A phase II study of sulofenur,a novel sulfonylurea,in recurrent epithelial ovarian cancer

Summary A total of 16 patients with recurrent epithelial ovarian cancer were treated with sulofenur (LY 186641), a novel oral sulfonylurea. All subjects had received previous chemotherapy. Anaemia occurred in all 16 patients, 14 of whom required a blood transfusion, and 2/16 patients received methylene blue for breathlessness due to methaemaglobinaemia. Treatment was discontinued in 2/16 cases due to rising liver enzyme values, which reverted to normal on cessation of the drug. There was no nausea or alopecia. Only two minor responses were seen. Plasma drug levels were insufficient to result in antitumour activity as extrapolated from animal data. Further studies that attempt to increase the bioavailability and improve the therapeutic index are warranted.     

Vertebral hydatidosis and paraplegia

We report the management of two children and 11 adults with paraplegia secondary to vertebral hydatidosis. Destruction of pedicles, posterior vertebral elements and discs as well as the vertebral bodies was common and all six patients with thoracic disease had involvement of adjacent ribs. The 13 patients had a total of 42 major surgical procedures; two patients died from postoperative complications and four from complications of the disease and paraplegia. All eight patients initially treated by laminectomy or anterior decompression alone relapsed within two years and seven required further surgery. Circumferential decompression and grafting gave the best results, six of nine patients being in remission an average of three years and six months later. The prognosis for such patients is poor; remission is the aim, rather than cure. Anthelminthic drugs may improve the prognosis, but radical surgery is likely to remain the keystone of treatment in the foreseeable future.     

Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. The Multiple Sclerosis Genetics Group

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system. While its etiology is not well understood, genetic factors are clearly involved. Until recently, most genetic studies in MS have been association studies using the case-control design testing specific candidate genes and studying only sporadic cases. The only consistently replicated finding has been an association with the HLA-DR2 allele within the major histocompatibility complex (MHC) on chromosome 6. Using the genetic linkage design, however, evidence for and against linkage of the MHC to MS has been found, fostering suggestions that sporadic and familial MS have different etiologies. Most recently, two of four genomic screens demonstrated linkage to the MHC, although specific allelic associations were not tested. Here, a dataset of 98 multiplex families was studied to test for an association to the HLA-DR2 allele in familial MS and to determine if genetic linkage to the MHC was due solely to such an association. Three highly polymorphic markers (HLA-DR, D6S273 and TNFbeta) in the MHC demonstrated strong genetic linkage (parametric lod scores of 4.60, 2.20 and 1.24, respectively) and a specific association with the HLA-DR2 allele was confirmed (TDT; P < 0.001). Stratifying the results by HLA-DR2 status showed that the linkage results were limited to families segregating HLA-DR2 alleles. These results demonstrate that genetic linkage to the MHC can be explained by the HLA-DR2 allelic association. They also indicate that sporadic and familial MS share a common genetic susceptibility. In addition, preliminary calculations suggest that the MHC explains between 17 and 62% of the genetic etiology of MS. This heterogeneity is also supported by the minority of families showing no linkage or association with loci within the MHC.      

The influence of variations in electrolyte concentration on skin potential level and response amplitude

The application of electrolytes of low concentration to the palm causes hydration of the epidermis with swelling of the skin, closure of the sweat gland pores, and reduction of skin potential level (SPL). Solutions of high concentration are known not to produce poral closure. Previous reports of increases in SPL with increased concentration of electrolyte did not control for possible effects of hydration associated with differences in concentration. The experiments reported here compared the effects of varying concentration with and without holding hydration constant. The results indicated that the effect of concentration on both positive and negative skin potential response amplitude can be attributed to hydration, whereas the effect on SPL is not influenced by hydration. The effect of concentration on SPL was the same whether measured during rest or during periods of considerable sweat gland activity. This last finding is difficult to interpret in terms of the traditional assumption that the membrane responsible for the concentration-potential effect lies deep in the epidermis, and it was suggested that the membrane may be located in the upper sweat gland duct.     

Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation

The tumour suppressor gene PTEN , which maps to 10q23.3 and encodes a 403 amino acid dual specificity phosphatase (protein tyrosine phosphatase; PTPase), was shown recently to play a broad role in human malignancy. Somatic PTEN deletions and mutations were observed in sporadic breast, brain, prostate and kidney cancer cell lines and in several primary tumours such as endometrial carcinomas, malignant melanoma and thyroid tumours. In addition, PTEN was identified as the susceptibility gene for two hamartoma syndromes: Cowden disease (CD; MIM 158350) and Bannayan-Zonana (BZS) or Ruvalcaba-Riley-Smith syndrome (MIM 153480). Constitutive DNA from 37 CD families and seven BZS families was screened for germline PTEN mutations. PTEN mutations were identified in 30 of 37 (81%) CD families, including missense and nonsense point mutations, deletions, insertions, a deletion/insertion and splice site mutations. These mutations were scattered over the entire length of PTEN , with the exception of the first, fourth and last exons. A 'hot spot' for PTEN mutation in CD was identified in exon 5 that contains the PTPase core motif, with 13 of 30 (43%) CD mutations identified in this exon. Seven of 30 (23%) were within the core motif, the majority (five of seven) of which were missense mutations, possibly pointing to the functional significance of this region. Germline PTEN mutations were identified in four of seven (57%) BZS families studied. Interestingly, none of these mutations was observed in the PTPase core motif. It is also worthy of note that a single nonsense point mutation, R233X, was observed in the germline DNA from two unrelated CD families and one BZS family. Genotype-phenotype studies were not performed on this small group of BZS families. However, genotype-phenotype analysis inthe group of CD families revealed two possible associations worthy of follow-up in independent analyses. The first was an association noted in the group of CD families with breast disease. A correlation was observed between the presence/absence of a PTEN mutation and the type of breast involvement (unaffected versus benign versus malignant). Specifically and more directly, an association was also observed between the presence of a PTEN mutation and malignant breast disease. Secondly, there appeared to be an interdependent association between mutations upstream and within the PTPase core motif, the core motif containing the majority of missense mutations, and the involvement of all major organ systems (central nervous system, thyroid, breast, skin and gastrointestinal tract). However, these observations would need to be confirmed by studying a larger number of CD families.      

Electrolyte Medium Effects on Measurements of Palmar Skin Potential

Two experiments with 12 subjects each compared skin potential recordings taken simultaneously with four different electrolytes. These were polyethylene glycol, hydrated agar (at a site presoaked with water), fresh agar (i.e., not presoaked), and Unibase. The glycol controlled epidermal hydration at a minimal level, while presoaking produced a high level of hydration at the hydrated agar site. Fresh agar and Unibase represented normal recording conditions for these two electrolytes which have been recommended as “standard” for electrodermal measurements. This design permitted a comparison of two standard electrolytes with each other and with recordings from hydrated and unhydrated sites. These comparisons were made for both monophasic negative SPRs and positive SPRs and the prestimulus levels associated with each. The results replicated previous studies in showing a large effect of epidermal hydration on skin potential measurements. Recordings with agar and Unibase did not differ significantly. The effects of hydration were interpreted in terms of a reduction in the resistance of the stratum corneum and of alterations in the functioning of the dermal and epidermal membranes as a result of blockage of the sweat gland pore. In the light of this interpretation, it was suggested that both agar and Unibase substantially alter the functioning of the sweat glands under some conditions, and neither may be entirely suitable for skin potential measurements.     

Association of volume with outcome of coronary artery bypass graft surgery. Scheduled vs nonscheduled operations

Empirical evidence suggests that mortality rates for coronary artery bypass graft (CABG) surgery are lower in hospitals that perform a higher volume of the procedure. In recent years, the criteria for CABG surgery have been expanded to include patients with a wide variety of co-morbidities. To address the question of whether the volume-outcome relationship continues to exist for this new group of patients, discharge abstracts for 18,986 CABG operations at 77 hospitals in California in 1983 were analyzed using multiple-regression techniques. Higher-volume hospitals had lower in-hospital mortality (adjusted for case mix); this effect was greatest in patients who might be characterized as having "non-scheduled" CABG surgery. Higher-volume hospitals also had shorter average postoperative lengths of stay and fewer patients with extremely long stays. The results of this study suggest that the greatest improvement in average outcomes for CABG surgery would result from the closure of low-volume surgery units.     

高效液相色谱法测定小儿磨积片中橙皮苷的含量

目的:建立以高效液相色谱法测定小儿磨积片中橙皮苷含量的方法。方法:色谱柱为SpherisorbC18,流动相为甲醇-冰醋酸-水(25∶4∶71),检测波长为283nm,流速为2·0ml/min,柱温为50℃,灵敏度为0·16AUFS,进样量为20μl。结果:橙皮苷进样量在0·024μg~1·2μg范围内与峰面积积分值呈良好的线性关系(r=0·9999),平均回收率为99·1%(RSD=0·8%)。结论:本方法简便、快捷,灵敏度及准确度高,可为小儿磨积片质量控制提供依据。     

Increased circulating CSF-1 (M-CSF) in myeloproliferative disease: association with myeloid metaplasia and peripheral bone marrow extension

Myeloproliferative disease (MPD) is heterogeneous in phenotypic expression and may display features consistent with expansion and activation of the monocyte/macrophage population during its course. The role of colony-stimulating factor-1 (CSF-1) in the pathophysiology of MPD was investigated by measuring circulating CSF-1 levels and examining their relationship to disease phenotype. Serum CSF-1 concentrations, measured by radioimmunoassay, were elevated in all MPD phenotypes. CSF-1 levels differed significantly between groups of patients with essential thrombocythemia, polycythemia vera, and postpolycythemic or agnogenic myeloid metaplasia (in ascending order). CSF-1 serum levels were positively correlated with spleen size and the degree of peripheral bone marrow extension, determined by scintigraphy using a macrophage-seeking isotope. There was no correlation between CSF-1 concentration and circulating levels of erythrocytes, neutrophils or platelets, or the presence of bone marrow fibrosis. Elevated serum CSF-1 levels appear to be associated with an expanded monocyte/macrophage population in MPD. In view of the known cooperativity between CSF-1 and other growth factors in regulating hematopoiesis, the finding of increased serum CSF-1 concentrations and its association with myeloid metaplasia and bone marrow extension may indicate a pathophysiologic role for CSF-1 in determining the phenotypic expression of MPD.