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PubMed2004

Blastic natural killer (NK)-cell lymphoma: report of an unusual CD4 negative case and review of the CD4 negative neoplasms with blastic features in the literature.

Blastic Natural Killer (NK)-cell lymphoma is a relatively new entity which has been recently included in the WHO classification. CD4 expression is observed in most cases of blastic NK-cell lymphomas and has been related with skin tropism. We report an unusual CD4 negative blastic NK-cell lymphoma with primary presentation in the skin, subsequent infiltration of the bone marrow and aggressive behavior. It is emphasized that extensive immunophenotyping and EBER RNA in situ hybridization are required in order to establish the diagnosis of blastic NK-cell lymphoma. We also present a review of the literature with respect to the CD4 negative NK-cell lymphomas with blastic morphological features.

Adult↗

PubMed2005

Dissociation of Akt1 from its negative regulator JIP1 is mediated through the ASK1-MEK-JNK signal transduction pathway during metabolic oxidative stress: a negative feedback loop.

We have previously observed that metabolic oxidative stress-induced death domain-associated protein (Daxx) trafficking is mediated by the ASK1-SEK1-JNK1-HIPK1 signal transduction pathway. The relocalized Daxx from the nucleus to the cytoplasm during glucose deprivation participates in a positive regulatory feedback loop by binding to apoptosis signal-regulating kinase (ASK) 1. In this study, we report that Akt1 is involved in a negative regulatory feedback loop during glucose deprivation. Akt1 interacts with c-Jun NH(2)-terminal kinase (JNK)-interacting protein (JIP) 1, and Akt1 catalytic activity is inhibited. The JNK2-mediated phosphorylation of JIP1 results in the dissociation of Akt1 from JIP1 and subsequently restores Akt1 enzyme activity. Concomitantly, Akt1 interacts with stress-activated protein kinase/extracellular signal-regulated kinase (SEK) 1 (also known as MKK4) and inhibits SEK1 activity. Knockdown of SEK1 leads to the inhibition of JNK activation, JIP1-JNK2 binding, and the dissociation of Akt1 from JIP1 during glucose deprivation. Knockdown of JIP1 also leads to the inhibition of JNK activation, whereas the knockdown of Akt1 promotes JNK activation during glucose deprivation. Altogether, our data demonstrate that Akt1 participates in a negative regulatory feedback loop by interacting with the JIP1 scaffold protein.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Dominant-negative mutants of prgX: evidence for a role for PrgX dimerization in negative regulation of pheromone-inducible conjugation.

PrgX negatively regulates prgQ transcriptional readthrough in the pheromone-inducible enterococcal conjugative plasmid pCF10. We isolated and characterized 13 dominant-negative prgX mutants, all of which mapped in either the N- or the C-terminus of PrgX. In all mutants, the in vivo level of Qa RNA, an antisense RNA to prgQ RNA, was greatly reduced. When oligomerization of PrgX was tested with a phage lambda cI repressor fusion system, the oligomerization domain was found to be between amino acid residues 78 and 280. When histidine-tagged PrgX (His-PrgX) was purified by nickel column chromatography from a strain also expressing PrgX, PrgX was co-purified with His-PrgX. Although PrgX was expressed at a much higher level than His-PrgX, an approximately equal amount of PrgX was co-purified. Pheromone induction greatly decreased the co-purification of PrgX. Based on these data, we propose that both the N- and the C-terminal domains of PrgX are required for PrgX positive autoregulation and for the repression of prgQ transcription readthrough. In vivo, PrgX exists as a dimer, and dimerization is mediated by the central region of PrgX.

Amino Acid Sequence↗

PubMed2006

Accentuate the negative: the positive effects of negative acknowledgment.

Three studies investigated the capacity of negative acknowledgment, the admission of an unfavorable quality, to elicit relatively positive responses. In Study 1, an acknowledgment that a written paragraph was confusing led individuals to rate the paragraph as clearer than they did when no acknowledgment was offered. In Study 2, a foreign speaker was rated as possessing a clearer voice when he acknowledged his strong accent than when he did not. In Study 3, a hypothetical college applicant's acknowledgment of receiving less than stellar high school grades resulted in a more positive evaluation of those grades. The interpersonal risks and benefits of negative acknowledgment as an impression-management strategy are discussed.

Adolescent↗

PubMed1983

Production and Characteristics of Raw Starch-Digesting Glucoamylase O from a Protease-Negative, Glycosidase-Negative Aspergillus awamori var. kawachi Mutant.

Production of a raw starch-digesting glucoamylase O (GA O) by protease-negative, glycosidase-negative mutant strain HF-15 of Aspergillus awamori var. kawachi was undertaken under submerged culture conditions. The purified GA O was electrophoretically homogeneous and similar to the parent glucoamylase I (GA I) in the hydrolysis curves toward gelatinized potato starch, raw starch, and glycogen and in its thermostability and pH stability, but it was different in molecular weight and carbohydrate content (250,000 and 24.3% for GA O, 90,000 and ca. 7% for GA I, respectively). The chitin-bound GA O hydrolyzed raw starch but the chitin-bound GA I failed to digest raw starch because chitin was adsorbed at the raw starch affinity site of the GA I molecule. The removal of the raw starch affinity site of GA O with subtilisin led to the formation of a modified GA O (molecular weight, 170,000), which hydrolyzed glycogen 100%, similar to GA O and GA I, and was adsorbed onto chitin and fungal cell wall but not onto raw starch, Avicel, or chitosan. The modified GA I (molecular weight, 83,000) derived by treatment with substilisin hydrolyzed glycogen up to only 80% and failed to be adsorbed onto any of the above polysaccharides. The N-bromosuccinimide-oxidized GA O lost its activity toward gelatinized and raw starches, but the abilities to be adsorbed onto raw starch and chitin were preserved. It was thus suggested that both the raw starch affinity site essential for raw starch digestion and the chitin-binding site specific for the binding with chitin in the cell wall could be different from the active site, located in the three respective positions in the GA O molecule.

Journal Article↗

PubMed2001

Ancestral divergence, genome diversification, and phylogeographic variation in subpopulations of sorbitol-negative, beta-glucuronidase-negative enterohemorrhagic Escherichia coli O157.

The O157:H7 lineage of enterohemorrhagic Escherichia coli is a geographically disseminated complex of highly related genotypes that share common ancestry. The common clone that is found worldwide carries several markers of events in its evolution, including markers for acquisition of virulence genes and loss of physiological characteristics, such as sorbitol fermentation ability and beta-glucuronidase production. Populations of variants that are distinct with respect to motility and the sorbitol and beta-glucuronidase markers appear to have diverged at several points along the inferred evolutionary pathway. In addition to these variants, distinct subpopulations of the contemporary non-sorbitol-fermenting, beta-glucuronidase-negative O157:H7 clone were recently detected among bovine and human clinical isolates in the United States by using high-resolution genome comparison. In order to determine if these recently described subpopulations were derived from a regional or ancestral divergence event, we used octamer-based genome scanning, marker sorting, and DNA sequence analysis to examine their phylogenetic relationship to populations of non-sorbitol-fermenting, beta-glucuronidase negative O157:H7 and O157:H- strains from Australia. The inferred phylogeny is consistent with the hypothesis that subpopulations on each continent resulted from geographic spread of an ancestral divergence event and subsequent expansion of distinct subpopulations. Marker sorting and DNA sequence analyses identified sets of monophyletic markers consistent with the pattern of divergence and demonstrated that phylogeographic variation occurred through emergence of regional subclones and concentration of regional polymorphisms among distinct subpopulations. DNA sequence analysis of representative polyphyletic markers showed that genome diversity accrued through random drift and bacteriophage-mediated events.

Animals↗

PubMed2006

Dominant-negative TLR5 polymorphism reduces adaptive immune response to flagellin and negatively associates with Crohn's disease.

Crohn's disease (CD) is associated with elevated adaptive immunity to commensal microbes, with flagellin being a dominant antigen. In light of heightened awareness of the importance of innate immunity in regulating adaptive immunity and ambiguity as to the role of CD-associated immune responses in CD pathophysiology, we sought to determine whether natural acquisition of immune responses to flagellin were regulated by the innate immune flagellin receptor toll-like receptor 5 (TLR5) and determine whether persons carrying a recently defined common dominant-negative TLR5 polymorphism (TLR5-stop) might be protected from developing CD. Carriage rates of a recently defined dominant-negative TLR5 polymorphism (TLR5-stop) and levels of serum immunoreactivity to bacterial products were measured in inflammatory bowel disease patients, first-degree relatives, and unrelated controls. We observed that, in healthy subjects, persons carrying TLR5-stop had significantly lower levels of flagellin-specific IgG and IgA but had similar levels of total and LPS-specific Ig. Moreover, we observed that, among Jewish subjects, the carriage rate of TLR5-stop (in heterozygous state) was significantly less in CD patients, but not ulcerative colitis (UC) patients, compared with unaffected relatives and unrelated controls (5.4, 0.9, 6.0, and 6.5% for unaffected relatives, CD, UC, and unrelated Jewish controls, respectively, n = 296, 215, 185, and 416, respectively; P = 0.037 by likelihood calculation for CD vs. controls), indicating that TLR5-stop can protect persons of Jewish ethnicity against CD. We did not observe a significant association of TLR5-stop with CD in a non-Jewish cohort (11.1, 10.4, and 11.7% for unaffected relatives, CD, and UC, respectively; n = 841, 543, and 300 for unaffected relatives, respectively). These results demonstrate that natural acquisition of immune responses to flagellin are regulated by TLR5 and suggest that immune responses to flagellin are not merely associated with CD but rather promote the pathogenic response.

Adaptation, Physiological↗

PubMedDate not supplied

Mismatch negativity and late discriminative negativity in investigating speech perception and learning in children and infants.

For decades, behavioral methods, such as the head-turning or sucking paradigms, have been the primary tools to investigate speech perception and learning of a language in infancy. Recently, however, new methods provided by event-related potentials have emerged. These are called mismatch negativity (MMN) and late discriminative negativity (LDN). MMN, the brain's automatic change-detection response in audition, has been intensively used in adults in both basic and clinical studies for longer than 20 years. LDN, on the other hand, was only recently discovered. There seem to be many differences between these two responses. MMN is developmentally quite stable and can be obtained even from preterm infants. LDN, however, can be obtained most reliably from young children, and its amplitude decreases as a function of age. New data suggest that both of these responses have a special role in language processing, although both of them can also be elicited by nonspeech stimuli.

Child↗

PubMed1997

Existence of c-kit receptor-positive, tryptase-negative, IgE-negative cells in human allergic nasal mucosa: a candidate for mast cell progenitor.

The accumulation of mast cells in the allergic nasal epithelium is well known, yet the mechanism remains unclear. We studied whether there is a candidate for mast cell progenitors in the allergic nasal mucosa tissue removed at the time of surgery. We first confirmed that most mast cells in nasal mucosae of 10 nasal allergic patients had c-kit receptor by immunohistochemistry using the mirror sectioning technique. We then investigated whether c-kit receptor+, tryptase-, IgE- cells existed in nasal mucosae of 15 nasal allergic patients and 15 nonallergic ones using sequential triple immunohistochemistry. We observed the area in which 1,000 to 1,100 tryptase-positive cells (mast cells) existed in both the subepithelial layer and the deep layer of each nasal lamina propria. The epithelial layer above this area was also examined. Some c-kit receptor+, tryptase- cells existed in the nasal mucosae of 11 patients with nasal allergy and of 5 patients with nonallergic rhinitis. From one to four of these cells in the nasal epithelium and subepithelial layer of the 4 allergic patients were IgE-negative. In contrast, no IgE-negative cells existed in the deep layer of allergic nasal mucosae or in any nonallergic nasal mucosae. Our results suggest that mast cell progenitors, hematopoietic progenitor cells or multipotential blood cells exist in the allergic nasal mucosa, and may contribute to the increase of mast cells in the epithelium and subepithelial layer of allergic nasal mucosa.

Adolescent↗

PubMed2005

Participation in operation starting line, experience of negative emotions, and incidence of negative behavior.

The prison industry in the United States has experienced an unprecedented period of growth during the past three decades. Growing dissatisfaction with the monetary investment in the criminal justice system, state-level budget constraints, and high recidivism rates have led many criminal justice professionals to rethink issues of offender resocialization and rehabilitation. Faith-based prison programs are increasingly being used as inexpensive methods for potentially improving the institutional behavior of inmates and reducing their likelihood of postrelease arrest. Unfortunately, however, there is little systematic research on this issue. Using data from Mississippi's largest state prison, the authors explore the relationship between participation in the faith-based prison event, Operation Starting Line, and subsequent experience of negative emotions and incidence of negative behaviors. Descriptive results suggest modest, yet positive, effects of attendance at the event. The article concludes with comments about the potential efficacy of faith-based prison programs and suggestions for future research.

Adult↗

PubMed2003

Angiogenesis relates to estrogen receptor negativity, c-erbB-2 overexpression and early relapse in node-negative ductal carcinoma of the breast.

Tumor angiogenic activity is an important process linked to tumor growth, metastasis, and invasion. In the present study we investigated whether intratumoral microvessel density (MVD), as assessed with immunohistochemistry, is of prognostic relevance in a series of 77 breast cancer patients with node-negative disease. The mean MVD in the hot spots ranged from 9 to 106 (median 31) vessels per x200 optical field. Patients were grouped into 3 categories of low (27 pts), medium (26 pts), and high (24 pts) MVD. Angiogenesis was not related to the primary tumor dimensions (T-stage) or the histology differentiation. An inverse association of MVD with estrogen receptor (ER) expression was noted (p=0.0007), while high MVD was directly related to c-erbB-2 overexpression (p=0.04) and high MIB1 proliferation index (p=0.02). In univariate and multivariate analysis of relapse-free survival, MVD was the only variable significantly and independently linked to relapse. It is concluded that high intratumoral angiogenic activity is linked with early relapse in node-negative breast cancer.

Breast Neoplasms↗

PubMed2001

Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23.

PURPOSE: Uncertainty about the relative worth of doxorubicin/cyclophosphamide (AC) and cyclophosphamide/methotrexate/fluorouracil (CMF), as well as doubt about the propriety of giving tamoxifen (TAM) with chemotherapy to patients with estrogen receptor-negative tumors and negative axillary nodes, prompted the National Surgical Adjuvant Breast and Bowel Project to initiate the B-23 study. PATIENTS AND METHODS: Patients (n = 2,008) were randomly assigned to CMF plus placebo, CMF plus TAM, AC plus placebo, or AC plus TAM. Six cycles of CMF were given for 6 months; four cycles of AC were administered for 63 days. TAM was given daily for 5 years. Relapse-free survival (RFS), event-free survival (EFS), and survival (S) were determined by using life-table estimates. Tests for heterogeneity of outcome used log-rank statistics and Cox proportional hazards models to detect differences across all groups and according to chemotherapy and hormonal therapy status. RESULTS: No significant difference in RFS, EFS, or S was observed among the four groups through 5 years (P =.96,.8, and.8, respectively), for those aged < or = 49 years (P =.97,.5, and.9, respectively), or for those aged > or = 50 years (P =.7,.6, and.6, respectively). A comparison between all CMF- and all AC-treated patients demonstrated no significant differences in RFS (87% at 5 years in both groups, P =.9), EFS (83% and 82%, P =.6), or S (89% and 90%, P =.4). There were no significant differences in RFS, EFS, or S between CMF and AC in patients aged < or = 49 or > or = 50 years. No significant difference in any outcome was observed when chemotherapy-treated patients who received placebo were compared with those given TAM. RFS in both groups was 87% (P =.6), 87% in patients aged < or = 49 (P =.9), and 88% and 87%, respectively (P =.4), in those aged > or = 50 years. CONCLUSION: There was no significant difference in the outcome of patients who received AC or CMF. TAM with either regimen resulted in no significant advantage over that achieved from chemotherapy alone.

Age Factors↗

PubMed2004

Ten-year outcomes in a population-based cohort of node-negative, lymphatic, and vascular invasion-negative early breast cancers without adjuvant systemic therapies.

PURPOSE: To discuss the absolute benefits from adjuvant systemic therapy knowledge of long-term outcomes and baseline risks of relapse and disease-specific survival are required. We assessed the 10-year outcomes in a population-based cohort of node-negative (N-) lymphovascular negative (LV-) early breast cancers diagnosed from 1989 to 1991 who did not receive adjuvant systemic therapy. METHODS: One thousand one hundred eighty-seven cases of pT(1-2)N(0) LV- breast cancers with a median follow-up of 10.4 years were reviewed. Kaplan-Meier survival curves for relapse free survival (RFS), breast cancer-specific survival (BCSS) and overall survival (OS) were compared with log-rank tests with cohorts stratified for tumor size and grade. RESULTS: The median age of this series was 62 years. Four hundred thirty tumors were < or = 1 cm in diameter (cohort 1), 507 were 1.1-2 cm (cohort 2), and 250 were 2.1 to 5 cm in diameter (cohort 3). The 10-year outcomes for cohorts 1, 2, and 3, respectively, were significantly different: RFS, 82%, 75%, and 66%; BCSS, 92%, 90%, and 77%; and OS, 79%, 78%, and 66%. Tumor grade significantly altered outcome within size cohorts, particularly in pT(1)N(0) breast cancers. CONCLUSION: This study provides detailed information on the continued relapse and breast cancer death rate to 10 years of follow-up. Specifically, without adjuvant systemic therapy, patients with LV-, N - breast cancer had a > or = 25% 10-year risk of relapse and a corresponding 10-year breast cancer death rate of > or = 10% if they had either a grade 3 tumor < or = 1 cm, a grade 2 to 3 tumor from 1.1 to 2 cm, or any grade tumor greater than 2 cm.

Adult↗

PubMed1997

Strain specific production of a negative regulator of IL-3 (NIL-3): difference in the negative feedback mechanism of hemopoiesis among mouse strains.

The producing cells of the negative regulator of interleukin-3 (NIL-3) were investigated. The 5-fluorouracil-treated bone marrow cells did not produce NIL-3. The bone marrow cells of stem cell-depleted W/WV mouse did not produce the NIL-3, either. The production of NIL-3 was different among mouse strains. Mice of C3H/HeN, A/J and ICR strains produced NIL-3, but the C57BL/6 mice did not produce NIL-3. These results indicate that the negative feedback mechanism of hemopoiesis is different among mouse strains. In the present study, we could not definitely identify the NIL-3 producing cells, although the present results are suggestive that the stem cells in cycle are a NIL-3 producer. Instead, we found that hemopoietic regulatory mechanisms might be different among mouse strains, especially in C57BL/6 mice.

Animals↗

PubMed1987

The use of intradermal tests and relevance of negative controls in patients with negative or equivocal modified RAST test scores to inhalant allergens.

Patients with suspected inhalant allergy that demonstrate a Modified RAST Test (MRT) Class 0 and 1 (equivocal) may demonstrate positive infradermal (ID) skin whealing to suspect allergens. This whealing may be due, however, to an irritant reaction from glycerin used as a preservative in the extract. The purpose of this study is to establish the incidence of allergy as demonstrated by ID testing in patients with MRT Class 0 or 1 and to reinforce the importance of negative controls during ID testing. Fifty-five consecutive patients evaluated for allergy with MRT Classes 0 or 1 were studied. Intradermal testing with 1:500 wt/vol concentrations of allergenic extracts and a 2% glycerin control were performed. Thirty-eight patients (69%) were found to have ID whealing to allergenic extracts greater than the negative glycerin controls. We conclude that ID allergen testing of patients with MRT Class 0 or 1, when using a glycerin control, identifies additional allergens to be considered for immunotherapy.

Allergens↗

PubMed1988

The negative therapeutic reaction: the uses of negation.

The negative therapeutic reaction can be used as a lens illuminating issues of psychoanalytic technique and therapeutic change. Its paradoxical development is examined within the context of current controversies involving the concepts of borderline personality organization and empathy. Negative therapeutic reactions are seen to reflect, among other failings, the failure of theory to "contain" dialectical tensions between self and other, subject and object, health and illness. Greater theoretical sophistication can point the way toward vigorous and more hopeful therapeutic engagement of these challenging reactions.

Borderline Personality Disorder↗

PubMed1979

Effects of response-independent negative reinforcers on negatively reinforced key pecking.

Previous research has shown that presenting response-independent positive reinforcers reduces the response rate of an operant maintained by positive reinforcement. The present experiment investigated a similar effect using shock-free time as a negative reinforcer. Brief shocks were delivered in the presence of a distinctive stimulus, and pigeon's key pecks were reinforced by the occasional presentation of a 2-minute shock-free period. Extra 2-minute shock-free periods were added independently of behavior. For each of three pigeons, response rate during shock-on periods declined with added shock-free periods; the more frequently the extra shock-free periods occurred the greater the decline in response rate. This outcome is predicted by extending the Law of Effect to include negative reinforcement.

Journal Article↗

PubMed1996

B2 bradykinin receptors in cultured neonatal rat cardiomyocytes mediate a negative chronotropic and negative inotropic response.

Receptors for bradykinin (BK) were characterized in primary cultures of beating neonatal rat cardiomyocytes using [3H]BK was radioligand. Degradation studies demonstrated that [3H]BK was stable for at least 2 h when incubated with cardiomyocytes at 2 and 37 degrees C in the presence of bacitracin in combination with captopril or ramiprilat. Without these inhibitors, > 80% of the [3H]BK was degraded within 2 h at 37 degrees C. This indicates that angiotensin-converting enzyme (ACE) is responsible for the main BK-degrading activity in cardiomyocytes. Scatchard plots were linear and gave a Kd of 1.5 +/- 0.8 nmol/l (mean +/- SD, n = 4) and a maximum binding capacity of 55-125 fmol/mg protein. Association and dissociation studies showed that binding of [3H]BK was saturable and reversible. Binding of [3H]BK at 37 degrees C led to internalization of the ligand. Competition studies with B1 and B2 agonists and antagonists were consistent with a B2 subtype of receptor. Addition of BK to beating cardiomyocytes (> 1 nmol/l) at 37 degrees C gave a strong but transient negative chronotropic effect. This response was paralleled by changes in the pulsation amplitude, which indicated a simultaneous negative inotropic effect of BK. These results provide a basis for the hypothesis that ACE inhibition exerts its cardioprotective effect at the level of a population of cardiomyocytes by virtue of kinin receptor-mediated mechanisms.

Angiotensin-Converting Enzyme Inhibitors↗