis. It has been demonstrated that the chronic use of non-steroidal anti-inflammatory drugs (COX inhibitors) partially protects patients from colorectal cancer (CRC) development and progression but induces severe cardiovascular side effects. New strategies for selective COX-2 blockade are required.

Methods:

We developed an improved technique, based on RNA interference (RNAi), to gain a selective COX-2 silencing in CRC cells by a tumour-dependent expression of anti-COX-2 short-hairpin RNA (shCOX-2). Anti-COX-2 shRNA-expressing vectors were delivered in CRC cells (in vitro) and in colon tissues (ex vivo) using engineered Escherichia coli strains, capable of invading tumour cells (InvColi).

Results:

A highly tumour-dependent shCOX-2 expression and a significant COX-2 silencing were observed in CRC cells following InvColi strain infection. Cyclooxygenase-2 silencing was associated with a strong reduction in both proliferative and invasive behaviour of tumour cells. We also demonstrated a pivotal role of COX-2 overexpression for the survival of CRC cells after bacterial infection. Moreover, COX-2 silencing was achieved ex vivo by infecting colon tissue samples with InvColi strains, leading to anti-inflammatory and anti-tumour effects.

Conclusion:

Our RNAi/InvColi-mediated approach offers a promising tool for a highly selective COX-2 blockade in vitro and in vivo.     

Modelling, prediction and adaptive adjustment of recruitment in multicentre trials

This paper is focused on statistical modelling, prediction and adaptive adjustment of patient recruitment in multicentre clinical trials. We consider a recruitment model, where patients arrive at different centres according to Poisson processes, with recruitment rates viewed as a sample from a gamma distribution. A statistical analysis of completed studies is provided and properties of a few types of parameter estimators are investigated analytically and using simulation. The model has been validated using many real completed trials. A statistical technique for predictive recruitment modelling for ongoing trials is developed. It allows the prediction of the remaining recruitment time together with confidence intervals using current enrolment information, and also provision of an adaptive adjustment of recruitment by calculating the number of additional centres required to accomplish a study up to a certain deadline with a pre-specified probability. Results are illustrated for different recruitment scenarios.     

Metal-free C–H arylation of imidazoheterocycles with aryl hydrazines

A simple and efficient metal-free arylation of imidazo[1,2-a]pyridines at the C-3 position with arylhydrazine has been achieved at room temperature under ambient air conditions. Various 2,3-disubstituted imidazopyridines and imidazothiazoles were synthesized with high yields. The present methodology demonstrates the usefulness of commercially available aryl hydrazine as an arylating agent.

Metal-free C–H arylation of imidazo[1,2-a]pyridines at C-3 position with arylhydrazines in presence of DBU has been developed at room temperature under ambient air.