Showing papers by "University of Rochester published in 1998"

The involvement of cell-to-cell signals in the development of a bacterial biofilm

Abstract: Bacteria in nature often exist as sessile communities called biofilms. These communities develop structures that are morphologically and physiologically differentiated from free-living bacteria. A cell-to-cell signal is involved in the development of Pseudomonas aeruginosa biofilms. A specific signaling mutant, a lasI mutant, forms flat, undifferentiated biofilms that unlike wild-type biofilms are sensitive to the biocide sodium dodecyl sulfate. Mutant biofilms appeared normal when grown in the presence of a synthetic signal molecule. The involvement of an intercellular signal molecule in the development of P. aeruginosa biofilms suggests possible targets to control biofilm growth on catheters, in cystic fibrosis, and in other environments where P. aeruginosa biofilms are a persistent problem.

Retinoblastoma protein recruits histone deacetylase to repress transcription

Abstract: The retinoblastoma protein (Rb) silences specific genes that are active in the S phase of the cell cycle and which are regulated by E2F transcription factors Rb binds to the activation domain of E2F and then actively represses the promoter by a mechanism that is poorly understood Here we show that Rb associates with a histone deacetylase, HDAC1, through the Rb 'pocket' domain Association with the deacetylase is reduced by naturally occurring mutations in the pocket and by binding of the human papilloma virus oncoprotein E7 We find that Rb can recruit histone deacetylase to E2F and that Rb cooperates with HDAC1 to repress the E2F-regulated promoter of the gene encoding the cell-cycle protein cyclin E Inhibition of histone deacetylase activity by trichostatin A (TSA) inhibits Rb-mediated repression of a chromosomally integrated E2F-regulated promoter Our results indicate that histone deacetylases are important for regulating the cell cycle and that active transcriptional repression by Rb may involve the modification of chromatin structure

Roles of histone acetyltransferases and deacetylases in gene regulation

Abstract: Acetylation of internal lysine residues of core histone N-terminal domains has been found correlatively associated with transcriptional activation in eukaryotes for more than three decades. Recent discoveries showing that several transcriptional regulators possess intrinsic histone acetyltransferase (HAT) and deacetylase (HDAC) activities strongly suggest that histone acetylation and deacetylation each plays a causative role in regulating transcription. Intriguingly, several HATs have been shown an ability to acetylate nonhistone protein substrates (e.g., transcription factors) in vitro as well, suggesting the possibility that internal lysine acetylation of multiple proteins exists as a rapid and reversible regulatory mechanism much like protein phosphorylation. This article reviews recent developments in histone acetylation and transcriptional regulation. We also discuss several important, yet unanswered, questions.

Thermodynamic parameters for an expanded nearest-neighbor model for formation of RNA duplexes with Watson - Crick base pairs

Abstract: Improved thermodynamic parameters for prediction of RNA duplex formation are derived from optical melting studies of 90 oligoribonucleotide duplexes containing only Watson−Crick base pairs. To test end or base composition effects, new sets of duplexes are included that have identical nearest neighbors, but different base compositions and therefore different ends. Duplexes with terminal GC pairs are more stable than duplexes with the same nearest neighbors but terminal AU pairs. Penalizing terminal AU base pairs by 0.45 kcal/mol relative to terminal GC base pairs significantly improves predictions of ΔG°37 from a nearest-neighbor model. A physical model is suggested in which the differential treatment of AU and GC ends accounts for the dependence of the total number of Watson−Crick hydrogen bonds on the base composition of a duplex. On average, the new parameters predict ΔG°37, ΔH°, ΔS°, and T M within 3.2%, 6.0%, 6.8%, and 1.3 °C, respectively. These predictions are within the limit of the model, based on...

Supporting autonomy to motivate patients with diabetes for glucose control

Abstract: OBJECTIVE We applied the self-determination theory of human motivation to examine whether patient perceptions of autonomy supportiveness (i.e., patient centeredness) from their diabetes care providers related to improved glucose control over a 12-month period. RESEARCH DESIGN AND METHODS We conducted a prospective cohort study of patients with diabetes from a diabetes treatment center at a university-affiliated community hospital. Participants were 128 patients between 18 and 80 years of age who took medication for diabetes, had no other major medical illnesses, and were responsible for monitoring their glucose and taking their medications. The main outcome measure was a change in HbA 1c values over the 12 months of the study. RESULTS Patient perception of autonomy support from a health care provider related to a change in HbA 1c values at 12 months ( P P P 1c values over 12 months ( P CONCLUSIONS The findings support the prediction of the self-determination theory that patients with diabetes whose health care providers are autonomy supportive will become more motivated to regulate their glucose levels, feel more able to regulate their glucose, and show improvements in their HbA 1c values.

Long-term effects of nurse home visitation on children's criminal and antisocial behavior: 15-year follow-up of a randomized controlled trial.

Abstract: Context.— A program of home visitation by nurses has been shown to affect the rates of maternal welfare dependence, criminality, problems due to use of substances, and child abuse and neglect. However, the long-term effects of this program on children’s antisocial behavior have not been examined. Objective.— To examine the long-term effects of a program of prenatal and early childhood home visitation by nurses on children’s antisocial behavior. Design.— Fifteen-year follow-up of a randomized trial. Interviews were conducted with the adolescents and their biological mothers or custodial parents. Setting.— Semirural community in New York. Participants.— Between April 1978 and September 1980, 500 consecutive pregnant women with no previous live births were recruited, and 400 were enrolled. A total of 315 adolescent offspring participated in a follow-up study when they were 15 years old; 280 (89%) were born to white mothers, 195 (62%) to unmarried mothers, 151 (48%) to mothers younger than 19 years, and 186 (59%) to mothers from households of low socioeconomic status at the time of registration during pregnancy. Intervention.— Families in the groups that received home visits had an average of 9 (range, 0-16) home visits during pregnancy and 23 (range, 0-59) home visits from birth through the child’s second birthday. The control groups received standard prenatal and well-child care in a clinic. Main Outcome Measures.— Children’s self-reports of running away, arrests, convictions, being sentenced to youth corrections, initiation of sexual intercourse, number of sex partners, and use of illegal substances; school records of suspensions; teachers’ reports of children’s disruptive behavior in school; and parents’ reports of the children’s arrests and behavioral problems related to the children’s use of alcohol and other drugs. Results.— Adolescents born to women who received nurse visits during pregnancy and postnatally and who were unmarried and from households of low socioeconomic status (risk factors for antisocial behavior), in contrast with those in the comparison groups, reported fewer instances (incidence) of running away (0.24 vs 0.60; P = .003), fewer arrests (0.20 vs 0.45; P = .03), fewer convictions and violations of probation (0.09 vs 0.47; P,.001), fewer lifetime sex partners (0.92 vs 2.48; P = .003), fewer cigarettes smoked per day (1.50 vs 2.50; P = .10), and fewer days having consumed alcohol in the last 6 months (1.09 vs 2.49; P = .03). Parents of nurse-visited children reported that their children had fewer behavioral problems related to use of alcohol and other drugs (0.15 vs 0.34; P = .08). There were no program effects on other behavioral problems. Conclusions.— This program of prenatal and early childhood home visitation by nurses can reduce reported serious antisocial behavior and emergent use of substances on the part of adolescents born into high-risk families. JAMA. 1998;280:1238-1244 JUVENILE CRIME is a significant problem in the United States. In 1996, law enforcement agencies made 2.9 million arrests of juveniles (children ,18 years). Moreover, 19% of all arrests and 19% of all violent crime arrests were accounted for by juveniles. Although the number of juvenile Violent Crime Index arrests (ie, for murder, forcible rape, robbery, and aggravated assault) declined in both 1995 and 1996, the rate in 1996 was still 60% higher than the 1987 level. 1

Computation of Conditional Probability Statistics by 8-Month-Old Infants

Abstract: A recent report demonstrated that 8-month-olds can seg- ment a continuous stream of speech syllables, containing no acoustic or prosodic cues to word boundaries, into wordlike units after only 2 min of listening experience (Saffran, Aslin, & Newport, 1996). Thus, a powerful learning mechanism capable of extracting statistical informa- tion from fluent speech is available early in development. The present study extends these results by documenting the particular type of statis- tical computation—transitional (conditional) probability—used by infants to solve this word-segmentation task. An artificial language corpus, consisting of a continuous stream of trisyllabic nonsense words, was presented to 8-month-olds for 3 min. A postfamiliarization test compared the infants' responses to words versus part-words (tri- syllabic sequences spanning word boundaries). The corpus was con- structed so that test words and part-words were matched in frequency, but differed in their transitional probabilities. Infants showed reliable discrimination of words from part-words, thereby demonstrating rapid segmentation of continuous speech into words on the basis of transi- tional probabilities of syllable pairs.

The development of depression in children and adolescents.

Abstract: In recent decades, research on child and adolescent depression has proliferated. Currently, attention in the field is directed toward examining the epidemiology, causes, course, sequelae, and treatment response of children at risk for developing or presently experiencing depressive disorders. In this article, a developmental psychopathology approach is used to elucidate the development of depressive disorders, the diverse pathways that evolve, and the processes that contribute to varied outcomes. The developmental psychopathology perspective underscores the importance of moving beyond the identification of isolated aberrations in psychological and biological components of depressive presentations to the understanding of how those components have evolved and how they are integrated within and transact across biological, psychological, and social systems. Implications for prevention and intervention are addressed as is the importance of increasing the public awareness of depressive disorders and reducing the social stigma that interfere with the attainment of treatment for depressed persons.

Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: A key role for bioavailable estrogen

Abstract: Estrogen (E) deficiency associated with the menopause is the major cause of bone loss in aging women. However, men also lose significant amounts of bone with age, but they do not have the equivalent of menopause, and serum total testosterone (T) and E levels decline only marginally with age in men. Thus, it has been difficult to attribute bone loss in aging men to either T or E deficiency. Here, we show in a population-based, age-stratified sample of 346 men, aged 23-90 yr, that serum total T and E (estradiol plus estrone) levels decreased over the life span by 30% and 12%, respectively, but bioavailable (or nonsex hormone-binding globulin-bound) T and E levels decreased by 64% and 47%, respectively. In these men and in a parallel cohort of 304 women, aged 21-94 yr, serum PTH increased 84% and 64% over the life span, and urinary N-telopeptide of type I collagen (NTx) excretion, a bone resorption marker, increased 77% and 80% between age 50-85 yr in the men and women, respectively. By univariate analyses, serum bioavailable T and E levels correlated positively with bone mineral density (BMD) at the total body, spine, proximal femur, and distal radius and negatively with urinary NTx excretion in men and women. Urinary NTx excretion was also negatively associated with BMD in both sexes. By multivariate analyses, however, serum bioavailable E level was the consistent independent predictor of BMD in both men and postmenopausal women. Thus, bioavailable E levels decline significantly with age and are important predictors of BMD in men as well as women. These studies suggest that in contrast to traditional belief, age-related bone loss may be the result of E deficiency not just in postmenopausal women, but also in men.

The population genetics of adaptation : the distribution of factors fixed during adaptive evolution

Abstract: We know very little about the genetic basis of adaptation. Indeed, we can make no theoretical predictions, however heuristic, about the distribution of phenotypic effects among factors fixed during adaptation nor about the expected "size" of the largest factor fixed. Study of this problem requires taking into account that populations gradually approach a phenotypic optimum during adaptation via the stepwise substitution of favorable mutations. Using Fisher's geometric model of adaptation, I analyze this approach to the optimum, and derive an approximate solution to the size distribution of factors fixed during adaptation. I further generalize these results to allow the input of any distribution of mutational effects. The distribution of factors fixed during adaptation assumes a pleasingly simple, exponential form. This result is remarkably insensitive to changes in the fitness function and in the distribution of mutational effects. An exponential trend among factors fixed appears to be a general property of adaptation toward a fixed optimum.

The molecular elasticity of the extracellular matrix protein tenascin

Abstract: Extracellular matrix proteins are thought to provide a rigid mechanical anchor that supports and guides migrating and rolling cells. Here we examine the mechanical properties of the extracellular matrix protein tenascin by using atomic-force-microscopy techniques. Our results indicate that tenascin is an elastic protein. Single molecules of tenascin could be stretched to several times their resting length. Force-extension curves showed a saw-tooth pattern, with peaks of force at 137pN. These peaks were approximately 25 nm apart. Similar results have been obtained by study of titin. We also found similar results by studying recombinant tenascin fragments encompassing the 15 fibronectin type III domains of tenascin. This indicates that the extensibility of tenascin may be due to the stretch-induced unfolding of its fibronectin type III domains. Refolding of tenascin after stretching, observed when the force was reduced to near zero, showed a double-exponential recovery with time constants of 42 domains refolded per second and 0.5 domains per second. The former speed of refolding is more than twice as fast as any previously reported speed of refolding of a fibronectin type III domain. We suggest that the extensibility of the modular fibronectin type III region may be important in allowing tenascin-ligand bonds to persist over long extensions. These properties of fibronectin type III modules may be of widespread use in extracellular proteins containing such domain.

Self-Assembled Aggregates of Rod-Coil Block Copolymers and Their Solubilization and Encapsulation of Fullerenes

Abstract: Amphiphilic poly(phenylquinoline)-block-polystyrene rod-coil diblock copolymers were observed to self-organize into robust, micrometer-scale, spherical, vesicular, cylindrical, and lamellar aggregates from solution. These diverse aggregate morphologies were seen at each composition, but their size scale decreased with a decreasing fraction of the rigid-rod block. Compared to coil-coil block copolymer micelles, the present aggregates are larger by about two orders of magnitude and have aggregation numbers of over 10(8). The spherical and cylindrical aggregates have large hollow cavities. Only spherical aggregates with aggregation numbers in excess of 10(9) were formed in the presence of fullerenes (C60, C70) in solution, resulting in the solubilization and encapsulation of over 10(10) fullerene molecules per aggregate.

Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability

Abstract: Recent studies have demonstrated the presence of microsatellite instability (MSI) in tumors from patients with hereditary nonpolyposis colon cancer and in a subset of patients with sporadic colorectal cancer (CRC). In sporadic CRC, three tumor phenotypes have been defined: microsatellite stable (MSS), low-frequency MSI, and high-frequency MSI (MSI-H). Although defective mismatch repair, consisting primarily of alterations in hMSH2 and hMLH1, is believed to be responsible for the MSI phenotype in the majority of patients with hereditary nonpolyposis colon cancer, the genetic defect responsible for this phenotype in sporadic CRC has yet to be clearly delineated. Somatic or germ-line alterations in these two genes have been identified in only a minority of these cases. Analysis of the protein expression patterns of hMSH2 and hMLH1 in unselected CRC, however, suggests that alterations in hMLH1 may account for a majority of the MSI-H cases. In an effort to explore the underlying molecular basis for these findings, we have examined the methylation status of the presumptive hMLHI promoter region in 31 tumors that vary in regard to their MSI status (MSI-H or MSS), their hMLH1 protein expression (MLH- or MLH+), and their gene mutation (Mut+ or Mut-) status. Hypermethylation of the hMLH1 promoter occurred in all 13 MSI-H/ MLH- tumors that did not have a detectable mutation within the hMLH1 gene. Of those MSI-H tumors containing germ-line or somatic alterations in hMLH1 (n = 7, including 3 frameshift, 1 nonsense, 2 missense mutations, and 1 tumor containing multiple mutations: missense, splice-site alteration, and a frameshift), four had a normal methylation pattern, whereas three others demonstrated hypermethylation of the hMLH1 promoter region. Two of these cases had a missense alteration, the other a frameshift alteration. The single MSI-H/Mut+ tumor that had normal hMLH1 and hMSH2 expression, as well as 9 of the 10 MSS cases, lacked methylation of the hMLH1 promoter. Hypermethylation of the hMSH2 promoter was not observed for any of the cases. These results suggest that hypermethylation of the hMLH1 promoter may be the principal mechanism of gene inactivation in sporadic CRC characterized by widespread MSI.

Cell-to-cell signaling and Pseudomonas aeruginosa infections.

Abstract: Pseudomonas aeruginosa is a bacterium responsible for severe nosocomial infections, life-threatening infections in immunocompromised persons, and chronic infections in cystic fibrosis patients. The bacterium's virulence depends on a large number of cell-associated and extracellular factors. Cell-to-cell signaling systems control the expression and allow a coordinated, cell-density-dependent production of many extracellular virulence factors. We discuss the possible role of cell-to-cell signaling in the pathogenesis of P. aeruginosa infections and present a rationale for targeting cell-to-cell signaling systems in the development of new therapeutic approaches.

Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group.

Abstract: Objectives To evaluate the safety and physiologic response of inhaled nitric oxide (NO) in patients with acute respiratory distress syndrome (ARDS). In addition, the effect of various doses of inhaled NO on clinical outcome parameters was assessed. Design Prospective, multicenter, randomized, double-blind, placebo-controlled study. Setting Intensive care units of 30 academic, teaching, and community hospitals in the United States. Patients Patients with ARDS, as defined by the American-European Consensus Conference, were enrolled into the study if the onset of disease was within 72 hrs of randomization. Interventions Patients were randomized to receive placebo (nitrogen gas) or inhaled NO at concentrations of 1.25, 5, 20, 40, or 80 ppm. Measurements and main results Acute increases in PaO2, decreases in mean pulmonary arterial pressure, intensity of mechanical ventilation, and oxygenation index were examined. Clinical outcomes examined were the dose effects of inhaled NO on mortality, the number of days alive and off mechanical ventilation, and the number of days alive after meeting oxygenation criteria for extubation. A total of 177 patients were enrolled over a 14-month period. An acute response to treatment gas, defined as a PaO2 increase > or =20%, was seen in 60% of the patients receiving inhaled NO with no significant differences between dose groups. Twenty-four percent of placebo patients also had an acute response to treatment gas during the first 4 hrs. The initial increase in oxygenation translated into a reduction in the FIO2 over the first day and in the intensity of mechanical ventilation over the first 4 days of treatment, as measured by the oxygenation index. There were no differences among the pooled inhaled NO groups and placebo with respect to mortality rate, the number of days alive and off mechanical ventilation, or the number of days alive after meeting oxygenation criteria for extubation. However, patients receiving 5 ppm inhaled NO showed an improvement in these parameters. In this dose group, the percentage of patients alive and off mechanical ventilation at day 28 (a post hoc analysis) was higher (62% vs. 44%) than the placebo group. There was no apparent difference in the number or type of adverse events reported among those patients receiving inhaled NO compared with placebo. Four patients had methemoglobin concentrations >5%. The mean inspired nitrogen dioxide concentration in inhaled NO patients was 1.5 ppm. Conclusions From this placebo-controlled study, inhaled NO appears to be well tolerated in the population of ARDS patients studied. With mechanical ventilation held constant, inhaled NO is associated with a significant improvement in oxygenation compared with placebo over the first 4 hrs of treatment. An improvement in oxygenation index was observed over the first 4 days. Larger phase III studies are needed to ascertain if these acute physiologic improvements can lead to altered clinical outcome.

Influence of the Genotype on the Clinical Course of the Long-QT Syndrome

Abstract: Background The congenital long-QT syndrome, caused by mutations in cardiac potassium-channel genes (KVLQT1 at the LQT1 locus and HERG at the LQT2 locus) and the sodium-channel gene (SCN5A at the LQT3 locus), has distinct repolarization patterns on electrocardiography, but it is not known whether the genotype influences the clinical course of the disease. Methods We determined the genotypes of 541 of 1378 members of 38 families enrolled in the International Long-QT Syndrome Registry: 112 had mutations at the LQT1 locus, 72 had mutations at the LQT2 locus, and 62 had mutations at the LQT3 locus. We determined the cumulative probability and lethality of cardiac events (syncope, aborted cardiac arrest, or sudden death) occurring from birth through the age of 40 years according to genotype in the 246 gene carriers and in all 1378 members of the families studied. Results The frequency of cardiac events was higher among subjects with mutations at the LQT1 locus (63 percent) or the LQT2 locus (46 percent) than am...

Not all Personal Goals are Personal: Comparing Autonomous and Controlled Reasons for Goals as Predictors of Effort and Attainment

Abstract: Even when goals are self-generated, they may not feel truly "personal," that is, autonomous and self-integrated. In three studies (one concurrent and two prospective), we found that the autonomy of personal goals predicted goal attainment. In contrast, the strength of "controlled" motivation did not predict attainment. Studies 2 and 3 validated a mediational model in which autonomy led to attainment because it promoted sustained effort investment. In Study 3, the Goal Attainment Scaling methodology was used to provide a more objective measure of goal attainment, and additional analyses were performed to rule out expectancy, value, and expectancy x value explanations of the autonomy-to-attainment effects. Results are discussed in terms of contemporary models of volition and self-regulation.

Effects of Prenatal and Postnatal Methylmercury Exposure From Fish Consumption on Neurodevelopment Outcomes at 66 Months of Age in the Seychelles Child Development Study

Abstract: Context.—Human neurodevelopmental consequences of exposure to methylmercury (MeHg) from eating fish remain a question of public health concern.Objective.—To study the association between MeHg exposure and the developmental outcomes of children in the Republic of Seychelles at 66 months of age.Design.—A prospective longitudinal cohort study.Participants.—A total of 711 of 779 cohort mother-child pairs initially enrolled in the Seychelles Child Development Study in 1989.Setting.—The Republic of Seychelles, an archipelago in the Indian Ocean where 85% of the population consumes ocean fish daily.Main Outcome Measures.—Prenatal and postnatal MeHg exposure and 6 age-appropriate neurodevelopmental tests: the McCarthy Scales of Children's Abilities, the Preschool Language Scale, the Woodcock-Johnson Applied Problems and Letter and Word Recognition Tests of Achievement, the Bender Gestalt test, and the Child Behavior Checklist.Results.—The mean maternal hair total mercury level was 6.8 ppm and the mean child hair total mercury level at age 66 months was 6.5 ppm. No adverse outcomes at 66 months were associated with either prenatal or postnatal MeHg exposure.Conclusion.—In the population studied, consumption of a diet high in ocean fish appears to pose no threat to developmental outcomes through 66 months of age.

Reactive Aggression Among Maltreated Children: The Contributions of Attention and Emotion Dysregulation

Abstract: Examined the complex interplay among emotion, attention, and aggression in a sample of 141 maltreated and 87 non-maltreated impoverished, inner-city children. Data were collected during a summer day camp, which provided an ecologically valid setting for studying children's behavior in social contexts. Maltreated children were more likely than non-maltreated children to be aggressive, with findings suggesting that physically abused children were at heightened risk for reactive aggression. Maltreated children also evidenced attention deficits, and subclinical or nonpathological dissociation was more likely among children who had experienced physical or sexual abuse. A history of abuse also predicted emotion dysregulation, affective lability/negativity, and socially inappropriate emotion expressions. This emotion dysregulation, fostered by poor attention modulation, was a mechanism of the effects of maltreatment on reactive aggression.

An ecological-transactional analysis of children and contexts: The longitudinal interplay among child maltreatment, community violence, and children's symptomatology

Abstract: Cicchetti and Lynch have conceptualized ecological contexts as consisting of nested levels with varying degrees of proximity to the individual. These levels of the environment interact and transact with each other over time in shaping individual development and adaptation. With a sample of maltreated (n = 188) and nonmaltreated (n = 134) children between the ages of 7 and 12 years, this investigation employed a 1-year longitudinal design to conduct an ecological-transactional analysis of the mutual relationships among community violence, child maltreatment, and children's functioning over time. Indicators of children's functioning were externalizing and internalizing behavior problems and self-rated traumatic stress reactions, depressive symptomatology, and self-esteem. Either full or partial support was obtained for the study's primary hypotheses. Rates of maltreatment, particularly physical abuse, were related to levels of child-reported violence in the community. In addition, child maltreatment and exposure to community violence were related to different aspects of children's functioning. Specific effects were observed for neglect and sexual abuse and for witnessing and being victimized by violence in the community. Finally, there was evidence that children and their contexts mutually influence each other over time. Results were discussed within the framework of an ecological-transactional model of development.

The evolutionary genetics of speciation

Abstract: The last decade has brought renewed interest in the genetics of speciation, yielding a number of new models and empirical results. Defining speciation as 'the origin of reproductive isolation between two taxa', we review recent theoretical studies and relevant data, emphasizing the regular patterns seen among genetic analyses. Finally, we point out some important and tractable questions about speciation that have been neglected.

Chemotherapy Compared with Autologous or Allogeneic Bone Marrow Transplantation in the Management of Acute Myeloid Leukemia in First Remission

Abstract: Background In young adults with acute myeloid leukemia, intensive chemotherapy during the initial remission improves the long-term outcome, but the role of bone marrow transplantation is uncertain. We compared high-dose cytarabine with autologous or allogeneic marrow transplantation during the first remission of acute myeloid leukemia. Methods Previously untreated adolescents and adults 16 to 55 years of age who had acute myeloid leukemia received standard induction chemotherapy. After complete remission had been achieved, idarubicin (two days) and cytarabine (five days) were administered. Patients with histocompatible siblings were offered allogeneic marrow transplantation, whereas the remaining patients were randomly assigned to receive a single course of high-dose cytarabine or transplantation of autologous marrow treated with perfosfamide (4-hydroperoxycyclophosphamide). Oral busulfan and intravenous cyclophosphamide were used as preparative regimens for both allogeneic and autologous marrow transplan...

Phosphatidylinositol 3-Kinase and Akt Protein Kinase Are Necessary and Sufficient for the Survival of Nerve Growth Factor-Dependent Sympathetic Neurons

Abstract: Recent studies have suggested a role for phosphatidylinositol (PI) 3-kinase in cell survival, including the survival of neurons. We used rat sympathetic neurons maintained in vitro to characterize the potential survival signals mediated by PI 3-kinase and to test whether the Akt protein kinase, a putative effector of PI 3-kinase, functions during nerve growth factor (NGF)-mediated survival. Two PI 3-kinase inhibitors, LY294002 and wortmannin, block NGF-mediated survival of sympathetic neurons. Cell death caused by LY294002 resembles death caused by NGF deprivation in that it is blocked by a caspase inhibitor or a cAMP analog and that it is accompanied by the induction of c-jun , c-fos , and cyclin D1 mRNAs. Treatment of neurons with NGF activates endogenous Akt protein kinase, and LY294002 or wortmannin blocks this activation. Expression of constitutively active Akt or PI 3-kinase in neurons efficiently prevents death after NGF withdrawal. Conversely, expression of dominant negative forms of PI 3-kinase or Akt induces apoptosis in the presence of NGF. These results demonstrate that PI 3-kinase and Akt are both necessary and sufficient for the survival of NGF-dependent sympathetic neurons.

A comparison of recombinant urokinase with vascular surgery as initial treatment for acute arterial occlusion of the legs. Thrombolysis or Peripheral Arterial Surgery (TOPAS) Investigators.

Abstract: Background Recent controlled trials suggest that thrombolytic therapy may be an effective initial treatment for acute arterial occlusion of the legs. A major potential benefit of initial thrombolytic therapy is that limb ischemia can be managed with less invasive interventions. Methods In this randomized, multicenter trial conducted at 113 North American and European sites, we compared vascular surgery (e.g., thrombectomy or bypass surgery) with thrombolysis by catheter-directed intraarterial recombinant urokinase; all patients (272 per group) had had acute arterial obstruction of the legs for 14 days or less. Infusions were limited to a period of 48 hours (mean [±SE], 24.4±0.86), after which lesions were corrected by surgery or angioplasty if needed. The primary end point was the amputation-free survival rate at six months. Results Final angiograms, which were available for 246 patients treated with urokinase, revealed recanalization in 196 (79.7 percent) and complete dissolution of thrombus in 167 (67.9...

COX-2 expression is induced by UVB exposure in human skin: implications for the development of skin cancer.

Abstract: Extensive documentation has validated the role of UV irradiation as a tumor initiator and promoter, inducing both squamous and basal cell carcinomas. Human epidermis is a tissue which undergoes active metabolism of arachidonic acid to prostaglandins which is regulated by the action of prostaglandin H synthase (also known as cyclooxygenase). One mechanism for the promotional activity of UV light may involve its ability to induce prostaglandin formation. Work in our laboratory has demonstrated that acute exposure of human keratinocytes to UVB irradiation results in increased production of prostaglandin E2 (PGE2). When cultured human keratinocytes were examined after irradiation with 30 mJ/cm2 UVB in vitro, Western blot analysis showed a 6-fold increase in COX-2 protein which was evident at 6 h and peaked 24 h after irradiation. Furthermore, when human subjects were irradiated on sun-protected skin with up to four times their minimal erythema dosage (MED) and biopsied 24 h later, upregulation of COX-2 protein expression was observed via immunofluorescence microscopy. RNAase protection assays supported this observation, showing induction of COX-2 message which peaked at approximately 12 h following irradiation in vitro. Furthermore, human squamous cell carcinoma biopsies exhibited strongly enhanced staining for COX-2 protein via immunohistochemistry and Western analysis when compared to normal non-sun-exposed control skin. Together, these data demonstrate acute upregulation of COX-2 via UVB irradiation and suggest the need for further studies of COX-2 expression as a potential pharmacological target mediating human skin tumor development.

Terror management and aggression: evidence that mortality salience motivates aggression against worldview-threatening others.

Abstract: The hypothesis that mortality salience (MS) motivates aggression against worldview-threatening others was tested in 4 studies. In Study 1, the experimenters induced participants to write about either their own death or a control topic, presented them with a target who either disparaged their political views or did not, and gave them the opportunity to choose the amount of hot sauce the target would have to consume. As predicted, MS participants allocated a particularly large amount of hot sauce to the worldview-threatening target. In Studies 2 and 3, the authors found that following MS induction, the opportunity to express a negative attitude toward the critical target eliminated aggression and the opportunity to aggress against the target eliminated derogation. This suggests that derogation and aggression are two alternative modes of responding to MS that serve the same psychological function. Finally, Study 4 showed that MS did not encourage aggression against a person who allocated unpleasant juice to the participant, supporting the specificity of MS-induced aggression to worldview-threatening others.