bluuebunny/crossref_metadata_2025 huggingface dataset:
Potent Antitumor Activity of an Auristatin-Conjugated, Fully Human Monoclonal Antibody to Prostate-Specific Membrane Antigen
Authors: Ma Dangshe , Hopf Christine E. , Malewicz Andrew D. , Donovan Gerald P. , Senter Peter D. , Goeckeler William F. , Maddon Paul J. , Olson William C.
Published: April 2006

Prostate-specific membrane antigen (PSMA) is the prototypic cell-surface marker of prostate cancer and provides an attractive target for monoclonal antibody (mAb) targeted therapies. In this study, a novel antibody-drug conjugate (ADC) was generated by linking a fully human PSMA mAb to monomethylauristatin E (MMAE), a potent inhibitor of tubulin polymerization. The PSMA ADC was evaluated for antitumor activity in vitro and in a mouse xenograft model of androgen-independent human prostate cancer. The PSMA ADC eliminated PSMA-expressing cells with picomolar potency and >700-fold selectivity in culture. When used to treat mice with established human C4-2 tumors, the PSMA ADC significantly improved median survival 9-fold relative to vehicle or isotype-matched ADC (P = 0.0018) without toxicity. Treatment effects were also manifest as significant (P = 0.0068) reduction in serum levels of prostate-specific antigen (PSA). Importantly, 40% of treated animals had no detectable tumor or measurable PSA at day 500 and could be considered cured. The findings support development of PSMA antibody-auristatin conjugates for therapy of prostate cancer.
Rapamycin Inhibits Growth of Premalignant and Malignant Mammary Lesions in a Mouse Model of Ductal Carcinoma In situ
Authors: Namba Ruria , Young Lawrence J.T. , Abbey Craig K. , Kim Lisa , Damonte Patrizia , Borowsky Alexander D. , Qi Jinyi , Tepper Clifford G. , MacLeod Carol L. , Cardiff Robert D. , Gregg Jeffrey P.
Published: April 2006

Purpose: Rapamycin has been shown to have antitumor effects in various tumor models. To study the effect of rapamycin at different stages of breast cancer development, we used two unique mouse models of breast cancer with activated phosphatidylinositol 3-kinase (PI3K) pathway. Met-1 tumors are highly invasive and metastatic, and mammary intraepithelial neoplasia-outgrowths (MIN-O), a model for human ductal carcinoma in situ, are transplantable premalignant mammary lesions that develop invasive carcinoma with predictable latencies. Both of these models were derived from mammary lesions in Tg(MMTV-PyV-mT) mice.

Experimental Design: Met-1 tumors were used to study the effect of rapamycin treatment on invasive disease. Transplanted MIN-O model was used to study the effect of rapamycin on premalignant mammary lesions. Animals were in vivo micro–positron emission tomography imaged to follow the lesion growth and transformation to tumor during the treatment. Cell proliferation, angiogenesis, and apoptosis was assayed by immunohistochemistry.

Results: Rapamycin inhibited in vitro tumor cell proliferation and in vivo Met-1 tumor growth. The growth inhibition was correlated with dephosphorylation of mammalian target of rapamycin (mTOR) targets. Rapamycin treatment significantly reduced the growth of the premalignant MIN-O lesion, as well as tumor incidence and tumor burden. Growth inhibition was associated with reduced cell proliferation and angiogenesis and increased apoptosis.

Conclusions: In PyV-mT mouse mammary models, rapamycin inhibits the growth of premalignant lesions and invasive tumors. Although the inhibitory effect of rapamycin was striking, rapamycin treatment did not completely obliterate the lesions.
Reduced Plasma RNA Integrity in Nasopharyngeal Carcinoma Patients
Authors: Wong Blenda C.K. , Chan K.C. Allen , Chan Anthony T.C. , Leung Sing-Fai , Chan Lisa Y.S. , Chow Katherine C.K. , Lo Y.M. Dennis
Published: April 2006

Purpose: Recent research has shown the feasibility of detecting cell-free RNA markers in human subjects. As elevated RNase activity has previously been described in the circulation of cancer patients, we hypothesized that cancer patients may have reduced plasma RNA integrity. In this study, we used nasopharyngeal carcinoma (NPC) as a model system to test this hypothesis.

Experimental Design: Plasma RNA integrity was determined using the ratio of the concentrations of transcript sequences corresponding to the 3′ to those from the 5′ end of a housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Transcript concentrations were measured using real-time quantitative reverse transcription-PCR assays targeting the 5′ and 3′ regions. We analyzed the plasma RNA integrity in 49 untreated NPC patients and 53 healthy controls. We also assessed the plasma samples from 19 NPC patients before and after radiotherapy to further show the clinical potential of this marker.

Results: The 3′ to 5′ GAPDH ratio was significantly lower in the plasma of untreated NPC patients when compared with healthy controls (0.0252 versus 0.0485, P = 0.024). Statistical analysis showed that plasma GAPDH ratio was correlated with tumor stage but not with sex and age. Moreover, 14 of 19 NPC patients (74%) showed significant increase in the plasma GAPDH ratio following radiotherapy (P = 0.003). All of these patients were in clinical remission after treatment.

Conclusions: Our findings suggest that NPC is associated with disturbances in the integrity of cell-free circulating RNA, raising the possibility that measurement of plasma RNA integrity may serve as a useful marker for the diagnosis and monitoring of malignant diseases.
Molecular Evidence for the Same Clonal Origin of Multifocal Papillary Thyroid Carcinomas
Authors: McCarthy Ryan P. , Wang Mingsheng , Jones Timothy D. , Strate Randall W. , Cheng Liang
Published: April 2006

Purpose: Patients with papillary thyroid carcinoma often have two or more distinct papillary tumors at thyroidectomy. Whether these multifocal papillary lesions are clonally related or whether they arise independently is unknown as previous studies have shown conflicting results. Molecular analysis of microsatellite alterations and X-chromosome inactivation status in separate tumors from the same patient can be used to define the genetic relationships among the multiple coexisting tumors.

Experimental Design: We examined 64 separate tumors from 22 female patients who underwent thyroidectomy for thyroid carcinoma. All patients had multiple and separate papillary carcinomas (range, two to six). Genomic DNA samples were prepared from formalin-fixed, paraffin-embedded tissue sections using laser-capture microdissection. Loss of heterozygosity assays for three microsatellite polymorphic markers for putative tumor suppressor genes on chromosomes 3p25 (D3S1597), 9p21 (D9S161), and 18p11.22-p11 (D18S53) were done. In addition, X-chromosome inactivation analysis was done on the tumors from all patients.

Results: Twenty of 22 (91%) cases showed allelic loss in one or more of the papillary lesions in at least one of the three polymorphic markers analyzed. Concordant allelic loss patterns between coexisting papillary tumors were seen in 20 of 23 (87%) cases. A concordant pattern of nonrandom X-chromosome inactivation in the multiple coexisting papillary lesions was seen in all informative cases.

Conclusion: Our data suggest that the multifocal tumors in patients with papillary thyroid carcinoma often arise from the same clone. Thus, intrathryoid metastasis may play an important role in the spread of papillary thyroid carcinoma, a finding that has important therapeutic, diagnostic, and prognostic implications.
Podocyte Injury Underlies the Glomerulopathy of Dahl Salt-Hypertensive Rats and Is Reversed by Aldosterone Blocker
Authors: Nagase Miki , Shibata Shigeru , Yoshida Shigetaka , Nagase Takashi , Gotoda Takanari , Fujita Toshiro
Published: April 2006

Recent clinical studies implicate proteinuria as a key prognostic factor for renal and cardiovascular complications in hypertensives. The pathogenesis of proteinuria in hypertension is, however, poorly elucidated. Podocytes constitute the final filtration barrier in the glomerulus, and their dysfunction may play a pivotal role in proteinuria. In the present study, we examined the involvement of podocyte injury in Dahl salt-hypertensive rats, an animal model prone to hypertensive glomerulosclerosis, and explored the effects of inhibition of aldosterone. Four-week–old Dahl salt-resistant and salt-sensitive rats were fed a 0.3% or 8.0% NaCl diet. Some salt-loaded Dahl salt-sensitive rats were treated with a selective aldosterone blocker eplerenone (1.25 mg/g diet) or hydralazine (0.5 mmol/L). After 6 weeks, salt-loaded Dahl salt-sensitive rats developed severe hypertension, proteinuria, and glomerulosclerosis. Immunostaining for nephrin, a constituent of slit diaphragm, was attenuated, whereas expressions of damaged podocyte markers desmin and B7-1 were upregulated in the glomeruli of salt-loaded Dahl salt-sensitive rats. Electron microscopic analysis revealed podocyte foot process effacement. Podocytes were already impaired at as early as 2 weeks of salt loading in Dahl salt-sensitive rats, when proteinuria was modestly increased. Both eplerenone and hydralazine partially reduced systemic blood pressure as measured by indirect and direct methods in salt-loaded Dahl salt-sensitive rats, but only eplerenone dramatically improved podocyte damage and retarded the progression of proteinuria and glomerulosclerosis. Our findings suggest that podocyte injury underlies the glomerulopathy of Dahl salt-hypertensive rats and that inhibition of aldosterone by eplerenone is protective against podocyte damage, proteinuria, and glomerulosclerosis in this hypertensive model.
Amelioration of Genetic Hypertension by Suppression of Renal G Protein–Coupled Receptor Kinase Type 4 Expression
Authors: Sanada Hironobu , Yatabe Junichi , Midorikawa Sanae , Katoh Tetsuo , Hashimoto Shigeatsu , Watanabe Tsuyoshi , Xu Jing , Luo Yingjin , Wang Xiaoyan , Zeng Chunyu , Armando Ines , Felder Robin A. , Jose Pedro A.
Published: April 2006

Abnormalities in D
1
dopamine receptor function in the kidney are present in some types of human essential and rodent genetic hypertension. We hypothesize that increased activity of G protein–coupled receptor kinase type 4 (GRK4) causes the impaired renal D
1
receptor function in hypertension. We measured renal GRK4 and D
1
and serine-phosphorylated D
1
receptors and determined the effect of decreasing renal GRK4 protein by the chronic renal cortical interstitial infusion (4 weeks) of GRK4 antisense oligodeoxynucleotides (As-Odns) in conscious- uninephrectomized spontaneously hypertensive rats (SHRs) and their normotensive controls, Wistar–Kyoto (WKY) rats. Basal GRK4 expression and serine-phosphorylated D
1
receptors were &90% higher in SHRs than in WKY rats and were decreased to a greater extent in SHRs than in WKY rats with GRK4 As-Odns treatment. Basal renal D
1
receptor protein was similar in both rat strains. GRK4 As-Odns, but not scrambled oligodeoxynucleotides, increased sodium excretion and urine volume, attenuated the increase in arterial blood pressure with age, and decreased protein excretion in SHRs, effects that were not observed in WKY rats. These studies provide direct evidence of a crucial role of renal GRK4 in the D
1
receptor control of sodium excretion and blood pressure in genetic hypertension.
Understanding the Coronary Heart Disease Versus Total Cardiovascular Mortality Paradox
Authors: Murray Christopher J.L. , Kulkarni Sandeep C. , Ezzati Majid
Published: April 2006

Background—

Coronary heart disease (CHD) represents the largest share of cardiovascular disease in the United States, but there are conspicuous discrepancies between CHD and total cardiovascular death rates across the states, possibly due in part to variations in physician assignment of causes of death. Our aim was to identify exogenous individual- and community-level predictors of cause-of-death assignment and variability and to use these predictors to improve the comparability of CHD mortality estimates across states.

Methods and Results—

We performed a multinomial logistic regression analysis to estimate the effect of individual- and community-level factors on the likelihood of a death being certified as 1 of 3 ill-defined clusters (general atherosclerosis and unspecified heart disease, heart failure, and cardiac arrest) relative to being certified as CHD. The individual-level variables were the decedent’s race, sex, age, education, and place of death; the community-level variable was the number of cardiologists per capita. We used the model to estimate state-level CHD rates that are standardized with regard to the levels of individual- and community-level determinants of cause-of-death assignment. Decedents who died in hospitals and in counties with more cardiologists per capita were more likely to be assigned to CHD than to the ill-defined categories, as were white males relative to other race-sex combinations. Adjustment for these factors resulted in substantially improved correlation between death rates for CHD and all cardiovascular causes. Increases in CHD death rates across states after adjustment for external predictors of cause-of-death assignment ranged from 2% (North Dakota) to 72% (Washington, DC); New York had a decrease (1%) in CHD death rates after adjustment. Nationally, CHD death rates increased 10% for males and 15% for females. The total number of deaths in 2001 attributed to CHD in patients over 30 years of age rose from 433 625 to 489 836 after adjustment.

Conclusions—

Greater presence of medical knowledge at the time of death, reflected by place of death and cardiologists per capita, reduces the use of the ill-defined cardiovascular clusters. Racial and gender effects on CHD assignment may reflect disparities in access to care and quality of care. By adjusting for differentials in these parameters, a comparable and consistent set of CHD mortality estimates can be created. The role of the exogenous predictors in validity and comparability of cause-of-death statistics should be confirmed in carefully designed validation autopsy studies.
Coffee Consumption and Coronary Heart Disease in Men and Women
Authors: Lopez-Garcia Esther , van Dam Rob M. , Willett Walter C. , Rimm Eric B. , Manson JoAnn E. , Stampfer Meir J. , Rexrode Kathryn M. , Hu Frank B.
Published: April 2006

Background—

We examined the association between long-term habitual coffee consumption and risk of coronary heart disease (CHD).

Methods and Results—

We performed a prospective cohort study with 44 005 men and 84 488 women without history of cardiovascular disease or cancer. Coffee consumption was first assessed in 1986 for men and in 1980 for women and then repeatedly every 2 to 4 years; the follow-up continued through 2000. We documented 2173 incident cases of coronary heart disease (1449 nonfatal myocardial infarctions and 724 fatal cases of CHD) among men and 2254 cases (1561 nonfatal myocardial infarctions and 693 fatal cases of CHD) among women. Among men, after adjustment for age, smoking, and other CHD risk factors, the relative risks (RRs) of CHD across categories of cumulative coffee consumption (<1 cup/mo, 1 cup/mo to 4 cups/wk, 5 to 7 cups/wk, 2 to 3 cups/d, 4 to 5 cups/d, and ≥6 cups/d) were 1.0, 1.04 (95% confidence interval 0.91 to 1.17), 1.02 (0.91 to 1.15), 0.97 (0.86 to 1.11), 1.07 (0.88 to 1.31), and 0.72 (0.49 to 1.07;
P
for trend=0.41); among women, the RRs were 1.0, 0.97 (0.83 to 1.14), 1.02 (0.90 to 1.17), 0.84 (0.74 to 0.97), 0.99 (0.83 to 1.17), and 0.87 (0.68 to 1.11;
P
for trend=0.08). Stratification by smoking status, alcohol consumption, history of type 2 diabetes mellitus, and body mass index gave similar results. Similarly, we found no effect when the most recent coffee consumption was examined. RRs for quintiles of caffeine intake varied from 0.97 (0.84 to 1.10) in the second quintile to 0.97 (0.84 to 1.11) in the highest quintile (
P
for trend=0.82) in men and from 1.02 (0.90 to 1.16) to 0.97 (0.85 to 1.11;
P
for trend=0.37) in women.

Conclusions—

These data do not provide any evidence that coffee consumption increases the risk of CHD.
Clinical Evaluation of QT/QTc Prolongation and Proarrhythmic Potential for Nonantiarrhythmic Drugs: The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use E14 Guideline
Authors: Darpo Borje , Nebout Thierry , Sager Philip T.
Published: April 2006

Proarrhythmias due to drug‐induced QT prolongation are the second most common cause for drug withdrawal and have caused increasing concern. Two new International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines were recently endorsed in which nonclinical (S7B) and clinical (E14) methodologies are discussed and guidance is given to the industry. This commentary describes the key components of the E14 document, the impact of nonclinical testing on the clinical program, the thorough QT study, and the impact of its result on late‐stage development. The studies described in S7B and E14 will contribute to a better understanding of the link between nonclinical assays and QT prolongation in humans. Differences in interpretation among individual regulators in the major regions with respect to measures proposed in the E14 guideline might impact regional regulatory decisions. These differences include the value of nonclinical assays for the subsequent clinical testing and how predictive a negative thorough QT study result is for proarrhythmic risk in patients.
From Single-Parent Families to Stepfamilies
Authors: Kirby James B.
Published: April 2006

This study addresses two questions: Is stepfamily formation associated with the likelihood that adolescents will initiate alcohol use, and if so, does this association differ by the type of single-parent families from which adolescents move or the type of stepfamilies to which they move? The author found that adolescents who moved to stepfamilies from single-parent families had an elevated risk of initiating alcohol use. A transition from a divorced single-parent family to a stepfamily is associated with an increase in alcohol initiation among boys, but a transition from an unwed single-parent family to a stepfamily is not. In contrast, girls who transition from an unwed single-parent family to a stepfamily show an elevated likelihood of initiating alcohol use, whereas those who transition from divorced single-parent families do not. Adolescents who move to cohabiting stepfamilies do not respond differently than do adolescents who move to married stepfamilies regardless of gender.
Medial Opening Wedge Tibial Osteotomy and the Sagittal Plane
Authors: Rodner Craig M. , Adams Douglas J. , Diaz-Doran Vilmaris , Tate Janet P. , Santangelo Stephen A. , Mazzocca Augustus D. , Arciero Robert A.
Published: April 2006

Background

Altering the tibial slope in an anterior cruciate ligament–deficient knee has been shown to affect anterior-posterior tibial translation. The effects on articular contact pressure of altering tibial slope during a high tibial osteotomy are unknown.

Hypotheses

Performing an opening wedge osteotomy anterior to the midaxial line will increase tibial slope. Increasing tibial slope with a high tibial osteotomy in an anterior cruciate ligament–deficient knee redistributes tibiofemoral joint contact pressures onto the posterior tibial plateau.

Study Design

Controlled laboratory study.

Methods

Medial opening wedge high tibial osteotomies were performed, and a plate fixation with a known diameter inset was placed along the medial tibia in an anterior position and a posterior position on 9 cadaveric knees. Medial and lateral tibiofemoral contact pressures were measured at the resulting 2 different tibial slopes in both ligament-intact and ligament-deficient states using thin electronic sensors.

Results

Anterior plate application resulted in an increase in posterior tibial slope by an average of 6.6°(P <.001) compared with posterior plate placement. After medial opening wedge high tibial osteotomy, the mean peak lateral tibiofemoral contact pressure (3.4 MPa) was significantly greater (P=.002) than was the mean peak medial pressure (2.6 MPa). In ligament-intact specimens, altering the tibial slope did not significantly shift peak contact pressures. However, in ligament-deficient knees, increasing tibial slope by an average of 5.5° significantly redistributed the location of peak intra-articular pressure, shifting it posteriorly by 24% (P=.003).

Conclusion

Increasing tibial slope in anterior cruciate ligament–deficient knees with a high tibial osteotomy redistributes pressure into the posterior tibial plateau.

Clinical Relevance

In knees with chronic anterior cruciate ligament deficiency, posteromedial compartment degeneration is observed. Inadvertent redistribution of contact pressure into this area may be a cause of pain and premature clinical failure after medial opening wedge tibial osteotomy.
The experience of burden in India
Authors: Emmatty Leena Mary , Bhatti Ranbir S. , Mukalel Mathew T.
Published: April 2006

Thirty caregivers of people living with dementia were investigated to examine the caregivers' experience of burden. The Clinical Dementia Rating Scale (CDRS), Burden Interviews and open-ended questions were administered on patients attending inpatient and outpatient services at the National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore (India).

Findings indicate that only 30 percent of the cases fell into the high burden group. No statistically significant results were observed between caregiver relationship and burden scores. Burden experienced in extended families was less compared to the other types of families. To conclude, the need to create awareness about the illness among different sections of the general population and interventions suited to the Indian caregivers are discussed.
Stigma and dementia
Authors: Mackenzie Jenny
Published: April 2006

This article draws on findings from a three-year project to develop and deliver culturally appropriate support group materials for South Asian and Eastern European family carers of relatives with dementia living in the UK. Analysis of interview and field note data revealed insights into how understandings of dementia in different cultural contexts can become operationalized through stigma processes and in turn influence the ways in which people with dementia and their family carers engage with formal and informal support.
Service provision for people with dementia in rural Scotland
Authors: Innes Anthea , Cox Sylvia , Smith Annetta , Mason Anne
Published: April 2006

The provision of health and social care services to people with dementia and their carers living in remote and rural areas has been neglected globally. Meeting the needs of people with dementia poses many challenges for service providers. Such challenges may be compounded by the difficulties of providing and accessing services in rural areas.This article explores the views of Scottish service providers drawn from the voluntary, statutory and private sectors. Our findings highlight the difficulties relating to dementia and rurality faced by service providers in Scotland. We also consider innovative measures reported by service providers. Such measures indicate that not only can the distinct challenges of dementia service provision be overcome, but also challenges posed by providing services to people with dementia and their carers in rural and remote areas.These findings extend the literature on rural dementia service provision.The article concludes with a consideration of the practice and policy implications of providing dementia services in remote and rural Scotland.
Motion as a phenotype: the use of live-cell imaging and machine visual screening to characterize transcription-dependent chromosome dynamics
Authors: Drubin David A , Garakani Arman M , Silver Pamela A
Published: April 2006

Background

Gene transcriptional activity is well correlated with intra-nuclear position, especially relative to the nuclear periphery, which is a region classically associated with gene silencing. Recently however, actively transcribed genes have also been found localized to the nuclear periphery in the yeast Saccharomyces cerevisiae. When genes are activated, they become associated with the nuclear pore complex (NPC) at the nuclear envelope. Furthermore, chromosomes are not static structures, but exhibit constrained diffusion in real-time, live-cell studies of particular loci. The relationship of chromosome motion with transcriptional activation and active-gene recruitment to the nuclear periphery has not yet been investigated.

Results

We have generated a yeast strain that enables us to observe the motion of the galactose-inducible GAL gene locus relative to the nuclear periphery in real-time under transcriptionally active and repressed conditions. Using segmented geometric particle tracking, we show that the repressed GAL locus undergoes constrained diffusive movement, and that transcriptional induction with galactose is associated with an enrichment in cells with GAL loci that are both associated with the nuclear periphery and much more constrained in their movement. Furthermore, we report that the mRNA export factor Sac3 is involved in this galactose-induced enrichment of GAL loci at the nuclear periphery. In parallel, using a novel machine visual screening technique, we find that the motion of constrained GAL loci correlates with the motion of the cognate nuclei in galactose-induced cells.

Conclusion

Transcriptional activation of the GAL genes is associated with their tethering and motion constraint at the nuclear periphery. We describe a model of gene recruitment to the nuclear periphery involving gene diffusion and the mRNA export factor Sac3 that can be used as a framework for further experimentation. In addition, we applied to the analysis of chromosome motion a machine visual screening approach that used unbiased visual data rather than segmented geometric data. This novel analytical approach will allow for high-throughput study of processes that can be monitored via alterations in chromosome motion and connectivity with the nuclear periphery.
Novel multi-component nanopharmaceuticals derived from poly(ethylene) glycol, retro-inverso-Tat nonapeptide and saquinavir demonstrate combined anti-HIV effects
Authors: Wan Li , Zhang Xiaoping , Gunaseelan Simi , Pooyan Shahriar , Debrah Olivia , Leibowitz Michael J , Rabson Arnold B , Stein Stanley , Sinko Patrick J
Published: April 2006

Background

Current anti-AIDS therapeutic agents and treatment regimens can provide a dramatically improved quality of life for HIV-positive people, many of whom have no detectable viral load for prolonged periods of time. Despite this, curing AIDS remains an elusive goal, partially due to the occurrence of drug resistance. Since the development of resistance is linked to, among other things, fluctuating drug levels, our long-term goal has been to develop nanotechnology-based drug delivery systems that can improve therapy by more precisely controlling drug concentrations in target cells. The theme of the current study is to investigate the value of combining AIDS drugs and modifiers of cellular uptake into macromolecular conjugates having novel pharmacological properties.

Results

Bioconjugates were prepared from different combinations of the approved drug, saquinavir, the antiviral agent, R.I.CK-Tat9, the polymeric carrier, poly(ethylene) glycol and the cell uptake enhancer, biotin. Anti-HIV activities were measured in MT-2 cells, an HTLV-1-transformed human lymphoid cell line, infected with HIV-1 strain Vbu 3, while parallel studies were performed in uninfected cells to determine cellular toxicity. For example, R.I.CK-Tat9 was 60 times more potent than L-Tat9 while the addition of biotin resulted in a prodrug that was 2850 times more potent than L-Tat9. Flow cytometry and confocal microscopy studies suggest that variations in intracellular uptake and intracellular localization, as well as synergistic inhibitory effects of SQV and Tat peptides, contributed to the unexpected and substantial differences in antiviral activity.

Conclusion

Our results demonstrate that highly potent nanoscale multi-drug conjugates with low non-specific toxicity can be produced by combining moieties with anti-HIV agents for different targets onto macromolecules having improved delivery properties.
Marker Expression in Peripheral T-Cell Lymphoma: A Proposed Clinical-Pathologic Prognostic Score
Authors: Went Philip , Agostinelli Claudio , Gallamini Andrea , Piccaluga Pier Paolo , Ascani Stefano , Sabattini Elena , Bacci Francesco , Falini Brunangelo , Motta Teresio , Paulli Marco , Artusi Tullio , Piccioli Milena , Zinzani Pier Luigi , Pileri Stefano A.
Published: April 2006

Purpose

Although peripheral T-cell lymphoma, unspecified (PTCL/U), is the most common T-cell tumor in Western countries, no study to date has been based on the application of a wide panel of markers to a large series of patients and assessed the impact of phenotype on survival. We evaluated the expression of 19 markers in 148 PTCLs/U and 45 PTCLs of the angioimmunoblastic type (AILD).

Patients and Methods

The analysis was performed on tissue microarrays by immunohistochemistry and in situ hybridization. Clinical data were available in 93 PTCL/U patients, most of whom had been included in a previous study proposing a prognostic index (PIT).

Results

An aberrant phenotype with frequent loss of CD5 and/or CD7 was typical for PTCLs, irrespective of whether they were U or AILD. Aberrantly expressed proteins rarely included CD20, CD15, and CD30. Positivity for Epstein-Barr virus–associated small RNAs and CD15 expression emerged as adverse prognostic factors. Among PTCLs/U, the proliferation-associated protein Ki-67 turned out to be prognostically relevant and was integrated in a new predictive score, incorporating age (> 60 years), high lactate dehydrogenase, poor performance status, and Ki-67 ≥ 80%. This score was associated with the patient outcome (P < .0001) and was found to be more robust than PIT (P = .0043) in the present series.

Conclusion

Our retrospective analysis shows a wide range of protein expression in PTCLs and proposes a new prognostic index. The latter represents one of the first examples of mixed score (including patient- and tumor-specific factors) applied to malignant lymphomas and may be the basis for future prospective therapeutic trials.
Total Synthesis of 10-Isothiocyanatoguaia-6-ene
Authors: Iwasawa Nobuharu , Funahashi Masahiro , Narasaka Koichi
Published: April 2006

Total synthesis of a unique isothiocyano sesquiterpene, 10-isothiocyanatoguaia-6-ene, was achieved utilizing the oxidative radical cyclization reaction of a bicyclo[4.1.0]heptanol derivative with Mn(pic)3 as the key step.
Structural Revision of Griseulin, a Bioactive Pyrone Possessing a Nitrophenyl Unit
Authors: Ishibashi Yasuharu , Nishiyama Shigeru , Yamamura Shosuke
Published: April 2006

Biologically active griseulin isolated from Streptomyces sp. was synthesized, however the spectral data of the synthetic sample did not agree with the reported one. Synthesis of the related sample and detailed reexamination of the spectroscopic properties resulted in the structural revision of griseulin, which should be identical with luteoreticulin.
Hydrostannation of Cyclopropene. Strain-Driven Radical Addition Reaction
Authors: Yamago Shigeru , Ejiri Satoshi , Nakamura Eiichi
Published: April 2006

Hydrostannation of substituted cyclopropenone acetals with trialkyltin hydride takes place smoothly under radical conditions to afford a variety of 2-alkyl-3-stannylcyclopropanone acetals in high yield. Comparison of the cyclopropene with acetylenes with the aid of inter- and intramolecular competitive experiments revealed the kinetically controlled nature of the reaction of the cyclopropene reaction.
Copper-catalyzed Selective Oxidation of Methane to Formaldehyde by Oxygen
Authors: Li Yang , Chen Shili , Zhang Qinghong , Wang Ye
Published: April 2006

Cu/SBA-15 exhibited the highest activity for the selective oxidation of methane to formaldehyde by oxygen among various M/SBA-15 catalysts (M = V, Cr, Mn, Fe, Co, Ni, Cu, Mo, and W) containing small amount of M (M/Si = 1/13200). Formaldehyde space-time yield reached 870 g kgcat−1 h−1 over the Cu/SBA-15 under the conditions maintaining single-pass formaldehyde yield higher than 1%. The turnover frequency for HCHO formation was 5.6 s−1 under the same conditions, significantly higher than other catalysts reported so far.
Clinical leaders at the forefront of change in health-care systems: advantages and issues. Lessons learned from the evaluation of the implementation of an integrated oncological services network
Authors: Touati Nassera , Roberge Danièle , Denis Jean-Louis , Cazale Linda , Pineault Reynald , Tremblay Dominique
Published: April 2006

Based on lessons learned from the evaluation of the implementation of an integrated oncological services network in Québec, this paper discusses the following question: to what extent is strong clinical leadership a propitious means of transforming health-care systems, especially when the change leads to significant evolution in inter-professional and inter-organizational relations? Through a qualitative case study, we analysed the exercising of leadership by studying over time the clinical leaders' initiatives while trying to understand the sources of influence, the nature of the tactics adopted and their consequences for the degree of integration of health services. This study seems to show that clinical leadership is effective but limited. We conclude that a constellation of clinical, administrative and political leaders found at different levels of the health-care system offers more promise of positive change for the health-care system.
Building IT capability in health-care organizations
Authors: Khatri Naresh
Published: April 2006

While computer technology has revolutionized industries such as banking and airlines, it has done little for health care so far. Most of the health-care organizations continue the early-computer-era practice of buying the latest technology without knowing how it might effectively be employed in achieving business goals. By investing merely in information technology (IT) rather than in IT capabilities they acquire IT components - primarily hardware, software, and vendor-provided services - which they do not understand and, as a result, are not capable of fully utilizing for achieving organizational objectives. In the absence of internal IT capabilities, health-care organizations have relied heavily on the fragmented IT vendor market in which vendors do not offer an open architecture, and are unwilling to offer electronic interfaces that would make their 'closed' systems compatible with those of other vendors. They are hamstrung as a result because they have implemented so many different technologies and databases that information stays in silos. Health systems can meet this challenge by developing internal IT capabilities that would allow them to seamlessly integrate clinical and business IT systems and develop innovative uses of IT. This paper develops a comprehensive conception of IT capability grounded in the resource-based theory of the firm as a remedy to the woes of IT investments in health care.
Experimental evidence for the influence of the excitation wavelength on the value of the equilibrium constant as determined by Time-Resolved Emission Spectroscopy (TRES)
Authors: Billard Isabelle , Montavon Gilles , Markai Sandrine , Galindo Catherine
Published: April 2006

In the case of a rapid photochemical process, a new theoretical result relating time-resolved emission spectroscopy data to three physical parameters of the chemical system has been recently proposed. This previous work, based on a simulation study, is experimentally evidenced in the present paper, using europium/acetate as a model system. The comparison of the emission spectra obtained upon direct excitation of europium (394 nm) and by use of the “antenna effect” (266 nm) evidences the occurring of a back-dissociation of excited europium complexes to form solvated excited free europium ions.
Pediatric Cinnarizine Overdose and Toxicokinetics
Authors: Turner Dan , Lurie Yael , Finkelstein Yoram , Schmid Tal , Gopher Asher , Kleid David , Bentur Yedidia
Published: April 2006

Cinnarizine, a piperazine derivative, is a widely prescribed medication for the treatment of vestibular disorders and motion sickness. Cinnarizine has antihistaminic, antiserotoninergic, antidopaminergic, and calcium channel–blocking properties. We present the first report in the English literature of cinnarizine poisoning and toxicokinetics. A 30-month-old toddler ingested 225 mg of cinnarizine, 18 times the recommended dose for older children. Four hours later, she became jittery with a wide-based gait and vomited 3 times. She was examined by her family physician, who reported stupor and twitching in both hands. On admission to the hospital, 6 hours after the ingestion, she was stuporous and had 3 short, generalized tonic-clonic convulsions that were controlled with a single dose of midazolam. Full clinical recovery was seen 10 hours after ingestion. Serum cinnarizine levels were 7407, 2629, and 711 ng/mL on admission and at 4 and 12 hours thereafter, respectively, 26.9 times higher than the therapeutic levels in adults. Elimination rate constant, calculated by linear regression of the ln concentrations of the 3 data points, was 0.19. Half-life, calculated from the equation t1/2 = 0.693/kel, where kel is the elimination rate constant, was 3.65 hours. The manufacturing company revealed that their database contains 23 reports of cinnarizine overdose (adult and children), received between 1972 and 2004. Clinically, these cases reflect mainly symptoms of alterations in consciousness ranging from somnolence to stupor and coma, vomiting, extrapyramidal symptoms, and hypotonia. In a small number of young children, convulsions developed; recovery was uneventful in 4 cases and not reported in 1. The neurologic complication may be explained by the antihistaminic effect of cinnarizine because central nervous system depression and convulsions are known complications of antihistaminic overdose. It is hypothesized that cinnarizine-induced convulsions also are related to the antidopaminergic effect of the drug. Apart from the convulsions, no other adverse effects related to calcium channel–blocking properties, such as bradycardia or hemodynamic instability, were observed. Pediatric patients with cinnarizine overdose need to be observed in a health care facility for potential neurologic complications and be treated symptomatically. The delay to onset of clinical effect should be considered in the observation period.
Importance of Flood Dynamics versus Intrinsic Physical Habitat in Structuring Fish Communities: Evidence from Two Adjacent Engineered Floodplains on the Sacramento River, California
Authors: Feyrer Frederick , Sommer Ted , Harrell William
Published: April 2006

We examined the factors structuring fish communities at two adjacent engineered floodplain systems on the Sacramento River, California: Yolo and Sutter bypasses. We intensively sampled fishes at each location during January–June 2002 and 2004 by rotary screw trap, collecting a total of 126,635 fish comprised of 29 species. Nonmetric multidimensional scaling indicated that distinct fish communities persisted between the locations during our study, despite nearly identical hydrographs and water temperature regimes. Regression models evaluated with an information-theoretic approach also indicated that location was an important factor explaining the abundances of selected species. Overall, Yolo Bypass had more species and a greater proportion of native species than did Sutter Bypass. Sutter Bypass had a greater proportion of species classified as freshwater, while Yolo Bypass had a greater proportion of species classified as either estuarine or anadromous. We believe these results are related to substantial differences in the underlying physical habitat within the floodplains, which are primarily associated with connectivity to the adjacent river. Although the dynamic flooding that occurs at both locations appeared unable to override the underlying physical habitat differences in structuring the overall fish communities, it was important in controlling the abundances of two prominent native species, Chinook salmon Oncorhynchus tshawytscha and splittail Pogonichthys macrolepidotus, which represented 79% of all individuals collected; splittails spawn on the inundated floodplains, and age-0 individuals of both species use these areas as rearing habitat. Our results have important restoration implications in that they illustrate the importance of both flood pulse dynamics and underlying physical habitat associated with connectivity in structuring river–floodplain fish communities.
Periodontal Status and Oral Hygiene in Two Populations of Cleft Patients
Authors: Stec Magdalena , Szczepańska Joanna , Pypeć Jacek , Hirschfelder Ursula
Published: April 2006

Objective:

To evaluate and compare the oral hygiene and periodontal status in children with unilateral and bilateral cleft lip and palate treated in Łódź, Poland, and Erlangen, Germany.

Design:

Oral health was assessed by the presence of dental plaque, pocket depth, clinical attachment levels, and pathologic teeth mobility.

Subjects and Methods:

Thirty-seven Polish and 63 German patients participated in this study.

Results:

Poor oral hygiene was found in 57% of all subjects. In Erlangen, 60% of patients had optimal oral hygiene, compared to 19% in Łódź. The highest scores for dental plaque were noted in both groups in the cleft region. Healthy periodontium was significantly more frequent among German patients, whereas gingival bleeding was significantly more frequent among Polish patients. Pocket depths greater than 6 mm occurred only in German subjects. No statistically significant difference was observed between the amount of tooth areas with gingival recessions and the country of origin. Periodontal pockets deeper than 3.5 mm occurred more frequently during active orthodontic treatment.

Conclusions:

The oral hygiene regimens in Germany and Poland were not comparable, as more plaque was found in the Polish than in the German population. Plaque accumulation seems not to be a key factor in causing periodontal destruction in the cleft area. Factors other than oral hygiene should be considered of major importance in relation to the development of gingival recession on teeth in cleft areas.
The Perils of Apostasy
Authors: Custer Jay F.
Published: April 2006

Almost all of the critical comments on my article “Ethics and the Hyperreality of the Archaeological Thought World” are clear examples of the very trends in thinking that I sought to highlight concerning archaeology's unethical treatment of American Indian people, past and present. The unpleasant personal attacks that dominate many of the comments show the unwillingness and inability of the authors to come to terms with the serious higher level ethical issues confronting Americanist archaeology.
Ibandronate: Once-Monthly and Intravenous Dosing Options for Osteoporosis Treatment
Authors: Emkey Ronald
Published: April 2006

Ibandronate is a potent nitrogen-containing bisphosphonate that is currently available as a daily and once-monthly oral formulation for the treatment and prevention of osteoporosis. It has recently been approved for intermittent intravenous administration. The oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe (BONE), Monthly Oral iBandronate In LadiEs (MOBILE), and Dosing IntraVenous Administration (DIVA) trials demonstrated that long-term daily and intermittent administration of ibandronate was efficacious for increasing bone mineral density and reducing markers of bone turnover. BONE demonstrated that ibandronate reduced the risk of new vertebral fractures and reduced the relative risk of nonvertebral fractures in higher-risk patients. Histomorphometric evaluations in the BONE and DIVA trials have demonstrated that bone quality is maintained following treatment. Giving patients the option of choosing their dose regimen and route of administration may increase overall adherence to treatment, leading to enhanced fracture protection in patients with osteoporosis.
Treatment Considerations during Pregnancy for Women with Epilepsy
Authors: Harden Cynthia L , Nadiminti Lakshmi
Published: April 2006

Women with epilepsy have many special considerations; one of the most important of these is the risk and management of pregnancy. Both recurrent seizures during pregnancy and antiepileptic medications may have adverse maternal–fetal outcomes. Multiple registries of pregnancy outcomes for women with epilepsy worldwide are underway and data from these studies are emerging. Converging evidence from the registries thus far indicates an increased risk of major fetal congenital malformations with valproate exposure and one registry has shown an increased risk with phenobarbital exposure; further supporting evidence of the phenobarbital risk is needed.
History and the Businessman
Authors: Woodruf W.
Published: April 2006

The distinguishing aspect of business in modern times, particularly in the United States, is that it has permeated the entire fabric of civilization. Historical interpretations of this circumstance have been in sharp conflict and have tended toward extremes. The wave of national self-criticism of the early twentieth century focused attention on the shortcomings of business, ignoring its constructive aspects. On the other hand, the modern revisionist school of historians, depicting the businessman not as a “robber baron” but as an “architect of material greatness,” has been prone to stress ends ahead of means and to overlook the deeper implications of the businessman's role in society as a whole. True perspective is not afforded by either of these opposing academic positions, nor is it likely to be gained by further blind amassing of facts-in-isolation on the part of business historians. A general theory of business evolution is needed — one that neither praises nor blames the businessman but seeks to locate him in the larger context of human experience.
The Rise of a Market for Industrial Securities, 1887-1902
Authors: Navin Thomas R. , Sears Marian V.
Published: April 2006

The performance of industrial securities in the depression of 1893-97 went far toward ridding the financial community of the idea that such securities generally lacked investment quality. This ship in investing sentiment was a factor of major significance in accelerating the merger movement, the promoters of which, in turn, broadened the market for industrials still further. This they accomplished by offering wide participations in promising ventures, by sweetening those participations through extensive recourse to preferred stocks, and by employing promotional techniques new to the field of industrial security marketing. The creation of a broad market for industrial stocks, hitherto highly inflexible administrative tools, meant vastly increased fluidity of ownership. By the turn of the century the transition was well under way from closely held, “inside” ownership of American business to semipublic, “outside” hands.
Bibliographical Note — The Vatican Film Library at Saint Louis University
Authors: Bolino August C.
Published: April 2006

Although the Vatican Film Library at Saint Louis University has been described recently in such diverse publications as the London Times, Osservatore Romano, Time, The American Historical Review, the Saturday Review and the National Geographic, it has never been explored fully by the scholarly world. The object of this article is to describe the extent of the microfilm collection at Saint Louis University, to provide some guides to the use of the manuscripts, and to indicate some possible areas of fruitful research in business and economic history.
The Judicial System and the Law of Life Insurance, 1888-1910
Authors: Keller Morton
Published: April 2006

Despite a widely prevailing judicial insensitivity to corporate reform and regulation, the large insurance companies found themselves under careful, constant, and not always sympathetic legal scrutiny. This scrutiny tended to emphasize the equity rather than the letter of the law, and kept the insurance contract the flexible servant of a dynamic society and industry.