Propagation of granulocytic Ehrlichia spp. from human and equine sources in HL-60 cells induced to differentiate into functional granulocytes

Ehrlichia spp. from human and equine sources in the northeastern Unites States were detected by PCR, isolated, and propagated in the HL-60 promyelocytic leukemia cell line. Growth of Ehrlichia from both equine and human sources was enhanced by addition of retinoic acid, which causes granulocytic differentiation of the HL-60 cells. DNA sequencing of a portion of the 16S rDNA gene supported the hypothesis that the same pathogen was responsible for both equine and human granulocytic ehrlichiosis.     

BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer

BACKGROUND: To define the incidence of BRCA1 mutations among patients seen in clinics that evaluate the risk of breast cancer, we analyzed DNA samples from women seen in this setting and constructed probability tables to provide estimates of the likelihood of finding a BRCA1 mutation in individual families. METHODS: Clinical information, family histories, and blood for DNA analysis were obtained from 263 women with breast cancer. Conformation-sensitive gel electrophoresis and DNA sequencing were used to identify BRCA1 mutations. RESULTS: BRCA1 mutations were identified in 16 percent of women with a family history of breast cancer. Only 7 percent of women from families with a history of breast cancer but not ovarian cancer had BRCA1 mutations. The rates were higher among women from families with a history of both breast and ovarian cancer. Among family members, an average age of less than 55 years at the diagnosis of breast cancer, the presence of ovarian cancer, the presence of breast and ovarian cancer in the same woman, and Ashkenazi Jewish ancestry were all associated with an increased risk of detecting a BRCA1 mutation. No association was found between the presence of bilateral breast cancer or the number of breast cancers in a family and the detection of a BRCA1 mutation, or between the position of the mutation in the BRCA1 gene and the presence of ovarian cancer in a family. CONCLUSIONS: Among women with breast cancer and a family history of the disease, the percentage with BRCA1 coding-region mutations is less than the 45 percent predicted by genetic-linkage analysis. These results suggest that even in a referral clinic specializing in screening women from high-risk families, the majority of tests for BRCA1 mutations will be negative and therefore uninformative.     

Genetic mapping of a major susceptibility locus for juvenile myoclonic epilepsy on chromosome 15q

The epilepsies are a group of disorders characterised by recurrent seizures caused by episodes of abnormal neuronal hyperexcitability involving the brain. Up to 60 million people are affected worldwide and genetic factors may contribute to the aetiology in up to 40% of patients. The most common human genetic epilepsies display a complex pattern of inheritance. These are categorised as idiopathic in the absence of detectable structural or metabolic abnormalities. Juvenile myoclonic epilepsy (JME) is a distinctive and common variety of familial idiopathic generalised epilepsy (IGE) with a prevalence of 0.5-1.0 per 1000 and a ratio of sibling risk to population prevalence (lambda(s)) of 42. The molecular genetic basis of these familial idiopathic epilepsies is entirely unknown, but a mutation in the gene CHRNA4, encoding the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (nAChR), was recently identified in a rare Mendelian variety of idiopathic epilepsy. Chromosomal regions harbouring genes for nAChR subunits were therefore tested for linkage to the JME trait in 34 pedigrees. Significant evidence for linkage with heterogeneity was found to polymorphic loci encompassing the region in which the gene encoding the alpha7 subunit of nAChR (CHRNA7) maps on chromosome 15q14 (HLOD = 4.4 at alpha = 0.65; Z(all) = 2.94, P = 0.0005). This major locus contributes to genetic susceptibility to JME in a majority of the families studied.     

Antibody-IL-2 fusion proteins: a novel strategy for immune protection

Advances in genetic engineering and expression systems have led to a rapid progress in the development of immunoglobulins fused to other proteins. These 'antibody fusion proteins' have novel properties and include antibodies fused to the cytokine interleukin-2. In the present review we describe strategies for construction of these antibody-interleukin-2 fusion proteins and discuss their in vitro and in vivo properties. Antibody-interleukin-2 fusion proteins retain both antibody associated functions such as antigen binding, complement activation and Fc gamma receptor binding as well as interleukin-2 associated functions such as the stimulation of proliferation of CTLL2 cells. In vivo, they produce strong potentiation of the host immune response against any associated antigen. In addition, these novel molecules are able to target tumor cells and produce a specific and effective T cell response capable of eliminating the tumor. These properties suggest that antibody-interleukin-2 fusion proteins will be useful in the diagnosis and/or treatment of human cancer as well as in the potentiation of human response against any associated antigen.     

Functional topography of cat primary auditory cortex: response latencies

Minimum onset latency (Lmin) of single- and multiple-unit responses were mapped in the primary auditory cortex (AI) of barbiturate-anesthetized cats. Contralateral Lmin for multiple units was non-homogeneously distributed along the dorso-ventral/isofrequency axis of the AI. Responses with shorter latencies were more often located in the central, more sharply tuned region while longer latencies were more frequently encountered in the dorsal and ventral portions of the AI. For single units, a large scatter of Lmin values was found throughout the extent of the AI including cortical depth. The relationship between Lmin and previously reported spectral, intensity and temporal parameters was analyzed and revealed statistically significant correlations between minimum onset latency and the following response properties in some but not all studied animals: sharpness of tuning of a frequency response area 10 dB above threshold, broadband transient response, strongest response level, monotonicity of rate/level functions, dynamic range, and preferred frequency modulation sweep direction. This analysis suggests that Lmin is determined by several independent factors and that the prediction of Lmin based on relationships with other spectral and temporal response properties is inherently weak. The spatial distribution and the functional relationship between these response parameters may provide an important aspect of the time-based cortical representation of specific features in the animal's natural environment.     

Effect of crosslinking agent content, monomer functionality, and repeat unit chemistry on properties of unfilled resins

Seven mechanical/physical properties were used to evaluate 10 unfilled resins: eight aromatic dimethacrylates and two urethane dimethacrylates. Physical property tests included compressive strength, Young's modulus in compression, uniaxial tensile strength, intrinsic yield point, toothbrush abrasion, Knoop hardness, and water sorption. Controlled changes were made in the following four material parameters: amount of crosslinking diluent present in the uncured monomer, functionality of the monomer, repeat unit chemistry of the monomer (urethane vs. aromatic structure) and mode of activation (chemical vs. visible light). Polymers containing a high concentration of crosslinking agent (50 wt%) were found to be tougher and to possess lower hardness than materials containing lesser amounts of crosslinking agent. This was attributed to the flexible nature of the triethylene glycol dimethacrylate crosslinking molecule. Exposure to water plasticized the highly crosslinked materials to the degree that the yield point and elastic modulus were effectively lowered. Most of the tested properties were unaffected by differences in functionality except resistance to toothbrush abrasion, which was enhanced for polymers derived from high functionality monomers. The urethane-based polymers sorbed substantially more water than the aromatic-based materials, which presumably resulted in lower values for surface hardness. However, the urethane resins were very tough, and excellent resistance to toothbrush abrasion was observed. Property differences caused by differences in activation mode were small, although the visible light materials did sorb more water.     

Potentiation of a three drug chemotherapy regimen by radiation

The combination of N-(phosphonacetyl)-L-aspartate, 6-methylmercaptopurine, and 6-aminonicotinamide has been shown to be an effective antineoplastic regimen and also to enhance the effects of other chemotherapeutic agents. The mechanism of action of this combination of drugs is not known definitively, but one possible mechanism is biochemical modulation of energy metabolism and inhibition of production of tumor ATP. Tumor-bearing mice were treated with N-(phosphonacetyl)-L-aspartate, followed 17 h later by 6-methylmercaptopurine and 6-aminonicotinamide. 31P nuclear magnetic resonance spectroscopic studies demonstrated a significant depletion of high energy phosphates at 10 h post-6-methylmercaptopurine and 6-aminonicotinamide. The addition of radiation at this time was shown to induce a significantly longer tumor growth delay and a greater number of regressions (including durable complete regressions) than either chemotherapy or radiation alone. The combination of chemotherapy and radiation was found to be supra-additive compared to the antineoplastic effects of either modality administered separately, without a measurable increase in host toxicity.