Synaptic convergence of motor and somatosensory cortical afferents onto GABAergic interneurons in the rat striatum

Cortical afferents to the basal ganglia, and in particular the corticostriatal projections, are critical in the expression of basal ganglia function in health and disease. The corticostriatal projections are topographically organized but also partially overlap and interdigitate. To determine whether projections from distinct cortical areas converge at the level of single interneurons in the striatum, double anterograde labeling from the primary motor (M1) and primary somatosensory (S1) cortices in the rat, was combined with immunolabeling for parvalbumin (PV), to identify one population of striatal GABAergic interneurons. Cortical afferents from M1 and S1 gave rise to distinct, but partially overlapping, arbors of varicose axons in the striatum. PV-positive neurons were often apposed by cortical terminals and, in many instances, apposed by terminals from both cortical areas. Frequently, individual cortical axons formed multiple varicosities apposed to the same PV-positive neuron. Electron microscopy confirmed that the cortical terminals formed asymmetric synapses with the dendrites and perikarya of PV-positive neurons as well as unlabelled dendritic spines. Correlated light and electron microscopy revealed that individual PV-positive neurons received synaptic input from axon terminals derived from both motor and somatosensory cortices. These results demonstrate that, within areas of overlap of functionally distinct projections, there is synaptic convergence at the single cell level. Sensorimotor integration in the basal ganglia is thus likely to be mediated, at least in part, by striatal GABAergic interneurons. Furthermore, our findings suggest that the pattern of innervation of GABAergic interneurons by cortical afferents is different from the cortical innervation of spiny projection neurons.     

Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease

Cowden disease, also known as multiple hamartoma syndrome, is an autosomal dominant cancer syndrome with a high risk of breast and thyroid cancer. The gene involved has been localized to chromosome 10q22-23. Recently, the tumour suppressor gene PTEN/MMAC1, encoding a putative protein tyrosine or dual-specificity phosphatase, was cloned from that region and three mutations were detected in patients with Cowden disease. We confirmed that the PTEN/MMAC1 gene is indeed the gene for Cowden disease by a refined localization of the gene to the interval between D10S1761 and D10S541, which contains the PTEN/MMAC1 gene and, by mutation analysis in eight unrelated familial and 11 sporadic patients with Cowden disease. Eight different mutations were detected in various regions of the PTEN/MMAC1 gene. One mutation was detected twice. All detected changes in the gene can be predicted to have a very deleterious effect on the putative protein. Five of the nine patients have a mutation in exon 5 coding for the putative active site and flanking amino acids. Evaluation of the clinical data of the patients in which a mutation could be detected gives no clear indications for a correlation between the genotype and phenotype. In 10 patients no mutation could be detected so far. In support of the linkage data, no evidence has emerged from the phenotype of these patients suggestive for genetic heterogeneity.      

Brine Shrimp Toxicity Evaluation of Some Tanzanian Plants Used Traditionally for the Treatment of Fungal Infections

Plants which are used by traditional healers in Tanzania have been evaluated to obtain preliminary data of their toxicity using the brine shrimps test. The results indicate that 9 out of 44 plant species whose extracts were tested exhibited high toxicity with LC₅₀ values below 20µg/ml. These include Aloe lateritia Engl. (Aloaceae) [19.1µg/ml], Cassia abbreviata Oliv. (Caesalpiniaceae) [12.7µg/ml], Croton scheffleri Pax (Euphorbiaceae) [13.7µg/ml], Hymenodactyon parvifolium Brig (Rubiaceae) [13.4µg/ml], Kigelia Africana L. (Bignoniaceae) [7.2µg/ml], and Ocimum suave Oliv. (Labiatae) [16.7µg/ml]. Twelve plants gave LC₅₀ values between 21 and 50µg/ml, 11 plants gave LC₅₀ values between 50 and 100 µg/ml, and 18 plants gave LC₅₀ values greater than 100 µg/ml.     

Human plasma protein Z antigen: range in normal subjects and effect of warfarin therapy

In contrast to the other well-studied vitamin K-dependent proteins that circulate in plasma, protein Z antigen is much more variable. The concentration in plasmas collected in EDTA from 455 normal, healthy donors is normally distributed with a mean of 2.9 micrograms/mL (46 nmol/L) and a SD of 1.0 microgram/mL (95% interval of 32% to 168% of the mean). No significant correlation to age or sex could be detected. In comparison, the concentration of protein C antigen measured with the same type of assay on the same 455 samples has a log normal distribution with a mean of 4.0 micrograms/mL (65 nmol/L) and a 95% interval of 70% to 138% of the mean. Also in marked contrast to other plasma vitamin K-dependent proteins, the total protein Z antigen level is extremely low in patients on stable warfarin therapy (range 1% to 16% of normal). Moreover, even though greater than 95% of the antigen in normal plasmas adsorbs to barium citrate (a crude reflection of the presence of gamma-carboxyglutamic acid (Gla) residues), in the patients taking warfarin almost all of the small amount of the antigen failed to adsorb, suggesting that virtually no protein Z had its full complement of Gla residues. Total protein C antigen in the same 25 patients averaged 53% of normal (34% to 72%) and 54% (average) of the total remaining antigen still adsorbed to barium citrate. The concentration of protein Z antigen in the plasma of a normal individual given a loading dose of warfarin fell at an initial rate of approximately 20% a day, indicating a plasma half-life (t1/2) of 2 to 3 days.     

从流行病学观点论精液分析

在《世界卫生组织人类精液分析实验室技术手册》(简称手册)第5版中,首次增加了人类精液特征的参考值范围。现阐述提供这些数据是否有助于平息就某些问题引发的广泛争议,如时间地点不同,精液计数差异明显;能否证实某些假设,如人类活动向环境中排放的化学物质损害男性生殖健康等。也解释了这些参考值并不能解决上述问题的原因。虽然既定的精液特征参考值对流行病学研究的价值有限,但世界卫生组织(WHO)手册对建立合适的研究方案极具价值。尽管精液分析有局限性,但仍然是流行病学研究的有用工具,而且至今尚无其他更好的方法能取而代之。     

The frequent BRCA1 mutation 1135insA has multiple origins: a haplotype study in different populations

Background  

Analysis of the chromosomal background upon which a mutation occurs can be used to reconstruct the origins of specific disease-causing mutations. The relatively common BRCA1 mutation, 1135insA, has been previously identified as a Norwegian founder mutation. We performed haplotype analysis of individuals from breast and ovarian cancer families from four different ethnic backgrounds who had been identified as carriers of the BRCA1: 1135insA mutation.     

萘磺酰胺衍生物对细菌脂多糖诱导小鼠腹腔巨噬细胞分泌肿瘤坏死因子的影响

研究了6种氯代萘磺酰胺衍生物对细菌脂多糖(LPS)诱导经卡西霉素A₂₃₁₈₇体外激活的巨噬细胞分泌肿瘤坏死因子(TNF)作用的影响。表明:将氯代萘磺酰胺的氨基接以亲水性不同长度碳链的胺基,所得衍生物可明显抑制LPS诱生TNF的作用;接以疏水性烷基,则可明显增强亚适剂量的LPS诱生TNF的作用,且碳链长度对化合物的作用强度有一定的影响。     

Measurement of free drug in phase I: is it useful?

Summary— Early investigation of protein binding of a new drug is mandatory. The following questions have to be answered: is unbound fraction constant over tested concentrations? Which proteins are involved? What are the binding parameters? Can the drug compete with other therapeutic agents for the binding sites or in other words can drug displacements be predicted? What is the interindividual variability in protein binding? Is the binding stereoselective? All this information is necessary in predicting the pharmacokinetic behaviour of the drug and in assisting in the design of future pharmacokinetic protocols in phases II and III. The use of free drug concentration should also be considered when comparing the bioavailability of regular vs sustained release dosage forms of drugs exhibiting concentration-dependent binding and when studying concentration-effect relationships.     

Abnormal membrane physical properties of red cells in McLeod syndrome

McLeod red cells (RBCs) lack Kx antigens and have weak expression of the Kell antigens. Individuals who carry the McLeod phenotype have acanthocytic RBCs and a compensated hemolytic state. To elucidate the role of the protein on which the Kx antigens reside in maintaining membrane deformability, the rheologic properties of McLeod RBCs were determined by ektacytometry. RBCs were obtained from normal individuals and from four patients with McLeod syndrome. Osmotic gradient deformability profiles of McLeod RBCs showed decreased whole cell deformability. Resealed ghosts from McLeod RBCs also showed decreased deformability, partly because of the decreased cell surface area and partly because of an intrinsic membrane stiffness in this syndrome. For the measurement of membrane mechanical stability, resealed ghosts were subjected to constant high shear stress in the ektacytomer, and deformability was recorded continuously as the deformable ghosts fragmented into rigid spherical vesicles. Membranes from McLeod RBCs showed a noticeable increase in mechanical stability. Acquired causes of acanthocytosis, such as liver disease, did not cause the rheologic abnormalities observed in McLeod cells. Other abnormalities noted in McLeod RBCs were decreased RBC potassium content and an increased number of dense RBCs, as determined by centrifugation on a discontinuous density gradient. The data indicate that McLeod RBCs are rigid and have decreased surface area and that their membranes are intrinsically rigid with increased mechanical stability. These abnormalities may account for the reduced RBC survival observed in McLeod syndrome. The protein that carries the Kx surface antigen seems to be required for the maintenance of the normal physical function of RBC skeletal proteins.