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D Schwartz Doris Schwartz has been outstanding in many ways: the only nurse and only woman to receive an invitation to participate in the World Health Organization Committee on Aging and Geriatric Care held in Geneva in 1965; the codirector of the first Primex program to prepare geriatric nurse practitioners ... ( view more )in 1976; the first nurse to receive a Fogerty Fellowship; and the first to be invited to work with Sir Ferguson Anderson and to participate in planning the care of the aged in Scotland. From this experience a fine textbook in gerontology and geriatric nursing emerged, possibly the first to combine the medical and nursing viewpoints in the care of the aged. In the early 1980s Ms. Schwartz expressed her indignation in a letter to Geriatric Nursing regarding the lack of clinical research investigating the implications and inhumane effects of tying up our elderly. Two young faculty researchers, Neville Strumpf and Lois Evans, took up the challenge and began a decade of extensive research into the use of restraints. Ms. Schwartz always seems to have been at the hub of clinical practice issues that affect quality of life. The following excerpts from an interview with Doris Schwartz will introduce our readers to her personal perspective. ( view less ) A Schwartz,P MeekThe purpose of this article is to report the results of additional construct validity testing of the Schwartz Cancer Fatigue Scale. Latent variable modeling was used to determine the best fit of the data to the model. Testing with a heterogeneous sample (n = 303) did not support the proposed model.... ( view more ) Using exploratory techniques a six-item, two-factor scale was formed which demonstrated that all measures of fit were consistently strong, and that the standardized solution factors loaded strongly. Reliabilities for the total scale and subscales were all greater than 0.80. These results provide preliminary support for the reliability and validity of the two-factor model of the six-item Schwartz Cancer Fatigue Scale. ( view less ) A L Schwartz PURPOSE/OBJECTIVES: To describe the psychometric development of the Schwartz Cancer Fatigue Scale (SCFS). DESIGN: A multiphase instrumentation study describing construct and operational definitions, informal and formal content validity, reliability, and validity analysis. SAMPLE: Content validity e... ( view more )stablished with 20 subjects. Reliability and validity evaluated with 166 subjects residing in diverse parts of the United States. FINDINGS: Eleven items that failed to show variance, had high interitem correlations, or failed to discriminate were eliminated. Factor analysis resulted in a four-factor solution that accounted for 70% of the variance. Cronbach's alpha for the total scale was estimated to be 0.96 and to be between 0.82 and 0.93 for the subscales. CONCLUSIONS: The 28-item SCFS has demonstrated reliability and content and construct validity. Factor analysis supports the four subscales (physical, emotional, cognitive, and temporal). Preliminary construct validity has been demonstrated by differences in fatigue between those people who are currently receiving treatment and those who have completed treatment and by scores on a visual analogue scale of fatigue. IMPLICATIONS FOR NURSING PRACTICE: The SCFS may prove to be clinically relevant in assessing the effect of interventions to treat and manage cancer-related fatigue. ( view less ) E N Schwartz,C A Schwartz,A Sebben,S W Largura,E G Mendes The skin secretion of the caecilian S. paulensis has an indirect cardiotoxic effect. It induces a rapid blockage of electrical activity and subsequent diastolic arrest on in situ toad heart preparations. This action is not blocked by atropine and is therefore not mediated through a cholinergic mech... ( view more )anism. In addition, S. paulensis skin secretion is ineffective in inducing any response in isolated perfused toad heart assay, in the spontaneously beating isolated toad atria or in the electrically driven toad ventricle strip. These results, and the observation that S. paulensis skin secretion exhibits an hemolytic activity ([Schwartz, E. F., Schwartz, C. A., Sebben, A., Mendes E. G. (1997) Cardiotoxic and hemolytic activities on the caecilian Siphonops paulensis skin secretion. J. Venom. Anim. Toxins 3(1), 190]), suggest that the skin secretion cardiotoxicity could be mediated through an endogenous agent. The cardiotoxic action of S. paulensis skin secretion was investigated in isolated toad cardiac tissues in the presence of toad red blood cells (TRBC). In both atria and ventricle it evoked the same responses observed in the in situ heart. The potassium concentrations of the suspending media, as determined by atomic absorption spectroscopy were 9.5 and 11.7 times greater, respectively, in the presence of TRBC than in its absence. Given that increased levels of potassium also showed a negative inotropic effect in the isolated ventricle strip, the action of the skin secretion was attributed to the hemolytic activity, which causesan increase in K+ concentration of the medium. ( view less ) F N Schwartz In 1989, Felice N. Schwartz's HBR article "Management Women and the New Facts of Life" generated a huge debate over the rules established by corporations in their handling of women executives. Now in "Women as a Business Imperative," Schwartz follows up with practical insights about the costs compa... ( view more )nies incur in passing over qualified businesswomen. In the form of a memo to a fictional CEO, Schwartz describes how the atmosphere within most companies is corrosive to women and must change. Preconceptions harbored by male senior managers about women are so deeply ingrained that many men are not even aware of them. Yet senior managers must help women advance. Those companies that accept their responsibility to make radical change--both in women's treatment and in family support--can improve their bottom lines enormously. Treating women as a business imperative is the equivalent of creating a unique R&D product for which there is great demand. Most companies ignore child care and other family concerns. Many companies hire women to ensure mere adequacy and avoid litigation. Women's ambitions and energies are stifled by such businesses at the same time that women have demonstrated their competence and potential in the best business schools. High turnover results. However, the restraints that now hold women back can be loosened easily. CEOs and other senior managers must support their female employees by (1) acknowledging the fundamental difference between women and men--the biological fact of maternity; (2) allowing flexibility for women and men who need it; (3) providing training that takes advantage of women's leadership potential; and (4) eliminating the corrosive atmosphere and the barriers that exist for women in the workplace. ( view less ) Lora Billings,Amy Fiorillo,Ira B SchwartzThis paper examines the effects of single-strain vaccine campaigns on the dynamics of an epidemic multistrain model with antibody-dependent enhancement (ADE). ADE is a disease spreading process causing individuals with their secondary infection to be more infectious than during their first infectio... ( view more )n by a different strain. We follow the two-strain ADE model described in Cummings et al. [D.A.T. Cummings, Doctoral Thesis, Johns Hopkins University, 2004] and Schwartz et al. [I.B. Schwartz, L.B. Shaw, D.A.T. Cummings, L. Billings, M. McCrary, D. Burke, Chaotic desynchronization of multi-strain diseases, Phys. Rev. E, 72:art. no. 066201, 2005]. After describing the model and its steady state solutions, we modify it to include vaccine campaigns and explore if there exists vaccination rates that can eradicate one or more strains of a virus with ADE. ( view less ) M Flück,J A Carson,R J Schwartz,F W Booth Serum response element 1 has previously been reported to be necessary and sufficient for activation of the skeletal alpha-actin promoter during hypertrophy of the anterior latissimus dorsi (ALD) muscle of roosters [J. A. Carson, R. J. Schwartz, and F. W. Booth. Am. J. Physiol. 270 (Cell Physiol. 39... ( view more )): C1624-C1633, 1996]. Serum response factor (SRF) protein is the transcription factor that binds as a homodimer to serum response element 1 and activates the skeletal alpha-actin promoter. An increased expression of exogenous SRF protein in replicating C2C12 myoblasts induced a three- to fourfold activation of the skeletal alpha-actin promoter (L. Wei, W. Zhou, J. D. Croissant, F.-E. Johansen, R. Prywes, A. Balasubramamyan, and R. J. Schwartz. J. Biol. Chem. 273: 30287-30294, 1998). Thus we hypothesized that SRF protein concentration would be increased during hypertrophy of skeletal muscle. In the present study, 10% of the rooster's body weight was attached to the left wing to induce enlargement of the ALD muscle compared with the contralateral muscle. With Western analysis, a significant increase in SRF protein per gram of wet weight of the ALD muscle was noted at 7 and 13 days of hypertrophy. Furthermore, the increase in SRF protein occurred in both crude nuclear protein and cytoplasmic fractions in 7-day stretched ALD muscles. This is the first report showing increased protein concentration for a transcription factor whose regulatory element in the skeletal alpha-actin promoter has previously been shown to be required for the transduction of a hypertrophy signal in overloaded skeletal muscle of an animal. ( view less ) X Meng,W Cai,D C Schwartz Activity of type II restriction endonuclease is affected by many common factors including buffer composition and sequences flanking the recognition site (Brabec et al., Eur.J. Biochem. 216, 183, 1993). The successful development of Optical Mapping (Schwartz et al., Science, 262, 110, 1993; Meng et ... ( view more )al., Nature Genet. 9, 432, 1995; Wang and Schwartz, PNAS, 1995 Cai et al., PNAS, 92, 5164, 1995) relied on optimization of light microscope-based imaging of fluorescently labeled DNA molecules during restriction endonuclease digestion. Little was known about the effects of commonly used DNA-fluorochromes on restriction endonuclease activity. Thus, we developed an enzyme activity assay using lambda bacteriophage DNA or adenovirus-2 DNA to evaluate the effects of five DNA binding fluorochromes (4'-6-daimidine-2-phenylindole (DAPI), ethidium bromide (EtdBr), ethidium bromide homodimer (EthD-1), bis-benzimide (H33258) and benzothiazolium-4-quinolinium dimer (TOTO-1)) on the enzymatic activities of eleven type II restriction endonucleases (Asc I, Csp I, Dra I, EcoR I, Hha I, Hind III, Not I, Rsr II, Sfi I, SgrA I and Sma I). We found that the minor groove binding fluorochrome, DAPI, did not measurably inhibit activity of this group, with the exception of Dra I. Similarly, another minor groove binding fluorochrome H33258 inhibited Dra I and Not I (slightly). The three intercalating fluorochromes EtdBr, EthD-1 and TOTO-1, however, variably inhibited the other enzymes. Since Beta-mercaptoethanol (Beta-ME) is used to discourage photodamage of stained DNA molecules, we also assessed its effect on restriction endonuclease activity. Interestingly, Dra I, Hind III, Sfi I and Sma I retained full activities at high concentration of Beta-ME (5%), but Asc I, Csp I, Not I, Rsr II and SgrA I showed varying sensitivities to the Beta-ME. Isoschizomers Csp I and Rsr II behaved differently to both fluorochromes and Beta-ME. The results presented here should provide a basis for further development of new Optical Mapping-based techniques requiring fluorescence labeling of other actively imaged enzymatic reactions. ( view less ) I Warshawsky,G Bu,A L Schwartz Tissue-type plasminogen activator (t-PA) is a plasma serine protease that catalyzes the initial and rate-limiting step in the fibrinolytic cascade. t-PA is widely used as a thrombolytic agent in the treatment of acute myocardial infarction. However, its use has been impaired by its rapid hepatic cl... ( view more )earance from the circulation following intravenous administration. Studies with both rat hepatoma MH1C1 cells (G. Bu, S. Williams, D. K. Strickland, and A. L. Schwartz, 1992. Proc. Natl. Acad. Sci. USA. 89:7427-7431) and human hepatoma HepG2 cells (G. Bu, E. A. Maksymovitch, and A. L. Schwartz. 1993. J. Biol. Chem. 28:13002-13009) have shown that binding of t-PA to its clearance receptor, the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor, is inhibited by a 39-kD protein that copurifies with this receptor. Herein we investigated whether administration of purified recombinant 39-kD protein would alter t-PA clearance in vivo. We found that intravenous administration of purified 39-kD protein to rats prolonged the plasma half-life of 125I-t-PA from 1 min to approximately 5-6 min. The plasma half-life of t-PA enzymatic activity was similarly prolonged following intravenous administration of purified 39-kD protein. In addition we found that the 39-kD protein itself was rapidly cleared from the circulation in vivo. Clearance of 125I-39-kD protein was a biphasic process with half-lives of 30 s and 9 min and the liver was the primary organ of clearance. Preadministration of excess unlabeled 39-kD protein slowed 125I-39-kD protein clearance in rats in a dose-dependent manner, suggesting that specific clearance receptors were responsible for this process. Administration of increasing doses of unlabeled 39-kD protein along with labeled 39-kD protein resulted in a decrease in the amount of labeled 39-kD protein associating with the liver and a concomitant increase in the amount of labeled 39-kD protein associating with the kidneys, indicating two clearance mechanisms exist for the 39-kD protein. ( view less ) H W SchwartzMr. Schwartz's article chronicles the development of continuous quality improvement in healthcare. Beginning with a discussion of the Joint Commission's shift from quality assurance to CQI, Mr. Schwartz goes on to explore the theories of Crosby, Deming, Juran and others whose ideas have shaped the ... ( view more )CQI movement. He also identifies quality assessment and improvement standards, statistical methods favored by the JCAHO, ways of demonstrating CQI, and the differences between QA and CQI/TQM. In addition, he provides suggestions on implementing a CQI action plan and describes some of the obstacles faced by managers trying to execute such programs. ( view less ) W Stoorvogel,A L Schwartz,G J Strous,R J Fallon One proposed function of the asialoglycoprotein receptor in hepatocytes is to mediate the endocytosis of galactose and N-acetylgalactosamine-exposing glycoproteins. Recently we defined a pool of intracellular H1 subunits of the asialoglycoprotein receptor (ASGPR) in the human hepatoma cell line Hep... ( view more )G2 which appeared not to be involved in endocytosis (Stoorvogel, W., Geuze, H. J., Griffith, J. M., Schwartz, A. L., and Strous, G. J. (1989) J. Cell Biol. 108, 2137-2148). In addition, a pool of stably phosphorylated intracellular ASGPR has been detected (Fallon, R. J., and Schwartz, A. L. (1988) J. Biol. Chem. 263, 13159-13166). In the current study we integrate these findings and provide evidence for the existence of two types of intracellular nonexchangeable compartments containing ASGPR. A transiently phosphorylated pool of ASGPR shuttles between the plasma membrane and endosomes, via a pathway identical to that of the transferrin receptor. The second pool comprises 20% of the total intracellular ASGPR, is stably phosphorylated at a serine residue, and is located in intracellular compartments devoid of recycling transferrin receptor. We refer to this ASGPR pool as the "silent pool." We furthermore show that the two receptor pools are confined to compartments exhibiting different buoyant densities on sucrose density gradients. ASGPR in the "silent pool" is fully glycosylated, suggesting a post-Golgi sorting mechanism for trafficking to this compartment. Possible functions of the "silent" ASGPR pool are discussed. ( view less ) V Lavie,M Murray,A Solomon,S Ben-Bassat,M Belkin,S Rumelt,M Schwartz Spontaneous growth of axons after injury is extremely limited in the mammalian central nervous system (CNS). It is now clear, however, that injured CNS axons can be induced to elongate when provided with a suitable environment. Thus injured CNS axons can elongate, but they do not do so unless their... ( view more ) environment is altered. We now show apparent regenerative growth of injured optic axons. This growth is achieved in the adult rabbit optic nerve by the use of a combined treatment consisting of: (1) supplying soluble substances originating from growing axons to be injured rabbit optic nerves (Schwartz et al., Science, 228:600-603, 1985), and (2) application of low energy He-Ne laser irradiation, which appears to delay degenerative changes in the injured axons (Schwartz et al., Lasers Surg. Med., 7:51-55, 1985; Assia et al., Brain Res., 476:205-212, 1988). Two to 8 weeks after this treatment, unmyelinated and thinly myelinated axons are found at the lesion site and distal to it. Morphological and immunocytochemical evidence indicate that these thinly myelinated and unmyelinated axons are growing in close association with glial cells. Only these axons are identified as being growing axons. These newly growing axons transverse the site of injury and extend into the distal stump of the nerve, which contains degenerating axons. Axons of this type could be detected distal to the lesion only in nerves subjected to the combined treatment. No unmyelinated or thinly myelinated axons in association with glial cells were seen at 6 or 8 weeks postoperatively in nerves that were not treated, or in nerves in which the two stumps were completely disconnected. Two millimeters distal to the site of injury, the growing axons are confined to a compartment comprising 5%-30% of the cross section of the nerve. A temporal analysis indicates that axons have grown as far as 6 mm distal to the site of injury, by 8 weeks postoperatively. Anterograde labeling with horseradish peroxidase, injected intraocularly, indicates that some of these newly growing axons arise from retinal ganglion cells. ( view less ) D Piomelli,S J Feinmark,E Shapiro,J H Schwartz 12-Hydroperoxy-5,8,10,14-eicosatetraenoic acid (12-HPETE), a lipoxygenase product, simulates the synaptic responses produced by the modulatory transmitter, histamine, and the neuroactive peptide, Phe-Met-Arg-Phe-amide (FMRFamide), in identified neurons of the marine mollusk, Aplysia californica (Pi... ( view more )omelli, D., Shapiro, E., Feinmark, S. J., and Schwartz, J. H. (1987) J. Neurosci. 7, 3675-3886; Shapiro, E., Piomelli, D., Feinmark, S., Vogel, S., Chin, G., and Schwartz, J. H. (1988) Cold Spring Harbor Symp. Quant. Biol. 53, in press). The 12-lipoxygenase pathway has not yet been fully characterized, but 12-HPETE is known to be metabolized further. We therefore began to search for other metabolites in order to investigate whether the actions of 12-HPETE might require its conversion to other active products. Here we report the identification of 12-keto-5,8,10,14-eicosatetraenoic acid (12-KETE), a metabolite of 12-HPETE formed by Aplysia nervous tissue. This product was identified in incubations of the tissue with arachidonic acid using high performance liquid chromatography, UV spectrometry, and gas chromatography/mass spectrometry. [3H]12-KETE was formed from endogenous lipid stores in nervous tissue, labeled by incubation with [3H]arachidonic acid, when stimulated by application of histamine. In L14 and L10 cells, identified neurons in the abdominal ganglion, applications of 12-KETE elicit changes in membrane potential similar to those evoked by histamine. 12(S)-Hydroxy-5,8,10,14-eicosatetraenoic acid, another metabolite of 12-HPETE, is inactive. These results support the hypothesis that 12-HPETE and its metabolite, 12-KETE, participate in transduction of histamine responses in Aplysia neurons. ( view less ) S J Chan,S Seino,P A Gruppuso,R Schwartz,D F Steiner Gruppuso et al. [Gruppuso, P.A., Gordon, P., Kahn, C. R., Cornblath, M., Zeller, W. P. & Schwartz, R. (1984) N. Engl. J. Med. 311, 629-634] have recently described a family in which hyperproinsulinemia is inherited in an autosomal dominant pattern, suggesting a structural abnormality in the proinsu... ( view more )lin molecule as the basis for this disorder. However, unlike two previous kindreds with a similar syndrome, the serum proinsulin-like material in this family did not appear to be an intermediate conversion product but instead behaved like normal human proinsulin by several criteria. To further characterize this disorder we isolated and sequenced the insulin gene of the propositus. Leukocyte DNA was cloned into lambda-WES and recombinants containing the two insulin alleles, lambda MD41 and lambda MD51, were isolated by plaque hybridization. DNA sequencing of lambda MD51 showed that it contained the normal coding sequence for human preproinsulin. Sequence analysis of lambda MD41, however, revealed a single nucleotide substitution in the codon for residue 10 of proinsulin (CAC----GAC) that predicts the exchange of aspartic acid for histidine in the insulin B chain region. This mutation was also found in an insulin allele cloned from a second affected family member (propositus's father). These results, along with the linkage analysis of Elbein et al. [Elbein, S.C., Gruppuso, P., Schwartz, R., Skolnick, M. & Permutt, M.A. (1985) Diabetes 34, 821-824], strongly implicate this mutation as the cause of the hyperproinsulinemia in this family. Inhibition of the conversion of proinsulin to insulin may be related to altered folding and/or self-association properties of the [Asp10]proinsulin. ( view less ) M Siegler,H SchwartzSiegler, a physician, and Schwartz, a former New York Times editor, debate whether physicians have a special moral obligation to provide free medical care to those unable to pay, specifically the unemployed who have lost their health benefits. Siegler, answering affirmatively, cites the special re... ( view more )sponsibility of the medical profession to society, the responsibility of the individual physician for his patients' health, and the obligation arising out of patient expectations. Schwartz argues that physicians have no special duty to provide service free to anyone who requests it. ( view less ) J Ofengand,R Liou,J Kohut,I Schwartz,R A Zimmermann The covalent cross-linking of unmodified Escherichia coli N-acetylvalyl-tRNA to the 16S RNA of Escherichia coli ribosomes upon near-UV irradiation previously reported by us [Schwartz, I., & Ofengand, J. (1978) Biochemistry 17, 2524--2530] has been studied further. Up to 70% of the unmodified tRNA, ... ( view more )nonenzymatically bound to tight-couple ribosomes at 7 mM Mg2+, could be cross-linked by 310--335-nm light. Covalent attachment was solely to the 16S RNA. It was dependent upon both irradiation and the presence of mRNA but was unaffected by the presence or absence of 4-thiouridine in the tRNA. The kinetics of cross-linking showed single-hit behavior. Twofold more cross-linking was obtained w-th tight-couple ribosomes than with salt-washed particles. Puromycin treatment after irradiation released the bound N-acetyl[3H]valine, demonstrating that the tRNA was covalently bound at the P site and that irradiation and covalent linking did not affect the peptidyl transferase reaction. Cross-linking was unaffected by the presence of O2, argon, ascorbate (1 mM), or mercaptoethanol (10 mM). Prephotolysis of a mixture of tRNA and ribosomes in the absence of puly(U2,G) did not block subsequent cross-linking in its presence nor did it generate any long-lived chemically reactive species. There was a strong tRNA specificity. E. coli tRNA1Val and tRNA1Ser and Bacillus subtilis tRNAVal and tRNAThr could be cross-linked, but E. coli tRNA2Val, 5-fluorouracil-substituted tRNA1Val, tRNAPhe, or tRNAFMet could not. By sequence comparison of the reactive and nonreactive tRNAs, the site of attachment in the tRNA was deduced to be the 5'-anticodon base, cmo5U, or ,o5U in all of the reactive tRNAs. The attachment site in 16S RNA is described in the accompanying paper [Zimmerman, R. A., Gates, S. M., Schwartz, I., & Ofengand, J. (1979) Biochemistry (following paper in this issue)]. The link between tRNA and 16S RNA is either direct or involves mRNA bases at most two nucleotides apart since use of the trinucleotide GpUpU in place of poly(U2,G) to direct the binding and cross-linking of N-acetylvalyl-tRNA to the P site did not affect either the rate or yield of cross-linking. Both B. subtilis tRNAVal (mo5U) and E. coli tRNA1Val (cmo5U) gave the same rate and yield of cross-linking when directed by the trinucleotide GpUpU. Therefore, the presence of the charged carboxyl group in the cmo5U-containing tRNA apparently does not markedly perturb the orientation of this base with respect to its reaction partner in the 16S RNA. The cross-linking of AcVal-tRNA only takes place from the P site. At 75 mM KCl and 75 mM NH4Cl, less than 0.4% cross-linking was found at the A site, while 55.5% was obtained at the P site. However, when the salt concentration was lowered to 50 mM NH4Cl, 5% cross-linking to the A site was detected, compared to 49% at the P site. Thus, a simple change in the ionic strength of the incubation mixture was able to alter the affinity labeling pattern of the ribosome. ( view less ) H C Schwartz,K C King,A L Schwartz,D Edmunds,R Schwartz Hemoglobin AIc, a normal minor hemoglobin, has glucose linked by a Schiff base to the N-terminal end of the beta chain. The glucose interferes with the binding of 2,3 diphosphoglycerate, probably resulting in an increased affinity of that hemoglobin for oxygen. Hb AIc is increased to twice normal l... ( view more )evels in juvenile-onset (insulin-dependent) diabetes. In the present studies, the Hb AIc, when expressed as per cent of total hemoglobin, was found to be elevated slightly in pregnany normal (m = 6.97 per cent), pregnant nondiabetic obese (m = 6.89 per cent), and gestationally diabetic subjects (m = 8.77 per cent) above that of normal females (m = 5.68 per cent). A remarkable difference was observed between the nonpregnant diabetics (m = 12.77 per cent) and the pregnant diabetics (m = 8.46 per cent). This decrease in the level of Hb AIc in diabetics who are pregnant more than 30 weeks may reflect either a better state of diabetic control and/or a compensatory mechanism to protect the fetus by facilitating oxygen exchange from mother to fetus. ( view less ) A L Schwartz,R Schwartz,H C Schwartz A system for the isolation and functional evaluation of fetal liver erythroblasts is described. Isolated erythroblasts were prepared from 14-day embryonic avian livers and incubated at various oxygen tension (0, 5, 12, and 95%). The concentration of ATP in erythroblasts remained constant for at lea... ( view more )st 4 hr at 37degree, but was rapidly reduced by incubation in nitrogen. Protein synthesis as measured by L-[14C]leucine incorporation into cell protein occurred at a linear rate in 5%, 12%, and 95% oxygen, whereas little protein synthesis occurred at 0% oxygen. The effect of hypoxia on the type of hemoglobin synthesized was studied in this system by isolating the hemoglobin A, hemoglobin D, and hemoglobin H fractions and determining the incorporation of L-[14C]leucine. The major fraction, hemoglobin A, contained most of the radioactivity; smaller amounts were present in hemoglobin D and hemoglobin H, respectively. The relative proportion of each hemoglobin synthesized was not altered by oxygen from 5% to 95%. These results argue against a direct effect of oxygen on the type of hemoglobin synthesized at this stage of development. ( view less ) T C Sacktor,K E Kruger,J H Schwartz 1.) Application of serotonin to Aplysia sensory neurons can result in facilitated synaptic transmission, both short- and long-term. This facilitation is likely to be produced by a complex set of molecular mechanisms: serotonin activates adenylate cyclase, increasing cAMP and protein kinase (Cedar a... ( view more )nd Schwartz, 1972); serotonin also changes the subcellular distribution of the Ca2+/calmodulin-dependent protein kinase (Saitoh and Schwartz, 1983). Recently, phorbol esters also have been shown to produce facilitation. We have therefore investigated how protein kinase C (PKC) participates in serotonin-mediated synaptic facilitation. 2.) We found that the Aplysia genome encodes PKC, which is expressed in nervous tissue as at least two abundant transcripts (about 0.003% of the total message). Its inferred amino acid sequence is 85% homologous to that of enzymes from mammals and Drosophila, and over 95% homologous if compared to both. The specific activity of the Aplysia kinase is comparable to that found in rat brain, with similar reaction parameters and dependencies on phosphatidylserine (PS), Ca2+, diacylglycerol and phorbol esters. While PKC is found on neuronal membrane in the basal state, the PKC activators, Ca2+ and phorbol esters, further translocate the kinase to membrane in crude extracts of neuronal tissue. The amounts of membrane-bound PKC, as determined by 3H-phorbol-ester binding, are greatest in neuropil and nerve. 3.) Exposure of sensory neurons and their terminals in Aplysia pleural-pedal ganglia to facilitating doses of either phorbol ester or serotonin results in the translocation of PKC from cytosol to membrane, activating the enzyme. cAMP does not produce this translocation.(ABSTRACT TRUNCATED AT 250 WORDS) ( view less ) Dmitry Pevni,Inna Frolkis,Itzhak Shapira,Doron Schwartz,Idit Schwartz,Tamara Chernichovski,Nahum Nesher,Gideon Uretzky BACKGROUND: Tumor necrosis factor alpha (TNF-alpha) is a key cytokine in the pathogenesis of ischemia-reperfusion injury (I/R) that also possesses negative inotropic and direct cardiotoxic effects. We investigated whether myocardial ischemia and/or reperfusion is the trigger for TNF-alpha synthesis... ( view more ) and whether TNF-alpha release is time dependent. METHODS: Isolated rat hearts undergoing 30 min of coronary perfusion with modified Krebs-Henseleit solution followed by cardioplegic arrest for 60 min of global cardioplegic normothermic ischemia (GCI) and 30 min of reperfusion using a modified Langendorff model. Myocardial TNF-mRNA expression and TNF-alpha protein levels in effluent from the coronary sinus were measured at baseline and then after 15, 30, and 60 min of GCI and after 10 and 30 min of reperfusion. RESULTS: GCI induced myocardial TNF-alpha mRNA expression and elevation protein TNF-alpha levels in a time-dependent manner after 30 min of ischemia from 78+/-17 pg/ml to 915+/-287 pg/ml after 60 min (p<0.0015). Reperfusion did not cause time-dependent increase of TNF-alpha synthesis and release but was accompanied by progressive decrease of left ventricular (LV) function. There was a correlation between TNF-alpha protein levels and depression of LV function immediately after GCI but not with TNF-alpha protein levels at 30 min of reperfusion. CONCLUSION: This study demonstrated that myocardial ischemia rather than reperfusion is the main trigger for time-dependent TNF-alpha synthesis. Depression of LV function during reperfusion correlated significantly only with TNF-alpha levels at the end of GCI. ( view less ) Dana F Work,George J Schwartz PURPOSE OF REVIEW: Glomerular filtration rate is the best determinant of kidney function in children. A decline in glomerular filtration rate may be the only sign of renal disease. A knowledge of glomerular filtration rate allows the clinician to appropriately dose medications, administer fluids, a... ( view more )nd intervene early to prevent end-stage renal failure. The aim of this review is to discuss the current options for determining glomerular filtration rate in children and the latest advances in research on this topic. RECENT FINDINGS: Owing to the limited availability of inulin, the gold standard for measuring glomerular filtration rate, and the concern for using radioactivity, the plasma disappearance of iohexol has been utilized to measure glomerular filtration rate in children, and this represents a practical option for glomerular filtration rate determination in both clinical and research studies. By contrast, creatinine-based estimates of glomerular filtration rate (e.g. Schwartz formula) are more practical for bedside use. To improve their precision, recent formulas have incorporated the use of additional endogenous markers, such as cystatin C, albumin, and blood urea nitrogen. SUMMARY: Iohexol plasma clearances should be used to accurately measure glomerular filtration rate in children. New estimating equations with multiple endogenous markers are being developed for everyday clinical use. However, at present, there is no substitute for an accurate glomerular filtration rate determination, particularly in children with conditions affecting muscle mass or body habitus. ( view less ) Arthur E Bragg,Benjamin J Schwartz The excited states of atomic anions in liquids are bound only by the polarization of the surrounding solvent. Thus, the electron-detachment process following excitation to one of these solvent-bound states, known as charge-transfer-to-solvent (CTTS) states, provides a useful probe of solvent struct... ( view more )ure and dynamics. These transitions and subsequent relaxation dynamics also are influenced by other factors that alter the solution environment local to the CTTS anion, including the presence of cosolutes, cosolvents, and other ions. In this paper, we examine the ultrafast CTTS dynamics of iodide in liquid tetrahydrofuran (THF) with a particular focus on how the solvent dynamics and the CTTS electron-ejection process are altered in the presence of various counterions. In weakly polar solvents such as THF, iodide salts can be strongly ion-paired in solution; the steady-state UV-visible absorption spectroscopy of various iodide salts in liquid THF indicates that the degree of ion-pairing changes from strong to weak to none as the counterion is switched from Na+ to tetrabutylammonium (t-BA+) to crown-ether-complexed Na+, respectively. In our ultrafast experiments, we have excited the I- CTTS transition of these various iodide salts at 263 nm and probed the dynamics of the CTTS-detached electrons throughout the visible and near-IR. In the previous paper of this series (Bragg, A. E.; Schwartz, B. J. J. Phys. Chem. B 2008, 112, 483-494), we found that for "counterion-free" I- (obtained by complexing Na+ with a crown ether) the CTTS electrons were ejected approximately 6 nm from their partner iodine atoms, the result of significant nonadiabatic coupling between the CTTS excited state and extended electronic states supported by the naturally existing solvent cavities in liquid THF, which also serve as pre-existing electron traps. In contrast, for the highly ion-paired NaI/THF system, we find that approximately 90% of the CTTS electrons are "captured" by a nearby Na+ to form (Na+, e-)THF "tight-contact pairs" (TCPs), which are chemically and spectroscopically distinct from both solvated neutral sodium atoms and free solvated electrons. A simple kinetic model is able to reproduce the details of the electron capture process, with 63% of the electrons captured quickly in approximately 2.3 ps, 26% captured diffusively in approximately 63 ps, and the remaining 11% escaping out into the solution on subnanosecond time scales. We also find that the majority of the CTTS electrons are ejected to within 1 or 2 nm of the Na+. This demonstrates that the presence of the nearby cation biases the relocalization of CTTS-generated electrons from I- in THF, changing the nonadiabatic coupling to the extended, cavity-supported electronic states in THF to produce a much tighter distribution of electron-ejection distances. In the case of the more loosely ion-paired t-BA+-I-/THF system, we find that only 10-15% of the CTTS-ejected electrons associate with t-BA+ to form "loose-contact pairs" (LCPs), which are characterized by a much weaker interaction between the electron and cation than occurs in TCPs. The formation of (t-BA+, e-)THF LCPs is characterized by a Coulombically induced blue shift of the free eTHF- spectrum on a approximately 5-ps time scale. We argue that the weaker interaction between t-BA+ and the parent I- results in little change to the CTTS-ejection process, so that only those electrons that happen to localize in the vicinity of t-BA+ are captured to form LCPs. Finally, we interpret the correlation between electron capture yield and counterion-induced perturbation of the I- CTTS transition as arising from changes in the distribution of ion-pair separations with cation identity, and we discuss our results in the context of relevant solution conductivity measurements. ( view less ) Ran Reshef,Doron Schwartz,Merav Ingbir,Alexander Shtabsky,Tamara Chernichovski,Benjamin A Isserlin,Gil Chernin,Yoram Levo,Idit F Schwartz While a specific role for nitric oxide (NO) in inducing the hemodynamic alterations of pregnancy is somewhat controversial, it is widely accepted that excess NO is generated during pregnancy. L-Arginine is the sole precursor for NO biosynthesis. Among several transporters that mediate L-arginine up... ( view more )take, cationic amino acid transporter-1 (CAT-1) acts as the specific arginine transporter for endothelial NO synthase. The present study was designed to test the hypothesis that, during pregnancy, when arginine consumption by the fetus is significantly increased, compensatory changes in maternal arginine uptake affect the endothelium. Uptake of radiolabeled arginine (L-[3H]arginine) by freshly harvested maternal aortic rings from pregnant rats decreased by 65 and 30% in mid- and late pregnancy, respectively, compared with those obtained from virgin animals. This decrease was associated with a significant increase in endothelial protein nitration (the footprint of peroxynitrite generation), as shown by both Western blotting and immunohistochemistry utilizing anti-nitrotyrosine antibodies, reflecting endothelial damage. Northern blot analysis revealed that steady-state aortic CAT-1 mRNA levels did not change throughout pregnancy, whereas CAT-1 protein abundance was significantly increased, peaking at mid-pregnancy. Protein content of protein kinase C (PKC)-alpha, which was previously shown to decrease CAT-1 activity, increased significantly in the pregnant animals and was associated with a significant increase in CAT-1 phosphorylation. Intraperitoneal injection of alpha-tocopherol, a PKC-alpha inhibitor, prevented the decrease in arginine transport and attenuated protein nitration. In conclusion, aortic arginine uptake is reduced during pregnancy, through posttranslational modulation of CAT-1 protein, presumably via upregulation of PKC-alpha. The aforementioned findings are associated with an increase in protein nitration and, therefore, in selected individuals, may lead to the development of certain forms of endothelial dysfunction, like preeclampsia. ( view less ) Alexandros Gryparis,Brent A Coull,Joel Schwartz A major concern in studies that address the health effects of air pollution is whether an observed association between concentrations of a pollutant and a health outcome is all, or in part, due to the correlation between that exposure and either a second pollutant or a confounder. The addition of e... ( view more )xposure measurement error to such data complicates matters further. To account for measurement error when data come from a multi-city study, Schwartz and Coull (2003) proposed a two-stage estimator. These authors showed via both first principles and simulation that their approach yields unbiased estimates for the parameters of interest. However, these estimates have large variability. In this paper, we describe a fully Bayesian approach that yields estimators that are much more efficient than the existing two-stage measurement error correction yet still unbiased. The proposed approach can also incorporate additional exposures or confounders without requiring strict assumptions that are necessary in existing formulations of the model. We compare the properties of the Bayesian estimators to existing approaches via simulation. ( view less ) George J Schwartz,Susan L Furth Glomerular filtration rate (GFR) assesses kidney function. GFR is measured by renal clearance techniques; inulin clearance is the gold standard but is not easily measured. Thus, other methods to determine GFR have been utilized. Endogenous creatinine clearance (CrCl) is the most widely used, but cr... ( view more )eatinine secretion falsely elevates GFR. Cimetidine inhibits creatinine secretion, such that CrCl equals GFR, provided there are no difficulties with bladder emptying. Estimation of GFR from serum creatinine (e.g. Schwartz formula) is useful clinically; however, such formulae have not been updated for enzymatic creatinine autoanalyzers. Cystatin C, a small protein, is produced at a relatively constant rate and is reabsorbed in the proximal tubule. Cystatin C may be more sensitive than creatinine in detecting a reduction in GFR, but further studies are needed to prove this. Single injection (plasma) clearance techniques are the most precise measures of GFR. Iohexol is an exogenous marker that is comparable to inulin and (51)Cr-EDTA and can be measured by high-performance liquid chromatography (HPLC). Our pilot and the Chronic Kidney Disease in Children (CKiD) North American studies show that iohexol can accurately measure GFR using a four-point plasma disappearance curve national studies show that iohexol can accurately measure GFR using a four-point plasma disappearance curve (10, 30, 120, and 300 min) or, in most cases, a two-point disappearance time (120 and 300 min). ( view less )
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