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M Kline

Publications and source records attributed to M Kline.

At least 19 recordsLinked to original sources
PubMed2005

Parallel, solution phase synthesis of dihydropyridine miticides via a versatile multicomponent reaction.

A novel class of highly active dihydropyridine miticides was prepared using a multicomponent reaction process. The initial lead was rapidly optimized using solution phase parallel synthesis techniques and a positional scanning approach. Detailed structure-activity relationships were developed for the amino and carbonyl components of the molecule and used to select the best candidates for broad field testing. The chemistry, biology and toxicology of these compounds will be presented along with numerous structural variants of the reaction products.

Agrochemicals↗
PubMed2001

Influence of polyamine architecture on the transport and topoisomerase II inhibitory properties of polyamine DNA-intercalator conjugates.

An efficient five-step synthetic method was developed to access a series of spermine derivatives containing appended acridine, anthracene, and 7-chloroquinoline motifs. The derivatives were composed of a spermine fragment covalently tethered at its N4 and N9 positions to an aromatic nucleus via an aliphatic chain (e.g., 8: acridine -[C4 aliphatic tether]-spermine-[C4 aliphatic tether]-acridine). The distance separating the spermine and aromatic nuclei was altered via different tethers composed of four or five methylene units. These bis ligands (8, 9, 12, and 13) were shown to inhibit human DNA topoisomerase II (topo II) activity at 5 microM. Enzymatic activity was assessed as the ability to unknot (decatenate) and cleave kinetoplast DNA (kDNA). Polyamine conjugation did not disrupt the ability of the acridine-spermine conjugates 8 and 9 to inhibit topo II activity as compared with the 9-aminoacridine and 9-(N-butyl)aminoacridine controls (at 5 microM). The parent polyamines, spermine (5 microM) and spermidine (10 microM), had little effect on topo II activity. In general, the bis-substituted spermine derivatives (8, 9, 12, and 13) were more efficient topo II inhibitors at 5 microM than their monosubstituted spermidine counterparts (22-25) at 10 microM. Within the bisintercalator spermine series, insertion of an additional methylene unit (i.e., C5 tethers) increased potency 2-fold (8, bis-C4-acridine, 47 h IC(50) = 40 microM; 9, bis-C5-acridine, IC(50) = 17 microM). Comparison of the bis- and monoacridine spermine motifs (8 and 17) revealed a 4-fold increase in potency for the latter architecture (94 h IC(50) for 8, 74 microM; for 17, 17 microM). In general the bisintercalators (8, 9, 12, and 13) behaved as cytostatic agents, while the monosubstituted acridine and anthracene derivatives (22-25) were cytotoxic. Anthracene-containing conjugates were generally more toxic than their acridine counterparts in an L1210 (murine leukemia) cell assay. Of the conjugates tested the (monointercalator)-spermine motif (e.g., 17) had the highest affinity for the L1210 polyamine transporter as revealed by spermidine protection experiments.

Acridines↗
PubMed2000

The effect of polyamine homologation on the transport and cytotoxicity properties of polyamine-(DNA-intercalator) conjugates.

An efficient five-step synthetic method was developed to access a homologous series of spermidine-acridine and spermidine-anthracene conjugates. The derivatives were comprised of a spermidine fragment covalently tethered at its N4 position to either an acridine or anthracene nucleus via an aliphatic chain (e.g., spermidine-[aliphatic tether]-acridine). The distance separating the spermidine and aromatic nucleus was altered by using different tethers comprised of four or five methylene units, respectively. These ligands (2-5) were shown to inhibit human DNA topoisomerase-II (TOPO-II) activity at 10 microM. Enzymatic activity was assessed as the ability to unknot (decatenate) and cleave kinetoplast DNA (kDNA). Polyamine conjugation did not disrupt the ability of the acridine-spermidine conjugates 2 and 3 to inhibit TOPO-II activity as compared with the 9-aminoacridine and 9-(N-butyl)aminoacridine controls (at 10 microM). In general, the acridine derivatives (2 and 3) showed higher TOPO-II inhibitory activity than their anthracene counterparts (4 and 5). However, this trend was reversed in a whole cell assay with L1210 (murine leukemia) cells, wherein the anthracene analogues were more potent than their acridine counterparts. In this regard the qualitative enzyme-based assay did not predict the trends in the corresponding IC(50) values. Within either series insertion of an additional methylene unit did not significantly alter activity. While the appended spermidine unit did not disrupt TOPO II inhibition by the tethered DNA intercalator, it did provide an alternative mode of entry into the cell as demonstrated by spermidine protection assays. These results were compared with a spermine-intercalator analogue. Of all the conjugates tested the N(4)-(4-(9-aminoacridinyl)butyl)spermine hexahydrochloride (conjugate 16)resulted in the highest degree of L1210 cell rescue upon cotreatment of the cells with exogenous spermidine. It was concluded that the monoalkylated spermine motif present in 16 holds promise as a better vector than its N4 monoalkylated spermidine counterpart.

Animals↗
PubMed2000

Osteochondritis dissecans of the tibial plafond: imaging characteristics and a review of the literature.

UNLABELLED: OBJECTIVE; Osteochondritis dissecans of the talar articular surface of the ankle joint has been well described. We report the imaging characteristics of osteochondritis dissecans of the tibial articular surface (tibial plafond). CONCLUSION: Osteochondritis dissecans of the tibial plafond is a rare condition that may not be detectable on radiography. Its radiologic findings are similar to those of osteochondritis dissecans located elsewhere in the body.

Adult↗
PubMed1998

Heat-shock protein-25/27 phosphorylation by the delta isoform of protein kinase C.

Small heat-shock proteins (sHSPs) are widely expressed 25-28 kDa proteins whose functions are dynamically regulated by phosphorylation. While recent efforts have clearly delineated a stress-responsive p38 mitogen-activated protein-kinase (MAPK)-dependent kinase pathway culminating in activation of the heat-shock (HSP)-kinases, mitogen-activated protein-kinase-activated protein kinase-2 and -3, not all sHSP phosphorylation events can be explained by the p38 MAPK-dependent pathway. The contribution of protein kinase C (PKC) to sHSP phosphorylation was suggested by early studies but later questioned on the basis of the reported poor ability of purified PKC to phosphorylate sHSP in vitro. The current study re-evaluates the role of PKC in sHSP phosphorylation in the light of the isoform complexity of the PKC family. We evaluated the sHSP phosphorylation status in rat corpora lutea obtained from two stages of pregnancy, mid-pregnancy and late-pregnancy, which express different levels of the novel PKC isoform, PKC-delta. Two-dimensional Western blot analysis showed that HSP-27 was more highly phosphorylated in vivo in corpora lutea of late pregnancy, corresponding to the developmental stage in which PKC-delta is abundant and active. Late-pregnant luteal extracts contained a lipid-sensitive HSP-kinase activity which exactly co-purified with PKC-delta using hydroxyapatite and S-Sepharose column chromatography. To determine whether there might be preferential phosphorylation of sHSP by a particular PKC isoform, purified recombinant PKC isoforms corresponding to those PKC isoforms detected in rat corpora lutea were evaluated for HSP-kinase activity in vitro. Recombinant PKC-delta effectively catalysed the phosphorylation of sHSP in vitro, and PKC-alpha was 30-50% as effective as an HSP-kinase; other PKCs tested (beta1, beta2, epsilon and zeta) were poor HSP-kinases. These results show that select PKC family members can function as direct HSP-kinases in vitro. Moreover, the observation of enhanced luteal HSP-27 phosphorylation in vivo, in late pregnancy, when PKC-delta is abundant and active, suggests that select PKC family members contribute to sHSP phosphorylation events in vivo.

Animals↗
PubMed1997

Inflammatory cytokine expression is correlated with the level of human immunodeficiency virus (HIV) transcripts in HIV-infected placental trophoblastic cells.

The inflammatory cytokines interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor alpha (TNF-alpha) have been associated with increased human immunodeficiency virus (HIV) expression and enhanced lymphocyte adhesion to trophoblastic cells in experimental systems. To determine if there is a correlation between the expression of these cytokines and the levels of HIV transcripts in trophoblasts of term placentas from HIV-infected women, we studied the placentae of 30 HIV-positive and 13 control gravidae. Twenty-three of the HIV-positive women received zidovudine (ZDV) as prophylaxis against HIV vertical transmission; only one of the seven women who did not receive ZDV was a transmitter, for an overall vertical transmission rate of 3.8%. Cytokine production was measured by enzyme-linked immunosorbent assay in the supernatants of trophoblastic cell cultures. Additionally, cytokine transcripts and HIV gag sequences were determined by a quantitative reverse transcription-PCR assay. In general, trophoblastic cells of HIV-positive placentas expressed significantly higher levels of IL-1beta, IL-6, and TNF-alpha than those of control placentas. All placentas from HIV-positive women expressed HIV gag transcripts at either a low (<156 copies per microg of total RNA) or a high (>156 copies per microg of total RNA) level. There was a statistically significant positive association between the basal level of TNF-alpha production and the level of HIV gag transcripts of HIV-positive placental trophoblastic cells. Nevertheless, these data, coupled with a low transmission rate, would indicate that some other factors, perhaps working in concert with cytokines, are necessary for vertical transmission of HIV from mother to infant.

Cells, Cultured↗
PubMed1996

Activation of heat shock factor 1 DNA binding precedes stress-induced serine phosphorylation. Evidence for a multistep pathway of regulation.

Exposure of mammalian cells in culture to the anti-inflammatory drugs sodium salicylate or indomethacin results in activation of heat shock factor 1 (HSF1) DNA binding activity. We have previously shown that the drug-induced HSF1 becomes associated with the heat shock elements of the hsp70 promoter, yet transcription of the hsp70 gene is not induced (Jurivich, D. A., Sistonen, L., Kroes, R. A., and Morimoto, R. I. (1992) Science 255, 1243-1245). In this study, we have examined the basis for uncoupling the heat shock transcriptional response. Comparison of heat shock and drug-induced forms of HSF1 has revealed that the transcriptionally inert drug-induced HSF1 is constitutively but not inducibly serine-phosphorylated, whereas heat shock-induced HSF1 is both constitutively and inducibly serine-phosphorylated. The transcriptionally inert intermediate represented by drug-induced HSF1 can be converted to the transcriptionally active state by a subsequent exposure to heat shock. The only detectable change in HSF1 is the acquisition of inducible serine phosphorylation. These data reveal that acquisition of the trimeric DNA binding state of HSF1 is independent of and precedes inducible phosphorylation and furthermore that inducible phosphorylation correlates with transcriptional activation.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1995

Benefits and challenges of school-based crisis response teams.

Given the increasing prevalence of schoolchildren's experience with crises and resulting loss through sudden or violent death, adoption of a school-based crisis prevention and response plan becomes crucial. This article reviews a model of regional, district, and school-based levels of response designed collaboratively by four school districts and consultants from Yale University. The team approach on which the model is based is examined through benefits it affords students, staff, parents, and the community. Obstacles that can impede full implementation of the model are identified, and strategies for overcoming logistical and systemic resistances are offered. This proactive design helps promote individual and organizational resiliency to traumatic events by promoting communication, collaboration, and service provision in an efficient and comprehensive manner.

Child↗
PubMed1994

School-based crisis intervention: a role for pediatricians.

We have presented an overview of issues to consider in school-based crisis intervention using an organizational model for crisis response within the school. A wide range of ways exist in which pediatricians and other pediatric primary care providers can assist in the development, implementation, and functioning of school-based crisis intervention services for children. Those pediatricians with an interest in this area will find such activities personally and professionally rewarding and will come to appreciate the impact that such services can have on the lives of the students within the school, within their pediatric practices, and within their community.

Child↗
PubMed1992

Relationship of anxiety and depression.

There has been considerable controversy regarding the relationship between depression and anxiety. We review briefly the descriptive, longitudinal, genetic, biological, and treatment response data indicating that there is overlap between depression and anxiety. Several possible models are explored that provide different conceptions of how this relationship may best be understood: (1) that there are a variety of more or less discrete, but sometimes coexisting, syndromes within the spectrum of anxiety and depression; (2) that symptoms of depression and anxiety represent different external manifestations of a more basic underlying cause; (3) that one condition may predispose to the other; (4) that the association may be due to artifactual definitional overlap, particularly since the instruments used to measure depression and anxiety share so many items. All these propositions are supported. An important, practical question is discussed--should the mixed anxiety/depressive disorder that has been suggested by ICD-10 be included in DSM-IV?

Anxiety↗
PubMed1989

Xanthomatous infiltrate of the face.

We report 2 cases which shared an unusual histopathologic pattern of a xanthomatous infiltrate occurring on the nose. Both patients were women in their fifth decade. Each presented to the dermatology clinic with multiple soft, flesh-colored papules, up to 1 cm, in diameter on the lateral aspects of the nose. The lesions had been present for several years. Both patients were otherwise completely well, and asymptomatic. In one case, focal telangiectasia and central umbilication was noted, and the clinical differential diagnoses included basal cell carcinomas and appendageal tumors. In each case, a biopsy was performed. The lesions appeared histologically quite similar. The epidermis was unremarkable. Within the dermis, there was a mid-reticular dermal infiltrate of macrophages with unilocular and multilocular fat laden cytoplasm, and scalloped nuclei. Only a scant inflammatory infiltrate of lymphocytes and histiocytes was present. Minimal dermal fibrosis was also present. We believe that xanthomatous infiltrate of the face is a distinct clinical entity which presents as multiple flesh-colored papules on the nose, which have a characteristic histologic appearance of abundant lipid-laden macrophages within the dermis.

Diagnosis, Differential↗
PubMed1989

Carolina Picture Vocabulary Test: validation with hearing-impaired students.

When mean Carolina Picture Vocabulary Test standard scores were compared with WISC-R Performance Scale IQs significant differences were observed. The Carolina test scores were also correlated with both Performance IQs and the Performance Scale subtest scores. Most correlations were minimal as the two tests were independent; only WISC-R Picture Arrangement scores correlated significantly with Carolina scores. These outcomes coupled with the technical limitations of the Carolina raise serious questions regarding its utility for hearing-impaired children.

Child↗