Neurotoxicity and dermatotoxicity of cyanomorpholinyl adriamycin

Summary The highly lipophilic cyanomorpholinyl adriamycin (CMA) is the most potent antineoplastic anthracycline yet described. CNS distribution and toxicity were examined after i.v. administration of CMA to mice. At doses 0.1 mg/kg, a neurotoxic syndrome including ataxia, hypokinesia, and tremors appeared. At doses of 0.05 mg/kg, which have been reported to be antineoplastic, no neurotoxicity was observed. On histopathologic examination, no changes were observed in the brain, spinal cord, or dorsal root ganglia. Unlike adriamycin (ADR), which rapidly appears in the nuclei of several tissues, CMA showed no fluorescence, suggesting a different cellular microcompartmentalization. The i.d. injection of CMA disclosed a 200-fold increase in toxicity compared with that of adriamycin. In comparisons of CMA and ADR, neurotoxicity and cardiotoxicity occurred equally only at higher doses; however, the dermatotoxicity and antineoplastic activity of CMA were increased several hundred-fold.     

Isolation of non-O1 Vibrio cholerae associated with enteric disease of herbivores in western Colorado.

Non-O1 Vibrio cholerae was isolated from a horse (Equus caballus), a lamb (genus Ovis), and two American buffalo (Bison bison) suffering from enteric disease in the western part of Colorado. In 1981, a foal died of apparent respiratory failure. Necropsy findings included heart failure and gastroenteritis. V. cholerae serovar 347 (Smith) was isolated from the colon of this animal. V. cholerae serovar 27 (Smith) was isolated in 1983 from the intestine of a feedlot lamb suffering from pneumonia and severe watery diarrhea. In 1984, an enteric disease occurred in a herd of American bison. The sick animals were depressed and separated from the herd, dying in about 3 days. Of approximately 100 adult bison, 7 died. Necropsy of one animal revealed that gross lesions were limited to the gastrointestinal tract. V. cholerae serovar 27 (Smith) was isolated from the abomasum, duodenum, and colon of this animal. A swab specimen from the intestine of another dead bison also yielded V. cholerae serovar 27 (Smith).     

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.      

Transfer of zona-free embryos improves outcome in poor prognosis patients: a prospective randomized controlled study

Assisted zona hatching (AZH) has been used in IVF programmes for several years. Recently one group has reported successful pregnancies after transfer of zona-free blastocysts. The aim of our study was to evaluate outcomes after transfer of zona-free day 3 embryos. Two groups of women undergoing intracytoplasmic sperm injection (ICSI) were included in the study. Group A consisted of 52 women under the age of 40 years undergoing their first ICSI attempt. They were alternately randomized to receive zona-free embryos (27 women) and zona-intact embryos (25 women). The second group (group B) included 71 women with a poor prognosis, as defined by age 40 years or more, and/or at least two previous failed IVF/ICSI attempts. They were randomized in a 3:4 ratio (30 zona-free, 41 zona-intact). Acid Tyrode's solution was used to remove the zona pellucida before embryo transfer on day 3 after oocyte collection. The pregnancy rate in group A was not significantly improved when the zona pellucida was removed. However, in the poor prognosis group B, zona removal resulted in a significantly higher pregnancy rate when compared with controls (23 versus 7.3%). We conclude that complete removal of the zona pellucida can improve pregnancy rates in women with poor IVF/ICSI prognosis.     

The Effect of End Group Modification on the Transparency of Vinyl Addition Norbornene Polymers at 193 nm

Summary: Homopolymers of a bis‐trifluorocarbinol substituted norbornene ( 1 ) (α,α‐bis(trifluoromethyl)bicyclo[2.2.1]hept‐5‐ene‐2‐ethanol or HFANB) and copolymers of 1 with t‐butyl ester of 5‐carboxylic acid ( 2 , t‐BuEsNB) were produced using palladium catalysts and olefinic chain transfer agents such as 1‐hexene and ethylene to control molecular weight. However, these low‐molecular‐weight polymers exhibited relatively low optical transparencies at 193 nm. In fact, the opacity (measured as optical densities in absorbance units per micron) of thin films of these homo‐ and co‐polymers was inversely proportional to their molecular weight. This relationship is consistent with an end group contribution to the film opacity. Spectroscopic analysis of these polymers by ¹H NMR and MALDI‐TOF MS confirmed that 1‐hexene and ethylene chain transfer agents generated olefin‐terminated vinyl addition polymers. The olefinic end group contribution to optical density can be eliminated by appropriate chemical modification. Both epoxidation and hydrogenation of the polymer olefinic end groups generated very low optical density materials, independent of molecular weight, that are suitable as 193‐nm photoresist binder resins.

End group modification of vinyl and hexenyl‐terminated homopolymers of 1 by epoxidation or hydrogenation.     

Use of lectin histochemistry in pancreatic cancer.

Lectin peroxidase histochemical analysis was carried out on pancreatic tissue from patients with pancreatic carcinoma and chronic pancreatitis and from subjects with normal pancreas to find a tumour specific pattern of lectin binding that would aid histological and cytological diagnosis. There were striking differences between the lectin binding characteristics of the different cell types in the normal pancreas. Acinar cells were uniformly positive for binding with wheat germ agglutinin and soy bean agglutinin while islet cells were usually negative for these lectins. Ulex europaeus I lectin however, was found not to be specific for endothelium, showing positivity also for acinar and ductal tissue. Griffonia simplicifolia II lectin was found to be highly specific for ductal epithelium, and because of this was tested in a hamster pancreatic cancer model where it was not specific for ductal epithelium, reflecting differing carbohydrate expression in the hamster pancreas. Pancreatic carcinomas and chronic pancreatitis bound all five lectins without any qualitative distinction from each other or from normal pancreatic tissue, but there was increased intensity of peanut agglutinin binding to secreted mucins in pancreatic carcinoma, which may be of potential use in radiolabelled lectin scanning.     

Defective potassium currents in ataxia telangiectasia fibroblasts

Similarities exist between the progressive cerebellar ataxia in ataxia telangiectasia (AT) patients and a number of neurodegenerative diseases in both mouse and man involving specific mutations in ion channels and/or ion channel activity. These relationships led us to investigate the possibility of defective ion channel activity in AT cells. We examined changes in the membrane potential of AT fibroblasts in response to extracellular cation addition and found that the ability of AT fibroblasts to depolarize in response to increasing concentrations of extracellular K⁺ is significantly reduced when compared with control fibroblasts. Electrophysiological measurements performed with a number of AT cell lines, as well as two matched sets of primary AT fibroblast cultures, reveal that outward rectifier K⁺ currents are largely absent in AT fibroblasts in comparison with control cells. These K⁺ current defects can be corrected in AT fibroblasts transfected with the full-length ATM cDNA. These data implicate, for the first time, a role for ATM in the regulation of K⁺ channel activity and membrane potential.     

Cluster of TRIM genes in the human MHC class I region sharing the B30.2 domain

The major histocompatibility complex (MHC), a region of high gene density, contains a large number of genes relevant to the immune response, belonging to different multigenic families. We studied the genomic organization and polymorphism of a set of genes in the MHC class I region containing the tripartite motif (TRIM), consisting of a RING domain, B-box and coiled coil region, and a B30.2-like domain. A cluster of seven genes at 6p21.33 and two related family members telomeric of the cluster were characterized. All MHC-encoded TRIM-B30.2 genes showed moderate levels of polymorphism, affecting predominantly the RING and B-box domains. In terms of structure, the genes varied by the loss of partial and, in some cases, complete domains. They were strongly conserved in exons 2, 3 and 4, which form the coiled-coil region. The last exon, encoding the B30.2-like domain, is shared with the otherwise unrelated butyrophilin-like (BTN) genes, located 4.3 Mb telomeric of the TRIM-B30.2 cluster. The data are consistent with multiple, ancient duplications giving rise to a set of related genes.     

Correlation between in vivo and in vitro functional tests for activated macrophages.

Mice undergoing graft-versus-host reaction, skin grafting, and inoculation with tumor cells were tested for nonspecific resistance by intravenous challenge with Listeria monocytogenes. Peritoneal exudate macrophages from mice treated in a similar manner were tested in vitro for increased degradation of [1-14C]glucose, ability to degrade antigen/antibody complexes, ability to inhibit intracellular growth of listeria, and staining for beta-galactosidase. There was good correlation between in vivo resistance towards L. monocytogenes and in vitro inhibition of intracellular growth. There was also good correlation between increase in beta-galactosidase and in vivo resistance in mice undergoing a graft-versus-host-reaction.     

HIV infection and AIDS in England and Wales: general practitioners' workload and contact with patients.

In mid-1988 a postal survey was conducted of one in five general practitioners in England and Wales, to examine their contact with people with human immunodeficiency virus (HIV) infection, with the acquired immune deficiency syndrome (AIDS) or with worries about HIV infection or AIDS. The response rate was 63.9%. Of the 3339 respondents 22.7% knew of an asymptomatic HIV positive patient within their practice, 5.4% knew of a symptomatic HIV positive patient and 6.4% knew of a patient with AIDS. The estimated annual rate for HIV-related consultations in general practice (including consultations with the 'worried well') was 6.5 per 1000 population. HIV-related consultations occurred more frequently in the four Thames health regions than elsewhere. A sample of 715 practitioners who reported consultations with HIV infected people or those with worries about infection in the previous month, were invited to keep a diary of HIV-related consultations for one week. The response rate to the diary was 64%. Nineteen per cent of the 273 consultations recorded in the diaries were initiated by homosexual men, 16.5% by injecting drug users, 10.3% by the sexual partners of people at risk of infection; 42.9% of consultations were not associated with recognized risk factors. The results indicate that general practitioners have substantial contact with patients with HIV infection, with AIDS and with worries about HIV infection or AIDS. This contact is likely to increase, alongside the anticipated spread of HIV infection, with consequent implications for general practice resources.