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PubMed1979

A variant of S49 mouse lymphoma cells with enhanced secretion of cyclic AMP.

A novel variant of S49 mouse lymphoma cells is described which is resistant to growth arrest and cytolysis by dibutyryl cyclic AMP but, in contrast to previously described variants, has normal cyclic AMP-dependent protein kinase. The variant is also resistant to N6-monobutyryl cAMP but is sensitive to killing by 8-bromo cAMP and cholera toxin. Extracts of the variant appear to contain wild type levels of both O2'-butyrylesterase and cyclic AMP phosphodiesterase activities. Accumulation of exogenous [3H]dibutyryl cyclic AMP is reduced in the variant suggesting a defect in either uptake or secretion of the analog or its metabolic products. Accumulation of cyclic AMP in variant cells after stimulation of adenylate cyclase with either isoproterenol or cholera toxin is also reduced compared with wild type cells, although cyclase activity of membranes prepared from the variant cells is normal. Extracellular accumulation of cyclic AMP after stimulation of variant cells with isoproterenol is greater than that found with wild type cells. It is concluded that the variant has an alteration in its cyclic AMP secretion mechanism resulting in more efficient extrusion of cyclic AMP than in wild type cells.

Animals↗

PubMed1985

Dominant and recessive mitogen-nonproliferative variants of 3T3 cells.

We have previously isolated 3T3 cell variants unable to respond to specific mitogens. In this report we analyze the dominant and/or recessive nature of these variants. Two independently isolated EGF nonproliferative variants are unable to bind EGF. Hybrids between 3T3R5 cells (thymidine kinase deficient, ouabain-resistant) and these variants express EGF receptors; the "EGF receptorless" phenotype of these variants is recessive. Hybrids between these two variants do not bind EGF; they are defective in a common, non-complementing function. A TPA nonproliferative 3T3 variant is also recessive; hybrids with 3T3R5 mount a mitogenic response to TPA. In contrast a fourth variant, which can neither bind labeled EGF nor respond to TPA, is dominant for both characteristics. Hybrids between this latter variant and 3T3R5 can neither bind EGF nor mount a mitogenic response to TPA.

Animals↗

PubMed1988

Altered molecular properties of tubulin in a multidrug-resistant variant of Chinese hamster cells selected for resistance to vinca alkaloids.

The basis for the markedly altered intracellular binding of [3H]vincristine in a multidrug-resistant variant (DC-3F/VCRd-5L) of Chinese hamster lung cells (DC-3F) was investigated. Binding of [3H]vincristine by protein in cytosol derived from each cell type exhibited a differing requirement for GTP in MgCl2 containing buffer of low-ionic strength. Binding of [3H]vincristine occurred to cytosolic protein derived from both variant and parental DC-3F cells, but after removal of GTP, binding only occurred to cytosolic protein from parental cells regardless of the presence of added GTP. Although binding by cytosolic protein from parental DC-3F cells did not require GTP, the addition of 0.1 mM GTP increased by two-fold the rate and extent of binding. When cytosol from variant and parental DC-3F cells was incubated with low concentrations of [3H]vincristine in high-ionic strength buffer and analyzed by molecular-sieve HPLC, most of the protein binding [3H]vincristine in parentally derived cytosol eluted as Mr 110,000-115,000 daltons, corresponding to that for dimeric tubulin. The same binding species was not detected in cytosol derived from variant cells. However, these same fractions derived with both parental and variant cytosols contained tubulin as shown by SDS-PAGE and immunoblotting. A smaller peak of [3H]vincristine binding and an amount of tubulin equal to that found in later fractions were found in the void volume during the same HPLC elution runs with cytosol from both variant and parental DC-3F cells. Evidence was also obtained for differences between parental and variant DC-3F cells in beta-tubulin isoforms following isoelectric focusing and immunoblotting. Parental-cell cytosol contains a single isoform of beta-tubulin. However, in variant cell cytosol the same isoform and, in addition, three more basic isoforms were found. These alterations in [3H]vincristine binding and in isoform compositions of beta-tubulin in variant versus parental DC-3F cells may have importance in regard to vincristine resistance in DC-3F cells.

Animals↗

PubMed1989

GH4 pituitary cell variants selected as nonresponsive to thyrotropin-releasing hormone-enhanced substratum adhesion are nonresponsive to epidermal growth factor: evidence for a common signaling defect.

Thyrotropin-releasing hormone (TRH) and epidermal growth factor both enhance prolactin synthesis and substrate adhesion (a morphological change called stretching) of GH4 rat pituitary cells. We have examined TRH- and EGF-induced cell stretching using genetic and pharmacologic approaches. We selected and isolated a series of GH4 cell variants nonresponsive to TRH-induced cell stretching (str-). This selection yielded several variants that were nonresponsive to both TRH- and EGF-induced stretching but were still responsive to stretching induced by several other agents (tetradecanoylphorbol acetate [TPA], butyrate, and Neplanocin A). One of the str- variants (a14) was examined in detail. TRH, EGF, and TPA each enhanced prolactin synthesis in a14 cells, indicating that the a14 variant contained functional receptor binding sites for all 3 ligands as well as the capacity to generate those intracellular signals required for enhanced prolactin synthesis. Because the str- variants were isolated without selective pressure for EGF-induced stretching and because the possibility of more than one selectable mutation in all the variants is unlikely, we suggest that TRH and EGF share a common mechanism to induce cell stretching. We next examined whether the str- variants had a defect in a signaling pathway or in the biochemical endpoint for TRH- and EGF-induced cell stretching. A pharmacologic approach was utilized to investigate the biochemical basis for induced cell stretching. A synthetic Arg-Gly-Asp-Ser tetrapeptide (RGDS), specific for fibronectin and vitronectin adhesion receptors, inhibited TRH-, EGF-, and TPA-induced GH4 cell stretching and attachment to fibronectin- and vitronectin-coated dishes. These results suggest that the interaction between fibronectin and/or vitronectin and their receptor(s) may be a biochemical endpoint by which several agonists induced stretching of GH4 cells. Because the str- variant has RGDS-specific binding sites for fibronectin and vitronectin and responds to some agents that induce cell stretching via an RGDS receptor, we conclude that the a14 str- variant has a defect in an intracellular signaling pathway, shared by TRH and EGF, which induces cell stretching.

Animals↗

PubMed2007

New approach for rapid detection of known hemoglobin variants using LC-MS/MS combined with a peptide database.

The identification of hemoglobin (Hb) variants is usually performed by means of different analytical steps and methodologies. Phenotypic methods, such as gel electrophoresis and high performance liquid chromatography, are used to detect the different electrophoretic or chromatographic behaviors of hemoglobin variants in comparison to HbA0 used as a control. These data often need to be combined with mass spectrometry analyses of intact globins and their tryptic peptide mixtures. As an alternative to a 'step-by-step' procedure, we have developed a 'single step' approach for the identification of Hb variants present in biological samples. This is based on the microHPLC-ESI-MS/MS analysis of the peptide mixture generated by a tryptic digestion of diluted Hb samples and an in-house new database containing solely the variant tryptic peptide of known human Hb variants. The experimental results (full MS and MS/MS spectra) are correlated with theoretical mass spectra generated from our in-house-built variant peptide database (Hbp) using the SEQUEST algorithm. Simple preparation of samples and an automated identification of the variant peptide are the main characteristics of this approach, making it an attractive method for the detection of Hb variants at the routine clinical level. We have analyzed 16 different samples, each containing a different known variant of hemoglobin.

Amino Acid Sequence↗

PubMed2003

Human papillomavirus type-16 variants in Quechua aboriginals from Argentina.

Cervical carcinoma is the leading cause of cancer death in Quechua indians from Jujuy (northwestern Argentina). To determine the prevalence of HPV-16 variants, 106 HPV-16 positive cervical samples were studied, including 33 low-grade squamous intraepithelial lesions (LSIL), 28 high-grade squamous intraepithelial lesions (HSIL), 9 invasive cervical cancer (ICC), and 36 samples from women with normal colposcopy and cytology. HPV genome variability was examined in the L1 and E6 genes by PCR-hybridization. In a subset of 20 samples, a LCR fragment was also analyzed by PCR-sequencing. Most variants belonged to the European branch with subtle differences that depended on the viral gene fragment studied. Only about 10% of the specimens had non-European variants, including eight Asian-American, two Asian, and one North-American-1. E6 gene analysis revealed that 43% of the samples were identical to HPV-16 prototype, while 57% corresponded to variants. Interestingly, the majority (87%) of normal smears had HPV-16 prototype, whereas variants were detected mainly in SIL and ICC. LCR sequencing yielded 80% of variants, including 69% of European, 19% Asian-American, and 12% Asian. We identified a new variant, the Argentine Quechua-51 (AQ-51), similar to B-14 plus two additional changes: G7842-->A and A7837-->C; phylogenetic inference allocated it in the Asian-American branch. The high proportion of European variants may reflect Spanish colonial influence on these native Inca descendants. The predominance of HPV-16 variants in pathologic samples when compared to normal controls could have implications for the natural history of cervical lesions.

Argentina↗

PubMed2004

Analysis of human papillomavirus type-16 variants in Italian women with cervical intraepithelial neoplasia and cervical cancer.

Human papillomavirus type 16 (HPV-16) classes (E, AA, As, Af1, Af2) and their variants have different geographic distribution and different degrees of association with cervical lesions. This study was designed to examine HPV-16 variants among Italian women and their prevalence in case patients (affected by invasive cervical carcinoma or cervical intraepithelial neoplasia grade 2-3 and cervical intraepithelial neoplasia grade 1), versus control subjects with normal cervical epithelium (controls). A total of 90 HPV-16 positive cervical samples from women of Italian Caucasian descent have been tested, including 36 invasive cervical carcinomas, 21 with cervical intraepithelial neoplasias grade 2-3, 17 with cervical intraepithelial neoplasia grade 1 and 16 controls. HPV-16 was detected with an E6/E7 gene-specific polymerase chain reaction, and variant HPV-16 classes and subclasses were identified by direct nucleotide sequencing of the region coding for the E6 and the E7 oncoproteins, the MY09/11-amplified highly conserved L1 region, and the long control region (LCR). Among the 90 HPV-16 samples, nine viral variants have been identified belonging to the European (Ep-T350 and E-G350) and non-European (AA and Af-1) branches. The E-G350 is the prevalent variant in all analyzed different disease stages being present in 55.5% of ICC, 52.4% of cervical intraepithelial neoplasias 2-3, 47.1% of cervical intraepithelial neoplasia grade 1, and 50.0% of control samples. The non-European variants AA and Af1, rarely detected in control samples, represent 33.3% of all HPV-16 infections in invasive cervical carcinoma (with a peak of 19.4% and 13.9%, respectively), showing a statistically significant increase in frequency in more advanced lesions (chi(2) trend = 7.2; P < 0.05). The prevalence of HPV-16 Ep-T350, however, is higher in controls (43.7%) and in of cervical intraepithelial neoplasia grade 1 (41.2%) than in cervical intraepithelial neoplasia grade 2-3 (28.6%) and in invasive cervical carcinoma (11.1%) cases strongly suggesting lack of progression for pre-neoplastic lesions associated with such variant. The increased frequency of non-European variants in invasive lesions suggests that they are more oncogenic than European variants. This could have implications for future diagnostic and therapeutic strategies.

Adult↗

PubMed1999

Characterization of recombinant human brain-derived neurotrophic factor variants.

The purpose of this work was the chemical characterization of variants of the recombinant human brain derived neurotrophic factor (rHu-BDNF), expressed in Escherichia coli. This paper also addresses the question of the in vitro activity of these variants. Chemical characterization of the variants employed peptide mapping using Glu-C protease and cyanogen bromide digestion on reduced and alkylated variants followed by the analysis of the digested peptides using mass spectrometry and Edman sequencing. The BDNF variants in this work have been designated by the order of their elution as observed from the high temperature RPLC assay. It was determined that Peaks 1 and 2, which eluted just before the predominant BDNF peak, had methionine sulfoxide instead of methionine at positions 31 and 61, respectively. Peak 4, which is chromatographically a single peak, contained three variants. Two of these variants had norleucine instead of methionine, at positions 61 and 92, respectively, while the third had methionine sulfoxide instead of methionine at position 92. Peak 5 had norleucine at position 31 instead of methionine. All of these variants showed in vitro biological activity consistent with the BDNF standard, suggesting the preservation of the trkB receptor-ligand binding domain of the variants.

Alkylation↗

PubMed2002

Function of the exon 7 deletion variant estrogen receptor alpha protein in an estradiol-resistant, tamoxifen-sensitive human endometrial adenocarcinoma grown in nude mice.

BACKGROUND: In addition to hormone and DNA binding, interactions, including competition with other proteins, appear to be a critical component of transcriptional regulation by the estrogen receptor alpha (ER(alpha)). In vitro studies suggest that exon deletion (Delta exon) variant forms of ER(alpha) may also play an important role in determining the progression from hormone dependence to hormone independence in receptor positive tumors. METHODS: We investigated the presence of ERalpha mRNA and protein variants and their possible role in a moderately differentiated human endometrial adenocarcinoma grown in nude mice. In addition to wild-type (wt), RT-PCR assay of the tumor revealed the presence of two mRNA variants, a low concentration of Delta5 and a high concentration of Delta7 ER(alpha). We detected wt, Delta7, and Delta5,7 mRNA by sequencing the transcripts after stable transfection of three HeLa cells with either splice variant. The linked in vitro translation/transcription assay of the transfected cells and the Western blot analysis of the original tumor generated both wt (66 kDa) and Delta7 (52 kDa), Delta5,7 (46 kDa) ER(alpha) proteins. RESULTS: Tumor growth was characterized as estradiol and progesterone resistant but tamoxifen sensitive, i.e., neither estradiol nor progesterone treatment altered the growth rate, whereas tamoxifen treatment significantly increased the tumor volume doubling time. Estradiol treatment decreased the wt and increased the Delta7 variant ER(alpha) protein expression significantly in a dose-dependent manner. Tamoxifen treatment, however, increased the expression of both proteins whereas progesterone had no effect. Estradiol treatment did not influence expression of the Delta5,7 variant protein, which increased significantly in the tamoxifen-treated tumors. Gel mobility shift assays revealed that both wt and Delta7 ER(alpha) proteins bind to the consensus DNA sequence, whereas the Delta5,7 variant protein did not. CONCLUSIONS: We conclude that estradiol, tamoxifen, and progesterone regulate wt and variant ER(alpha) mRNA and protein expression separately and differently and that this hormonal regulation probably occurs, via different mechanisms, at the transcriptional or posttranscriptional level. The Delta7 variant ER(alpha) may play a crucial role in the determination of hormone sensitivity and thus in the outcome of hormone treatment of human endometrial adenocarcinomas.

Adenocarcinoma↗

PubMed1997

Thermodynamics of the interactions of lac repressor with variants of the symmetric lac operator: effects of converting a consensus site to a non-specific site.

What are the thermodynamic consequences of the stepwise conversion of a highly specific (consensus) protein-DNA interface to one that is nonspecific? How do the magnitudes of key favorable contributions to complex stability (burial of hydrophobic surfaces and reduction of DNA phosphate charge density) change as the DNA sequence of the specific site is detuned? To address these questions we investigated the binding of lac repressor (LacI) to a series of 40 bp fragments carrying symmetric (consensus) and variant operator sequences over a range of temperatures and salt concentrations. Variant DNA sites contained symmetrical single and double base-pair substitutions at positions 4 and/or 5 [sequence: see text] in each 10 bp half site of the symmetric lac operator (Osym). Non-specific interactions were examined using a 40 bp non-operator DNA fragment. Disruption of the consensus interface by a single symmetrical substitution reduces the observed equilibrium association constant (K(obs)) for Osym by three to four orders of magnitude; double symmetrical substitutions approach the six orders in magnitude difference between specific and non-specific binding to a 40 bp fragment. At these adjacent positions in the consensus site, the free energy effects of multiple substitutions are non-additive: the first reduces /deltaG(obs)o/ by 3 to 5 kcal mol(-1), approximately halfway to the non-specific level, whereas the second is less deleterious, reducing /deltaG(obs)o/ by less than 3 kcal mol(-1). Variant-specific dependences of K(obs) on temperature and salt concentration characterize these LacI-operator interactions. In general, binding constants and standard free energies of binding both exhibit characteristic extrema near 290 K. As a consequence, both the enthalpic and entropic contributions to stability of Osym and variant complexes change from positive (i.e. entropy driven) at lower temperatures to negative (i.e. enthalpy driven) at higher temperatures, indicating that the heat capacity change upon binding, deltaC(obs)o, is large and negative. In general, /deltaC(obs)o/ decreases as the specificity and stability of the variant complex decreases. Stabilities of complexes of LacI with Osym and all variant operators are strongly [salt]-dependent. Binding constants for the variant complexes exhibit a power-dependence on [salt] that is larger in magnitude (i.e. more negative) than for Osym, but no obvious trend relates changes in contributions from the polyelectrolyte effect and the observed reductions in stability (delta deltaG(obs)o). These variant-specific thermodynamic signatures provide novel insights into the consequences of converting a consensus interface to a less specific one; such insights are not obtained from comparisons at the level of delta deltaG(obs)o. We propose that this variant-specific behavior arises from a strong effect of operator sequence on the extent of induced conformational changes in the protein (and possibly also in the DNA site) which accompany binding.

Bacterial Proteins↗

PubMed1994

Analysis of interstrain variation in a putative immediate-early region of human herpesvirus 6 DNA and definition of variant-specific sequences.

Sequences of a 2.6- to 2.9-kb open reading frame in a putative immediate-early region of the human herpesvirus 6 (HHV6) genome were determined and compared in three reference and six local isolates of HHV6. The sequences segregated into two variant groups (A and B) having only 75% nucleotide homology and 62% peptide homology, in part because of deletions in the variant A strains. Among the variant B isolates, further sequence grouping was evident; two clinical isolates segregated with reference strain Z29 into a cluster that had 96.6% nucleotide homology and 92.6% peptide homology when compared to a second variant B cluster of four isolates. Within each cluster of variant B isolates, nucleotide homology was 99.4% or more. Two pairs of isolates had identical sequences. The marked divergence of variants A and B permitted the design of variant-specific oligonucleotide primers that could detect in a single polymerase chain reaction the presence of either or both variant A and B HHV6 DNA. Variation in this gene region of HHV6 is more extensive than in the envelope glycoprotein (gB and gH) coding regions and could be related to known biological differences between variant groups.

Amino Acid Sequence↗

PubMed2002

Out-of-frame versus in-frame core internal deletion variants of human and woodchuck hepatitis B viruses.

Human hepatitis B virus (HBV) variants containing in-frame core internal deletion (CID) have been demonstrated to contain all the functional features of defective interfering (DI) particles (Yuan, T. T.-T., M.-H. Lin, D. S. Chen, and C. Shih, 1998, J. Virol. 72, 578-584). Here, we report that out-of-frame HBV CID variants exhibit defective interfering property similar to in-frame CID variants characterized previously. This result raises the possibility that it may be the deleted pregenomic RNA product, rather than the deleted core protein product, that is responsible for interference. Furthermore, a genomic deletion elsewhere does not cause interference since preS2 deletion variants exhibit no influence on wild-type HBV replication. Consistent with the natural occurrence of HBV CID variants, we recently identified CID variants of woodchuck hepatitis virus (WHV) in natural infection. However, unlike HBV CID variants, functional characterization of WHV CID variants using a human hepatoma cell line has not revealed any interference in tissue culture. In summary, defective interference is a general phenomenon for both in-frame and out-of-frame HBV CID variants.

Animals↗

PubMed1985

Genetic complementation in somatic cell hybrids of four variants of infantile GM2 gangliosidosis.

Cell hybridizations between fibroblasts of four variants (B, O, AB, and B1) of infantile GM2 gangliosidosis were performed. Cocultivated as well as hybrid cells were analyzed for their capability to degrade exogenously added [3H]-GM2. Hybridization of variant AB fibroblasts with fibroblasts of variant O, variant B, or variant B1 resulted in an enhanced rate of GM2 hydrolysis, showing intergenic complementation. Similar restoration of GM2 catabolism was observed after hybridization of variant B1 cells with variant O, but not with variant B cells. These results indicate that B1 cells carry a mutation in the gene locus for the alpha-subunit of beta-hexosaminidase. Studies of the processing of immature enzyme in variant B1 cells showed the presence of alpha-precursors and mature alpha-chains, but at a lower level as compared to normal cells.

Electrophoresis, Polyacrylamide Gel↗

PubMed1982

Heterogeneity of "Mediterranean type" glucose-6-phosphate dehydrogenase (G6PD) deficiency in Spain and description of two new variants associated with favism.

Glucose-6-phosphate dehydrogenase (G6PD); EC 1.1.1.49 from thirty-six unrelated Spanish males was partially purified from blood, and the variants were characterized biochemically and electrophoretically according to the methods recommended by the world Health Organization. Subjects were from multiple geographic regions within Spain, and all suffered from hemolytic anemia, either acute (34 cases) or chronic nonspherocytic (2 cases). Almost all the variants studied presented residual erythrocyte G6PD activity ranging from 0 to 10% of normal, and five different mutants were responsible for the deficient phenotype. Three variants were similar to others previously described: G6PD Mediterranean (11 cases), G6PD Athens-like (3 cases), and G6PD Union (2 cases). The remaining variants were different from the numerous variants already reported and have been considered as new mutants. Provisionally they are called G6PD Betica (19 cases) and G6PD Menorca (1 case). The present study constitutes the first attempt to characterize the deficient G6PD variants found in Spain and supplies new data on the relationship between molecular characteristics of deficient variants and their clinical manifestations. The most important findings can be summarized as follows: (1) The Spanish population is characterized by an important heterogeneity in G6PD deficiency. (2) Although G6PD Mediterranean is very frequent, it presents a relatively high degree of polymorphism. (3) Favism has been observed associated with all kinds of variants described here. (4) G6PD Betica, which is the most frequent variant found in subjects of Southern Spanish origin, has been observed associated with favism in all cases except one.

Adolescent↗

PubMed1995

Expression of variant CD44 epitopes in human astrocytic brain tumors.

Expression of CD44 and of specific splice-variants of CD44 has been causally related to metastatic behaviour in a variety of carcinomas and lymphomas. To elucidate whether, in principle, similar splice-variants could be involved in glioma cell invasion we examined the expression of CD44 and its splice-variants in a series of 38 primary human brain tumors (28 astrocytomas, WHO grade I-III and 10 glioblastomas, WHO grade IV) and in cell lines derived from 9 glioblastomas. All brain tumors examined showed strong immunoreactivity for an N-terminal epitope present on all CD44 isoforms known. Using a polyclonal antiserum raised against the complete sequence encoded by variant exons v3 to v10, CD44 splice-variants could be detected irrespective of the grade of malignancy in many of the tumor samples at a low level and often restricted to only a few clustered tumor cells. Thus, the N-terminal epitope probably indicates the presence of the smallest and most ubiquitous isoform CD44s. Interestingly, all glioblastomas expressed CD44 variants whereas expression in astrocytomas WHO grade I, II, and III could only be detected in about half of the tumor samples. Using reverse transcriptase-PCR we were able to detect different CD44 splice-variants in the glioblastoma cell lines and in cultured primary astrocytic cells. Glioblastoma cells analyzed by flow cytometry showed the expected binding capacity for hyaluronic acid which could be increased twofold after pretreatment with hyaluronidase. The results presented show that there is low expression of CD44 variants in human tumors of astrocytic origin. Expression of CD44 and its splice-variants could contribute to the migration capacity of neoplastic astrocytes, and may be considered as a target for new diagnostic and therapeutic approaches in the clinical management of brain tumors.

Alternative Splicing↗

PubMed1986

In vitro cytopathology and pathogenicity to inbred mice shown by five variants of a laboratory strain of type 1 herpes simplex virus.

The in vitro cytopathology and the neurovirulence to inbred mice demonstrated by five variants originally derived from one laboratory strain (Miyama) of type 1 herpes simplex virus (HSV-1) were studied comparatively. Three of the variants are syncytial [+GC (LPV), +GC (SPV), +GC (81)] and two are non-syncytial [-GCr and -GCf]. The size of plaques produced by the five variants was found to be in the order of +GC (LPV) greater than +GC (81) greater than +GC (SPV) greater than -GCf greater than -GCr. The pathogenicity of these variants was compared in three kinds of inbred mice (AKR, C 3 H/He and C 57 BL) after intraperitoneal (IP) or intracerebral (IC) inoculation. The +GC (LPV) variant was the most virulent as shown by the highest mortality of mice by either route of inoculation. The other four variants caused death of mice only after IC inoculation, and among these variants, +GC (81) was shown to be the most virulent. These data indicate that so far as these five variants of the Miyama strain of HSV-1 are concerned, neurovirulence is positively correlated with their cell fusion activity or the size of plaques which they produce. Pre-IP-inoculation with any of the less virulent variants [-GCr, +GC (SPV) and +GC (81)] protected mice from subsequent lethal infection with +GC (LPV) by the same route of inoculation.

Animals↗

PubMed1982

Increased morphological variants in children with learning disabilities.

Previous studies have shown that children with learning disabilities have more morphological variants or anomalies than normal children, suggesting that the morphological and central nervous system effects may be the result of the same prenatal factors. The morphological variants were assumed to have arisen in the first 3 months of prenatal development, which may not be so. We have partitioned variants into those that probably arise early in fetal development ("early" variants) and those that could arise later and could be due to altered growth ("late" variants). There was an increase in both "early" and "late" variants but only that the "late" variants was statistically significant. Although the method of measuring one "early" variant (dermal patterns) was sensitive enough to detect mild disturbances in children with isolated congenital heart disease, such a disturbance was not found in our group of learning-disabled patients. Our findings suggest that the developmental disturbances resulting in morphological variants may act later in prenatal development than was previously believed. This information may be helpful in searching for clues to the etiology of this heterogeneous group of disabilities.

Adolescent↗

PubMed1980

Selection of variants of Pseudomonas aeruginosa resistant of Beta-lactam antibiotics.

In broth cultures of Pseudomonas aeruginosa, containing carbenicillin or azlocillin, regrowth occurred after a period of bactericidal action, to reach visible proportions overnight. Regrowth in the presence of relatively high concentrations of carbenicillin or azlocillin could not be accounted for on the basis of growth of resistant variants nor as a result of drug inactivation. On the other hand, resistant variants could be selected from the regrowth which occurred at concentrations of carbenicillin or azlocillin only slight in excess of the minimum inhibitory concentrations (MIC). Antibiotic resistant variants could also be isolated from individual colonies growing on agar plates containing carbenicillin, ticarcillin, azlocillin or piperaccillin at concentrations above the MIC for the majority of the population. Two types of resistant variant were isolated. The first showed a 2-5 fold increase in resistance to carbenicillin, ticarcillin, azlocillin and piperacillin while Beta-lactamase production in these variants appeared to be unchanged. The second type of resistant variant showed unchanged sensitivity to carbenicillin and ticarcillin, or only a slight increase in resistance, whereas resistance to azlocillin and piperacillin was increased as much as 40-fold or more. These variants showed increased constitutive Beta-lactamase production and may be derepressed mutants of the parent culture. Variants of this type were readily selected by culture in the presence of azlocillin or piperacillin but only infrequently as a result of culture in the presence of carbenicillin or ticarcillin. The existence in cultures of P. aeruginosa of variants showing elevated Beta-lactamase production may account at least in part for the effect of inoculum size on the activity of azlocillin and piperacillin against P. aeruginosa and the marked discrepancy between MIC and minimum bactericidal concentration (MBC) which is characteristic of the ureido penicillins.

Animals↗