Phase I trial of the polyelectrolyte carbetimer administered i.v. once every four weeks

Summary Carbetimer, a new synthetic low molecular weight polyelectrolyte with a novel structure displayed antitumor activiy in a number of animal tumor model systems and in vitro investigations. Based on these findings it was brought to a phase I clinical trial in patients with advanced malignant disease after failure of conventional treatment or with no conventional treatment available. Forty-eight patients received 98 courses. The schedule was a one hour i.v. infusion every four weeks. The starting dose was 180 mg/m² and dose escalation was performed according to a modified Fibonacci formula up to 16,690 mg/m². At least three patients were treated at each dose level and each patient was eligible to receive repeat courses at the same dose, until progressive disease or dose-limiting toxicity intervened. No hematological toxicity was encountered. Some adverse effects such as reversible proteinuria, hypercalcaemia, pain at infusion site, nausea and vomiting and fatigue were seen partly in a dose-related manner but did not represent the maximum tolerated dose (MTD). The limiting toxicity at the highest dose level of 16,690 mg/m² consisted of ocular symptoms (light flashes) accompanied by a modest decrease of blood pressure and nausea or vomiting during a one hour infusion. 16,690 mg/m²/1 hour was considered the MTD. There were four deaths on study, all considered diseaserelated. Fourteen patients had stable disease for more than two courses, which, however, could also be explained by the natural course of disease. No clear-cut antitumor responses were noted in our study center.The recommended dose for phase II trials derived from our results is 12,550 mg/m²/2 hours. However, with regard to experiences in other phase I studies, the subsequent phase II studies will be performed with a dose of 6,500 mg/m².     

Soman intoxication-induced changes in serum acute phase protein levels,corticosterone concentration and immunosuppressive potency of the serum

We have studied the effect of soman intoxication on serum acute phase reactants (APR) levels, and the relationship of the APR and corticosterone concentrations and the immunosuppressive activity of the serum. One day after the injection of 1.8 LD₅₀ soman the concentrations of ₂-macroglobulin (₂-MG) and ₁-acid glycoprotein (AGP) in the serum of antidote protected rats increased 4- and 7-fold, respectively, whereas those of hemopexin (Hx), haptoglobin (Hp) and cysteine protease inhibitor (CPI) were two to three times higher than in the controls. A similar magnitude of increase of serum acute phase reactants levels was observed when 0.3 LD₅₀ soman was administered at 24-h intervals over the 5-day period. The relationship of changes in the APR concentration, corticosterone level and immunosuppressive activity of the serum was also comparable to that observed in the acute phase response to tissue injury.     

Effects of oral stimulation on the cephalic phase of pancreatic exocrine in dogs

In dogs with cannulated gastric and duodenal fistulas, gustatory receptors were stimulated by swab application of taste stimulus solutions. The experiments were performed with fistulas open. A single taste stimulus of either 0.29 M sucrose, 0.1 M critic acid or 0.001 M quinine sulfate produced a large increase in pancreatic secretion of both volume and protein output. Sucrose was a better stimulant than citric acid or quinine sulfate for pancreatic output. After only one or two trials with each stimulant, the secretory response was no longer seen in any of the dogs. Following this extinction of the secretory response, the same dogs were given orally 100 ml of taste stimulus solution mixed with 25 g cellulose. Pancreatic secretory response occurring within 40 min following administration was gradually restored primarily for sucrose-cellulose. Oral administrations of the unpalatable citric or quinine-cellulose mixtures resulted in low pancreatic output, similar to the control water-cellulose. In contrast to oral administrations, intragastric administrations of these taste stimulus-cellulose mixtures resulted in low pancreatic output within 40 min after administration. The results suggest that taste stimulation alone does not affect pancreatic secretion. However, when coupled with swallowing, there is a greater effect by palatable than unpalatable taste stimuli on the cephalic phase of pancreatic secretion.     

Solid phase C1q microassay for the rapid detection of circulating immune complexes

A C1q solid phase microassay was designed for the rapid detection of circulating immune complexes. Its level of sensitivity is comparable to that of the Raji cell and greater than the C1q binding assay; furthermore, it is faster and low in cost. These conditions make it more practical and applicable in the clinical setting.     

呼气相胸片的识别研究

根据呼气相胸片中肺部区域灰度较高的特点，通过边缘提取和边缘跟踪确定胸部区域，运用最大类间方差方法确定图像分割的阈值．再提取出肺部区域，然后求出肺部的灰度均值。但这样的结果并不理想。于是在此基础上提出修正方案，即以肺部灰度均值和骨骼灰度均值的比值作为特征值．即比例法。此方法可以较客观的识别呼气相胸片。最后用类间距离对这两种方法进行了量化比较。     

心室晚电位检测中消除振铃方法的研究

ＦＧＩＲ作者着重研究了心室晚电位（简称ＶＬＰ）检测中，进行带通滤波时，振铃现象对晚电位检测的影响及消除。我们采用双向滤波、最小相移滤波及ＦＩＲ滤波等方法探讨了振铃对ＶＬＰ的影响，比较了各种方法对振铃的抑制作用。为了考察各种方法对ＶＬＰ检出能力，作者采用了在相干平均后的心电波形上桑加与真实情况一致的仿真ＶＬＰ形的方法，比较了上述方法对ＶＬＰ的检出作用，并在证实了传统双向滤波对振铃作用的基础上，从理论     

The effects of distant and on-line visual information on the control of approach phase and step over an obstacle during locomotion

One of the goals of this study was to examine the nature and role of distant visual information sampled during locomotion in the feedforward control of leading and trailing limb while an individual is required to step over an obstacle in the travel path. In addition we were interested in whether or not on-line visual information available while the limb (lead or trail) is stepping over the obstacle influences limb trajectory control and whether the information provided during lead limb cross would be used to calibrate movement of the trail limb. Towards this end, we manipulated availability of vision following an initial dynamic sampling period during the approach phase in proximity to the obstacle and during the lead and trail limb stepping over the obstacle. Ten participants completed 40 trials of obstacle crossing in 8 testing conditions. Initial dynamic visual sampling was sufficient to ensure successful task performance in the absence of vision in the approach phase and during both lead and trail limb stepping over the obstacle. Despite successful task performance, foot placement of the lead and trail limb before obstacle crossing and limb elevation over the obstacle were increased after withdrawal of vision in the approach area. Furthermore, the correlation between toe clearance and foot placement was diminished. While both limbs require feedforward visual information to control the step over the obstacle, only lead limb elevation was influenced by availability of on-line visual information during obstacle crossing. Results were in agreement with the notion of primacy of information inherent in the optic array over those from static samples of the environment in guiding locomotion. It is suggested that the expected proprioceptive feedback information associated with the limb posture before the obstacle, reconstructed using visual memory from dynamic sampling of the environment, mismatched with those from the actual limb position. Accordingly, participants adopted a different strategy that enabled them to clear the obstacle with a higher safety margin.Financial assistance was provided by a grant from the Office of Naval Research, USA, NSERC/Canada, and CAPES/Brazil. We would like to thank Milad G. Ishac, Mike Greig, Zinat Shafaei-Shirazi, and Candida T. Goncalves for their assistance     

In search of candidate genes critically expressed in the human endometrium during the window of implantation

BACKGROUND: In this prospective randomized blinded clinical trial, we examined gene expression profiles of the human endometrium during the early and mid-luteal phases of the natural cycle. METHODS: An endometrial biopsy was performed on day 16 (LH +3) or on day 21 (LH +8), followed by RNA extraction and microarray analysis using an Affymetrix HG-U95A microchip. Data analysis was carried out using pairwise multiple group comparison with the significance analysis of microarrays (SAM) software. RESULTS: With a false discovery rate of 0, the analysis revealed that 107 genes were significantly and differently expressed (> or =2-fold) during the early versus the mid-luteal phase of the cycle. Forty-five of these genes have not been previously linked to endometrial receptivity. Validation of the microarray data was accomplished using semiquantitative RT-PCR. We demonstrated the presence of estrogen and progesterone response elements (ERE and PRE) by analysis of the 5'-flanking regions of a subset of differentially regulated genes. CONCLUSIONS: Using a strict bioinformatics approach of microarray data, we demonstrated significant changes in candidate genes during the transition of the early to the mid-luteal phase of the human endometrium that may have functional significance for the opening and maintenance of the window of implantation.     

Packing and Uniaxial Alignment of Liquid Crystalline Oligofluorenes

Summary: Liquid crystalline oligomers of 9,9‐bis(2‐ethylhexyl)fluorene of defined degree of polymerization 4, 5, 6, and 7 were investigated by X‐ray diffraction in the non‐oriented and in the aligned state. The diffraction data give evidence for a smectic B type phase for all of the oligomers. Quenching below the glass transition does not change the structure of the liquid crystalline phase. This allows to align spin‐coated films of these oligomers on rubbed polyimide substrates to give monodomain films. These are stable against thermal disordering below T_g, e.g. at room temperature. The degree of alignment is characterized by the dichroic spectra and polarized fluorescence spectra. Dichroic ratios and polarization ratios increase substantially with the chain length and values as high as D = 23 and P = 41 are obtained for the heptamer. The type of packing of the oligomers in the LC phase is discussed based on the X‐ray single crystal structure of models. In one such model the packing of the 2‐ethylhexyl side chains could be fully resolved, while the other model reveals the torsional angle between adjacent fluorene units in the same molecule as 144.2° which corroborates earlier work based on fiber diffraction of corresponding polyfluorenes.