Boron neutron capture therapy: Preliminary study of BNCT with sodium borocaptate (Na2B1 2H1 1SH) on glioblastoma

To plan the optimal BNCT using BSH for glioblastoma patients, the¹⁰B concentration in tumor and blood was investigated in 11newly diagnosed glioblastoma patients. All patients received 20 mg BSH/kgbody weight 2.5–16 hrs prior to tumor removal. The quantitativedistribution of ¹⁰B was determined by prompt gamma rayspectrometry and/or -track autoradiography. ¹⁰Bdistribution in tumors was heterogeneous, ± 25% of scatteringat the microscopic level, and the distribution was also heterogeneous at thetissue level. ¹⁰B concentration in blood decreased inbi-exponential decay as a function of the time after the end of theadministration. The T/B ratio showed non-exponential increase with largevariation. The maximum T/B ratio would be around 1. The tumor/normal brain(T/N) ratio of ¹⁰B concentration was 11.0 ± 3.2. The¹⁰B content in normal brain is originated in vascular¹⁰B in parenchyma, since the ¹⁰B content innormal brain to blood (N/B ratio) being compatible with the blood content inparenchyma. These values allow for BNCT, using thermal neutrons, on braintumors located less than approximately 3.3 cm in depth from the brainsurface of neutron incidence, providing that the dose on the normalendothelium is controlled to less than the tolerance limit. In ourpreliminary study of BNCT, a 31% 3-year survival was achieved overall for 16 glioblastoma patients and a 50% 2-year survival wasachieved on 8 glioblastoma patients in our recent dose escalation studybased on these data.     

Cerebrovascular effects of nitric oxide manipulation in spontaneously hypertensive rats

1. Evidence that nitric oxide (NO) bioactivity is altered in chronic hypertension is conflicting, possibly as a result of heterogeneity in both the nature of the dysfunction and in the disease process itself. The brain is particularly vulnerable to the vascular complications of chronic hypertension, and the aim of this study was to assess whether differences in the cerebrovascular responsiveness to the NO synthase (NOS) inhibitors, N^G-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI), and to the NO donor 3-morpholinosydnonimine (SIN-1) might indicate one possible source of these complications.
2. Conscious spontaneously hypertensive (SHR) and WKY rats, were treated with L-NAME (30 mg kg⁻¹, i.v.), 7-NI (25 mg kg⁻¹, i.p.), SIN-1 (0.54 or 1.8 mg kg⁻¹ h⁻¹, continuous i.v. infusion) or saline (i.v.), 20 min before the measurement of local cerebral blood flow (LCBF) by the fully quantitative [¹⁴C]-iodoantipyrine autoradiographic technique.
3. With the exception of mean arterial blood pressure (MABP), there were no significant differences in physiological parameters between SHR and WKY rats within any of the treatment groups, or between treatment groups. L-NAME treatment increased MABP by 27% in WKY and 18% in SHR groups, whilst 7-NI had no significant effect in either group. Following the lower dose of SIN-1 infusion, MABP was decreased to a similar extent in both groups (around −20%). There was no significant difference in MABP between groups following the higher dose of SIN-1, but this represented a decrease of −41% in SHR and −21% in WKY rats.
4. With the exception of one brain region (nucleus accumbens), there were no significant differences in basal LCBF between WKY and SHR. L-NAME produced similar decreases in LCBF in both groups, ranging between −10 and −40%. The effect of 7-NI upon LCBF was more pronounced in the SHR (ranging from −34 to −57%) compared with the WKY (ranging from −14 to −43%), and in seven out of the thirteen brain areas examined there were significant differences in LCBF.
5. Following the lower dose of SIN-1, in the WKY 8 out of the 13 brain areas examined showed significant increases in blood flow compared to the saline treated animals. In contrast, only 2 brain areas showed significant increases in flow in the SHR. In the rest of the brain areas examined the effects of SIN-1 upon LCBF were less marked than in the WKY.
6. Infusion of the higher dose of SIN-1 resulted in further significant increases in LCBF in the WKY group (ranging between +30% and +74% compared to saline-treated animals), but no significant effects upon LCBF were found in the SHR. As a result, there were significant differences in LCBF between SIN-1-treated WKY and SHR in six brain areas. In most brain areas examined, cerebral blood flow in SHR following the higher dose of SIN-1 was less than that measured with the lower dose of SIN-1.
7. Despite comparable reductions in MABP (∼20%) in both groups, calculated cerebrovascular resistance (CVR) confirmed that the vasodilator effects of the lower dose of SIN-1 were significantly more pronounced throughout the brain in the WKY (ranging between −3% and −50%; median=−38%) when compared to the SHR (ranging between −10% and −36%; median=−26%). In the animals treated with the higher dose of SIN-1, CVR changes were broadly similar in both groups (median=−45% in WKY and −42% in SHR), but with the reduction in MABP in SHR being twice that found in WKY, this is in keeping with an attenuated blood flow response to SIN-1 in the SHR.
8. The results of this study indicate that NO-dependent vasodilator capacity is reduced in the cerebrovasculature of SHR. In addition, the equal responsiveness to a non-specific NOS inhibitor but an enhanced effectiveness of a specific neuronal NO inhibitor upon LCBF in the SHR could be consistent with an upregulation of the neuronal NO system.

     

Locating human quantitative trait loci: Guidelines for the selection of sibling pairs for genotyping

Simulation studies were conducted to assess the relative merits of different nonrandom sampling strategies for the selection of sibling pairs for genotyping in the attempt to locate individual loci (QTLs) contributing to variation in human quantitative traits. For a constant amount of variation contributed by a QTL (25% of the total) the frequencies and dominance relationships of a trait increasing allele were varied. Three strategies for selection of pairs for genotyping were based on the phenotypic values of the siblings: Concordant sib pairs (CSP) are pairs in which both individuals exceed a given threshold value; discordant sib pairs (DSP) are pairs in which one member exceeds a given upper threshold and the other is below a specified lower threshold; and most similar pairs (MSP) are pairs selected for falling below a specified percentile ranking of the within-pair mean square for the quantitative trait. Tests for linkage with markers at 1, 2, 5, 10, and 20 cM from each of the QTLs were conducted for each of the selected samples and compared with tests based on the regression, in the entire sample, of within pair variation on the proportion of alleles identical by descent (IBD) at each marker locus. Tests for the effect of the increasing allele at the QTL (candidate gene) were also conducted for the DSP pairs. No single nonrandom selection procedure yields as much as half the information realized in the total sample. However, a combined strategy which involves genotyping the 5% of MSP and DSP for the upper and lower quintiles of values of the quantitative trait (a further 3% of the sample approximately) yields lod scores which are usually more than 65% of the values realized for the entire sample. Tests comparing the proportion of increasing alleles in high- and low-scoring siblings from DSP samples are uniformly very powerful for detecting candidate loci. Even when it is not possible to measure the entire range of the phenotype with uniform precision, some attempt to differentiate among individuals in a common unaffected class of individuals can lead to considerable increase in power.     

单克隆抗体夹心ELISA定量检测日本血吸虫循环抗原

目的反映日本血吸虫病活动性感染程度,探讨建立定量测定循环抗原的方法。方法筛选和制备单克隆抗体,将其进行优化组合,建立双抗体夹心ELISA,计算标准曲线,测试检测能力,检测样本。结果获6个抗日本血吸虫单克隆抗体,经优化组合试验,选择其中3个抗日本血吸虫虫卵TCA可溶性抗原和成虫TCA可溶性抗原进行搭配,用于检测日本血吸虫病患者血清中循环抗原效果较理想。检测慢性血吸虫病118例,阳性61例,阳性率51．7％;急性患者30例,全部阳性;正常人187例,5例阳性,特异性97．3％。单盲法检测一批血清,结果也较满意。法论定量检测日本血吸虫病患者血清中循环抗原,对提示活动性感染的程度和疫苗保护作用的评估具有一定的应用价值。     

Effects of sciatic neurectomy on the femur in growing rats: Application of peripheral quantitative computed tomography and Fourier transform infrared spectroscopy

The effects of unilateral sciatic neurectomy (USN) on the development of the femur were studied in 15 growing Wistar-derived rats (age, 5 weeks). The rats were divided into four groups: USN-operated group (right femur), USN-nonoperated group (left femur), sham-operated group (right femur), and sham-nonoperated group (left femur). Bone mineral density (BMD), bone mineral content (BMC), bone area, periosteal circumference, and endosteal circumference were measured by peripheral quantitative computed tomography (pQCT) and the mineral/matrix ratio was evaluated by Fourier transform infrared spectroscopy (FTIR). The USN-operated group showed a significant decrease in cortical BMC, bone area, and periosteal circumference compared with the other groups (P < 0.05). The cortical BMD did not vary significantly between the groups. In the cancellous bone, the USN-operated group showed a significant decrease in BMD and BMC at the metaphysis compared with the other groups (P < 0.05). The mineral/matrix ratio of the cortical bone did not differ significantly between the USN-operated and USN-nonoperated groups. These results suggest that in cortical bone, USN inhibits periosteal bone formation but has no significant effect on the mineral/matrix ratio of cortical bone in femurs. In cancellous bone, USN induces bone loss at the metaphysis. Received: Nov. 19, 1998 / Accepted: Feb. 12, 1999     

Application of the Electrotopological State Index to QSAR Analysis of Flavone Derivatives as HIV-1 Integrase Inhibitors

Purpose. A QSAR study based on electrotopological state (E-state) indices was conducted for a series of flavone HIV-1 integrase inhibitors to guide drug design. Methods. E-state indices formulated to encode electronic and topological information for each skeletal atom in a molecule (Kier and Hall Pharm. Res. 7:801–807 (1990)) were calculated using the Molconn-X program, and partial least squares (PLS) multivariate regression was used to derive QSAR models. Results. Predictive models with correlation coefficients (r²) of 0.98 (3 PLS components) and 0.99 (5 PLS components) and corresponding cross-validated correlation coefficients (c.v. r²) of 0.51 and 0.73, were obtained for inhibition of cleavage and integration, respectively, with one molecule omitted from the analysis. Conclusions. E-state indices at C6, C3, C5, C5, and O4 were found to be more important for prediction of activity than those for any of the other 12 flavone skeletal atoms that are common to the molecules in the data set.     

The mechanism of directional coronary atherectomy

An attempt was made to assess the mechanism of directional coronaryatherectomy using different methods of analysis. Quantitativecoronary angiography was used as the gold standard to assessthe immediate results of atherectomy, and a comparative quantitativeanalysis of atherectomy and balloon angioplasty was made. Todetermine whether the post-atherectomy cross-sectional areais close to a circle, we compared the area measurements obtainedby edge detection with those obtained by videodensitometry.Finally, the extent of a ‘Dotter’ effect was establishedby quantitative angiography following crossing the stenosiswith the atherectomy device. For the purpose of this study,the results of the first 113 successful atherectomy procedureswere reviewed. In matched lesions, directional atherectomy induceda greater increase in minimal luminal diameter than balloonangioplasty (1.6 mm vs 0.8 mm; P < 0.0001 However, this luminalimprovement is due to a substantial ‘Dotter’ effectinduced by the bulky atherectomy device. Following atherectomy,only a slight difference in cross-sectional area measurementsbetween edge detection and videodensitometry (mean difference:0.28 mm² was found. Histologic examination of an atherectomizedcoronary artery showed a near-circular post atherectomy areageometry. In conclusion, directional atherectomy is a very effectivedevice with a substantially better initial result than balloonangioplasty. However, insertion of this bulky device itselfcauses an important ‘Dotter’effect.     

Contributions of chronological age,age at menarche and menopaus and of anthropometric parameters to axial and peripheral bone densities

Bone mineral density (BMD) was measured in 128 normal postmenopausal women at different skeletal sites: lumbar spine and proximal femur, using dual-energy X-ray absorptiometry (DXA), and the cancellous and cortical envelopes of the distal third of radius and tibia, using precise low-dose quantitative computed tomography (QCT). Multivariate analysis included chronological age, ages related to menstrual history (menopause and menarche) and anthropometric factors, e.g. height and weight, as independent predictive variables. Weight is a much-studied predictor of bone density. At sites of high bone turnover, i.e. cancellous envelope, the effect of weight appeared overshadowed by estrogen-related parameters: age-past-menopause was the first predictor of BMD in the cancellous compartment of radius and in Ward's triangle, and the number of reproductive years was the strongest predictor of BMD in the cancellous compartment of tibia and in the spine (L2–4). This suggests that in addition to menopause, the length of menstrual life should be considered as an explanation for the variations in current bone mass in postmenopausal women.At the cortical level of radius, the effect of chronological age was predominant. At the cortical level of tibia, height and weight were the best predictors of BMD.We conclude that the influence of parameters related to menstrual history is predominant in sites with mainly cancellous tissue and that anthropometric factors constitute the best predictors of BMD in the cortical sites of weight-bearing bones.     

Autoradiographic study of iron-binding sites in the rat brain: distribution and relationship to aging

Specific binding of 59Fe to various brain structures was investigated in rats using nanomolar concentrations of 59FeCl3 and quantitative autoradiography. Saturation studies revealed high affinity binding (kd in the nanomolar range) with binding sites density (Bmax) which varied in different brain regions from 462 fmol per mg tissue in the central thalamic nuclei to over 4 pmol per mg tissue in the cerebral peduncle. Binding was seen in both white and gray matter structures. Bmax values for frontal cortex, dentate gyrus, and substantia nigra were significantly lower in older rats. The distribution of 59Fe binding sites was not consistent with the distribution of brain iron as reported by other investigators. 59Fe binding was reduced significantly in the presence of free radicals. These observations suggest that high affinity binding sites for iron are localized differentially in various brain structures and may play an important role in the translocation and storage of potentially harmful ferric cations in brain. The finding that the capacity of the brain tissue to bind iron diminished with age in discrete brain regions suggests that in the aged animal, the removal of "free" iron from the cellular domain may be impaired in such regions, leading to increased susceptibility to iron-enhanced lipid peroxidation and cell death.