bluuebunny/crossref_metadata_2025 huggingface dataset:
Thalidomide for Erythema Nodosum Leprosum and Other Applications
Authors: Okafor Mark C.
Published: May 2004

Thalidomide, administered as a sedative and antiemetic decades ago, was considered responsible for numerous devastating cases of birth defects and consequently was banned from markets worldwide. However, the drug remarkably has resurfaced with promise of immunomodulatory benefit in a wide array of immunologic disorders for which available treatments were limited. It is approved by the Food and Drug Administration for erythema nodosum leprosum (ENL). Although the relative paucity of leprosy and ENL worldwide may perceivably limit interest in and knowledge about thalidomide, increasing numbers of new and potential uses expand its applicability widely beyond ENL. Thalidomide, an inhibitor of tumor necrosis factor a, is the best known agent for short‐term treatment of ENL skin manifestations, as well as postremission maintenance therapy to prevent recurrence. For this indication, it is effective as monotherapy and as part of combination therapy with corticosteroids. Studies of thalidomide in chronic graft‐versus‐host disease showed benefit in children and adults as treatment, but not as prophylaxis. The agent has been administered successfully for treatment of cachexia related to cancer, tuberculosis, and human immunodeficiency virus infection, although evidence of efficacy is inconclusive. Thalidomide monotherapy effectively induced objective response in trials in patients with both newly diagnosed and advanced or refractory multiple myeloma. Combination therapy with thalidomide and corticosteroids was also effective in these patients, as well as in treatment of aphthous and genital ulcers. Limited evidence supports the drug's benefit in treatment of Kaposi's sarcoma. Other thalidomide applications include Crohn's disease, rheumatoid arthritis, and multiple sclerosis. Somnolence, constipation, and rash were the most frequently cited adverse effects in studies, but thalidomide‐induced neuropathy and idiopathic thromboembolism were critical causes for drug discontinuation. Thalidomide is still contraindicated in pregnant women, women of childbearing age, and sexually active men not using contraception. Clinicians should be conversant with thalidomide in ENL (its primary application) in the natural course of leprosy, as well as in the agent's other applications.
High‐Dose Hepatitis B Vaccine in Patients Waiting for Lung Transplantation
Authors: Hayney Mary S. , Welter Deborah L. , Reynolds Ann Marie , Francois Mary , Love Robert B.
Published: May 2004

Study Objective. To increase the response rate to hepatitis B vaccine in patients awaiting lung transplantation.

Design. Historically controlled, open‐label study.

Setting. Lung transplant clinic at a university hospital.

Subjects. Twenty‐seven consecutive individuals with end‐stage pulmonary disease who were enrolled to accrue 15 subjects who would complete the vaccine series before transplantation; and 27 lung transplant recipients who were immunized with the conventional dose before the study and served as historical controls.

Intervention. Intramuscular injection of high‐dose hepatitis B vaccine 40 μg at 0, 1, and 6 months.

Measurements and Main Results. Hepatitis B surface antibody (anti‐HBs) concentrations were measured 1–2 months after completing the high‐dose series. Individuals with undetectable anti‐HBs received additional vaccine to a maximum of six doses. The response rate to the series was compared with that in the control group. Seventeen individuals in the high‐dose group and 14 controls met the study criterion of complete vaccine series before transplantation. The former had a much higher response rate than the latter (9 [53%] vs 1 [7%], p<0.01). Four of six patients who received additional doses of vaccine seroconverted. Two of them underwent transplantation shortly after completing the three‐dose series.

Conclusion. The high‐dose hepatitis B vaccine series produced a protective immune response in lung transplant recipients; however, the response was suboptimal, and alternative immunization strategies should be studied.
Estradiol in Premenstrual Asthma: A Double‐Blind, Randomized, Placebo‐Controlled, Crossover Study
Authors: Ensom Mary H. H. , Chong Gina , Zhou Danyi , Beaudin Bev , Shalansky Stephen , Bai Tony R.
Published: May 2004

Study Objectives. To characterize asthma symptoms and pulmonary function throughout two menstrual cycles, with and without exogenous estradiol administration, in women with premenstrual asthma, and to determine the effect of estradiol administration on asthma symptoms, pulmonary function, quality of life, and biomarkers of airway inflammation.

Design. Double‐blind, randomized, placebo‐controlled, crossover study.

Setting. Respiratory clinic and clinical research center.

Subjects. Twelve women with documented premenstrual asthma ( 20% premenstrual worsening of asthma symptoms and/or of peak expiratory flow [PEF] during a 1‐month screening phase).

Intervention. Each woman received either estradiol 2 mg or placebo orally between cycle days 23 and 28 (i.e., premenstrually, or before the onset of menses) in the first cycle and then crossed over to the other arm in the second cycle. Throughout both cycles, the women recorded daily morning and evening PEF readings and asthma symptoms.

Measurements and Main Results. Spirometry testing and measurement of serum estradiol and biomarkers of airway inflammation were performed on days 8 (follicular phase), 22 (luteal phase), and 28 (premenstrually) of both the estradiol and placebo cycles. During the two premenstrual visits, the Asthma Quality of Life Questionnaire was administered. No notable differences were observed between the estradiol and placebo cycles in daily PEF recordings or composite asthma symptoms scores. The area under the curve (AUC) for the composite asthma symptoms versus time profile was numerically, but not statistically, lower (denoting less severe symptoms) during the estradiol cycle than during the placebo cycle. Likewise, no significant difference in AUC values for morning PEF or evening PEF was found between the estradiol cycle and the placebo cycle. Despite differences (p<0.05) in day‐28 estradiol concentrations for estradiol and placebo cycles, no significant differences were found in forced expiratory volume in 1 second, serum endothelin‐1, serum and urine eosinophil protein X, urine leukotriene E4, or quality‐of‐life scores.

Conclusion. Exogenously administered estradiol did not have a significant effect in women with premenstrual asthma whose asthma was classified predominantly as mild and under excellent control. As in the case of premenstrual syndrome, the placebo effect may be prominent in premenstrual asthma. Further trials, involving women with more severe asthma under poorer control, are warranted to discern underlying mechanisms for the worsening of asthma in relation to menstruation.
Enteral Fluconazole Population Pharmacokinetics in Patients in the Surgical Intensive Care Unit
Authors: Rajagopalan Prabhu , Pelz Robert K. , Lipsett Pamela A. , Swoboda Sandra M. , Rinaldi Michael G. , Hendrix Craig W.
Published: May 2004

Study Objective. To determine the population pharmacokinetic parameters of enterally administered fluconazole in patients in a surgical intensive care unit (SICU).

Design. Population pharmacokinetics component of a prospective, randomized clinical study.

Setting. The SICU at a university hospital.

Patients. One hundred ten patients with an expected length of stay in the SICU of 3 or more days and a need for intubation, in whom at least one fluconazole plasma concentration‐time measurement was available.

Intervention. Patients received fluconazole as an 800‐mg loading dose and as a 200‐ or 400‐mg (depending on renal function) daily maintenance dose. Fluconazole suspension was administered enterally followed by a 30‐ml free water flush.

Measurements and Main Results. Plasma samples were collected, and population pharmacokinetic analysis was performed with NONMEM software; a one‐compartment pharmacokinetic model was used. Fluconazole clearance was dependent on creatinine clearance, and volume of distribution was dependent on body weight and age. In patients with creatinine clearance values greater than 80 ml/minute, between 30 and 80 ml/minute, and less than 30 ml/minute, geometric mean (percentage coefficient of variation) fluconazole clearance was 14.39 ml/minute (21%), 10.53 ml/minute (28%), and 5.47 ml/minute (30%), respectively. The geometric mean (percentage coefficient of variation) volume of distribution in all patients was 1.27 L/kg (28%) and decreased with increasing age.

Conclusions. Fluconazole clearance values in patients in the SICU who had normal renal function and in those with renal impairment were in agreement with previously reported data. Fluconazole volume of distribution was larger and half‐life was longer in the SICU population than in healthy subjects.
The Effect of an Antimicrobial Restriction Program on Pseudomonas aeruginosa Resistance to β‐Lactams in a Large Teaching Hospital
Authors: Regal Randolph E. , DePestel Daryl D. , VandenBussche Heather L.
Published: May 2004

Study Objectives. To compare the use of β‐lactams and subsequent Pseudomonas aeruginosa sensitivity patterns before and after implementation of a clinical pharmacist‐facilitated antimicrobial restriction program in August 1997.

Design. Retrospective consecutive data collection.

Setting. Large university‐affiliated medical center.

Intervention. The study results are the accumulation of the daily intervention activities of the antimicrobial restriction program. Data on antimicrobial grams purchased/1000 patient‐days and susceptibility patterns were collected and analyzed retrospectively.

Measures and Main Results. Annual grams of ceftazidime, piperacillin, piperacillin‐tazobactam, and other antipseudomonal β‐lactams purchased/1000 patient‐days were compared during the 2 full calendar years before the antimicrobial restriction program (1995–1996) with the 4 full calendar years after the program was implemented (1998–2001). Pseudomonas aeruginosa resistance trends for the antipseudomonal β‐lactams, ciprofloxacin, and tobramycin also were compared for the 2 years before the program (1995–1996) with the last 2 years of the program (2000–2001). A 44% reduction in ceftazidime use was documented; ostensibly, minimal changes occurred in the overall use of piperacillin and piperacillin‐tazobactam. During the same time period, ceftazidime resistance fell from 24% to 11.8% (p<0.001), whereas piperacillin resistance fell from 32.5% to 18.5% (p<0.001). Imipenem resistance declined from 20.5% to 12.3% (p<0.001) with an 18% reduction in use. Aztreonam resistance declined from 29.5% to 16.5% (p<0.001) despite a 57% increase in use. No changes in resistance to either ciprofloxacin or tobramycin were found.

Conclusion. Through an antimicrobial restriction program, a dramatic reduction in ceftazidime use was achieved with judicious use of other antipseudomonal antimicrobials, which resulted in reduced resistance of P. aeruginosa to other β‐lactams.
Targeting Bacterial Virulence: The Role of Protein Synthesis Inhibitors in Severe Infections
Authors: Coyle Elizabeth A.
Published: May 2004

Morbidity and mortality due to certain bacterial pathogens have not declined despite the availability of effective antimicrobial treatments. Staphylococcus aureus and Streptococcus pyogenes cause a number of serious infections, such as necrotizing fasciitis and toxic shock syndrome, which are associated with the release of bacterial toxins. Animal studies have demonstrated clindamycin, a protein synthesis inhibitor, to be more effective in treating these severe infections than other more susceptible antimicrobial treatments. Linezolid, another protein synthesis inhibitor, also has shown efficacy in in vitro studies. Human trials to validate the effects of antibiotic therapies on bacterial virulence have not been performed. Future animal and human studies are needed to help elucidate the immunomodulatory mechanisms of protein synthesis inhibitors in order to optimize antimicrobial treatment and decrease the morbidity and mortality associated with severe bacterial infections.
Mississippi Mud No More: Cost‐Effectiveness of Pharmacokinetic Dosage Adjustment of Vancomycin to Prevent Nephrotoxicity
Authors: Darko William , Medicis Joseph J. , Smith Adrienne , Guharoy Roy , Lehmann David F.
Published: May 2004

Objective. To determine the cost‐effectiveness of pharmacokinetic dosage adjustment of vancomycin to prevent nephrotoxicity. An analysis was performed for subpopulations of patients receiving nephrotoxic agents (aminoglycosides, amphotericin, and acyclovir), those in the intensive care unit, and those on the oncology service.

Methods. Decision analysis was used to model the cost‐effectiveness of pharmacokinetic dosage adjustment of vancomycin. The reference case was determined, in part, by a retrospective review of 200 patients randomly selected from our clinical pharmacology consultation service. Patients were aged 18 years or older and had received intravenous vancomycin for at least 48 hours, with at least two—one peak and one trough—vancomycin serum concentrations obtained during therapy. Results of published clinical trials were used to determine the probability of vancomycin‐induced nephrotoxicity.

Results. The mean cost of treating nephrotoxicity was $11,233 at our institution. The mean cost for all patients was $25,166 (sensitivity analysis $15,000–27,500)/nephrotoxic episode prevented. The subgroup analysis revealed a cost of $8363 (sensitivity analysis $4368–10,500)/nephrotoxic episode prevented in intensive care patients, $5000 (sensitivity analysis $1687–13,250) in oncology patients, and a dominant strategy showing a cost savings of $5564 (sensitivity analysis $2724–12,428) in those receiving concomitant nephrotoxins.

Conclusion. Although pharmacokinetic monitoring and dosage adjustment are effective methods for reducing the toxicity of many drugs, controversy exists regarding the necessity of such monitoring with vancomycin. Evaluation by decision analysis over a range of assumptions, varying probabilities, and costs reveals that pharmacokinetic monitoring and vancomycin dosage adjustment to prevent nephrotoxicity are not cost‐effective for all patients. However, such dosage adjustment demonstrates cost‐effectiveness for patients receiving concomitant nephrotoxins, intensive care patients, and probably oncology patients.
Risperidone‐Associated Diabetes Mellitus: A Pharmacovigilance Study
Authors: Koller Elizabeth A. , Cross James T. , Doraiswamy P. Murali , Schneider Bruce S.
Published: May 2004

Study Objective. To explore the clinical characteristics of hyperglycemia in patients treated with risperidone.

Design. Pharmacovigilance survey of spontaneously reported adverse events in risperidone‐treated patients, with reports of haloperidol‐associated hyperglycemia used as a control.

Setting. Government‐affiliated drug evaluation center.

Intervention. The Food and Drug Administration MedWatch surveillance program was queried (risperidone, 1993‐February 2002; haloperidol, late 1970s‐February 2002) and results pooled with published cases.

Measurements and Main Results. We identified 131 reports of risperidone‐associated hyperglycemia in addition to seven reports of patients with hyperglycemia who received combined risperidone‐haloperidol therapy and six reports of acidosis that occurred in the absence of hyperglycemia. We found 13 reports of haloperidol‐associated hyperglycemia and 11 reports of acidosis without hyperglycemia. Of the reports of risperidone‐associated hyperglycemia (monotherapy), 78 patients had newly diagnosed hyperglycemia, 46 had exacerbated preexisting diabetes, and 7 could not be classified. Mean ± SD age was 39.8 ± 17.4 years (range 8–96 yrs). Patients with new‐onset diabetes (mean ± SD age 34.8 ± 15.7 yrs) were younger than those with preexisting diabetes (mean ± SD age 48.8 ± 17.5 yrs). The overall male:female ratio was 1.5. In most patients, hyperglycemia appeared within 3 months of the start of risperidone therapy. Severity of disease ranged from mild glucose intolerance to diabetic ketoacidosis or hyperosmolar coma. Twenty‐six patients with acidosis or ketosis were reported. Four patients died.

Conclusion. Atypical antipsychotic treatment may unmask or precipitate hyperglycemia. Although such cases attributed to clozapine or olanzapine are more numerous than those associated with risperidone, the number for risperidone‐associated hyperglycemia is relatively higher than that observed with the conventional neuroleptic haloperidol.
Acute Lithium Intoxication and Neuroleptic Malignant Syndrome
Authors: Gill Jasleen , Singh Harmohan , Nugent Kenneth
Published: May 2004

A 45‐year‐old man was admitted to our hospital after taking an intentional overdose of 90 sustained‐released lithium tablets (450 mg each). The patient was stabilized with three sessions of hemodialysis. On day 7 of his hospital stay, his serum lithium level was 0.5 mEq/L. On day 10, he developed high fever, tachypnea, muscle rigidity, rhabdomyolysis, acute renal insufficiency, mental confusion, and obtundation. His creatine kinase level was 698 IU/L, serum creatinine 3.5 mg/dl. Late‐onset neuroleptic malignant syndrome (NMS) was diagnosed. The patient died after developing acute renal failure and acute respiratory distress syndrome. Clinicians should be aware that lithium may cause NMS independent of other neuroleptic agents.
How Polycrystalline Devices Can Outperform Single‐Crystal Ones: Thin Film CdTe/CdS Solar Cells
Authors: Visoly‐Fisher I. , Cohen S. R. , Ruzin A. , Cahen D.
Published: May 2004

Grain boundaries (GBs) participate in the photovoltaic energy conversion process in polycrystalline solar cells as efficient photocurrent collectors and transporters, as shown by high‐ resolution characterization of CdTe GBs in CdTe/CdS cells (see Figure). This suggests that structural defects can be advantageous for device performance, if properly designed, even in devices whose operation is based on physics of ideal, perfect solids.
Genetics and alcoholism among at‐risk relatives II: Interest and concerns about hypothetical genetic testing for alcoholism risk
Authors: Gamm Jennifer L. , Nussbaum Robert L. , Bowles Biesecker Barbara
Published: May 2004

One purpose of this study was to examine hypothetical interest in genetic predisposition testing for alcoholism among at‐risk relatives. Qualitative interviews and several quantitative tools were administered to 27 individuals who had at least one first‐degree relative affected by alcoholism. Data analysis revealed that participants' interest in genetic testing for susceptibility to alcoholism was moderate. Lower educational level and a stronger belief in ‘others’ influencing health were related to participants' having a stronger interest in genetic testing. Participants' concerns about future use of genetic testing ranged from doubts about its usefulness in affecting behavior to apprehension regarding detrimental societal effects such as breaches in confidentiality and fear of being labeled an ‘alcoholic.’ Younger age and stronger interest in genetic testing were associated with deterministic or fatalistic beliefs, while drinking behaviors, gender, and other demographics were not. Participants questioned the utility of this type of testing. Their interest in testing and concerns about its hypothetical use may prove important for at‐risk relatives who may face decisions about genetic testing in the future. Data from this study can provide direction for researchers and health care providers as genetic testing for this and other behavioral conditions emerges. Scientists and the public should address the social concerns expressed by participants, including the fear of labeling. Also, we can begin to anticipate characteristics common in those who may have fatalistic responses, and who may possibly make adverse behavior choices, to results from alcoholism susceptibility testing. Published 2004 Wiley‐Liss, Inc.
Superficial siderosis: A potentially important cause of genetic as well as non‐genetic deafness
Authors: Dodson Kelley M. , Sismanis Aristides , Nance Walter E.
Published: May 2004

Superficial siderosis is an important disease that is increasingly being recognized as a cause of sensorineural hearing loss. Hemosiderin, resulting from repeated episodes of subarachnoid bleeding, is deposited preferentially on the surface of the eighth nerve, cerebellum, and brain stem as a consequence of glial catabolism of ferritin within those structures. This deposition eventually results in destruction and demyelination within the central nervous system, leading to the cardinal clinical findings of superficial siderosis: hearing loss, ataxia, and myelopathy. This mechanism may contribute to the pathogenesis of several forms of genetic deafness, and should be considered as a diagnostic possibility in cases of late onset deafness even in the absence of an overt history of subarachnoid bleeding. © 2004 Wiley‐Liss, Inc.
Genetics and alcoholism among at‐risk relatives I: Perceptions of cause, risk, and control
Authors: Gamm Jennifer L. , Nussbaum Robert L. , Biesecker Barbara Bowles
Published: May 2004

Genetic factors influence a person's risk for developing alcoholism. In other common disorders with a genetic component, a belief in a genetic cause can lead to less perceived control or fatalism among those at risk that may adversely affect undertaking health‐promoting behaviors. This study explores beliefs about the cause of alcoholism and risk perception among individuals with affected relatives. In‐depth interviews including both open‐ended questions and several quantitative measures were conducted with participants to explore the relationships between causal beliefs and perceptions of personal risk and control. Twenty‐seven individuals with at least one first‐degree relative affected with alcoholism participated. Transcript analysis of interviews revealed that all participants attribute multiple factors to the cause of alcoholism in their families, often as a combination of biological, genetic, environmental factors, and personal characteristics. Many perceived themselves as being ‘at‐risk,’ and this concern often stemmed from a belief in a genetic or biological cause of alcoholism. However, participants also had a strong sense of personal control, rooted in beliefs about environmental causes or personal characteristics influencing alcoholism risk. A participant's strong belief in a genetic cause was associated with a significantly increased risk perception, but not a fatalistic outlook towards developing alcoholism. Published 2004 Wiley‐Liss, Inc.
Purification and characterization of arginine kinase from the American cockroach (Periplaneta americana)
Authors: Brown Ashli E. , France Richard M. , Grossman Steven H.
Published: May 2004

The isolation and characterization of homogeneous arginine kinase from the cockroach is reported. The purification protocol produces 6.6 mg of pure enzyme from 6.8 g of whole cockroach. The purified enzyme cross‐reacts with a heterologous antibody and monoclonal antibody against arginine kinase from the shrimp. Both antibody preparations also cross‐react with extracts from several species known to contain monomeric arginine kinase, but fail to react with extracts from organisms containing dimeric arginine kinase. Cockroach arginine kinase has a molecular mass of approximately 43,000 determined from measurements by gel filtration and gel electrophoresis. Compared with other arginine kinases, the enzyme from the cockroach is relatively thermostable (50% activity retained at 50°C for 10 min) and has a pH optima of 8.5 and 6.5–7.5, for the forward and reverse reactions, respectively. Treatment with 5,5′dithiobis[2‐nitrobenzoic acid] indicates that arginine kinase has a single reactive sulfhydryl group and, interestingly, the reaction is biphasic. The Michaelis constants for the phosphagen substrates, arginine: 0.49 mM, phosphoarginine: 0.94 mM, and nucleotide substrates MgATP: 0.14 mM, MgADP: 0.09 mM, are in the range reported for other arginine kinases. A 1% solution of pure enzyme has an absorbance of 7.0 at 280 nm. Calculations based on circular dichroic spectra indicate that arginine kinase from the cockroach has 12% α‐helical structure. The intrinsic protein fluorescence emission maximum at 340 nm suggests that tryptophan residues are below the surface of the protein and not exposed to solvent. Arginine kinase from the cockroach and shrimp are known to be deleterious immunogens towards humans. The availability of pure protein, its characterization and potential regulation of activity, will be useful in developing agents to control the cockroach population and its destructive role in agriculture and human health. Arch. Insect Biochem. Physiol. 56:51–60, 2004. © 2004 Wiley‐Liss, Inc.
Mechanisms of the insecticidal action of TEL (Talisia esculenta lectin) against Callosobruchus maculatus (Coleoptera: Bruchidae)
Authors: Macedo Maria Lígia Rodrigues , De Castro Márcia Mota , Freire Maria Das Graças Machado
Published: May 2004

Plant lectins have insecticidal activity that is probably mediated through their ability to bind carbohydrates. To examine the influence of sugars on the insecticidal activity of a lectin from Talisia esculenta seeds (TEL), the lectin was mixed with mannose, glucose, or mannose plus glucose. Mannose abolished the insecticidal activity. Affinity chromatography showed that TEL bound to midgut proteins of the insect Callosobruchus maculatus. Immunoblotting showed that TEL recognized some proteins, probably glycoproteins, present in the midgut membrane of this insect. The principal proteases responsible for digestive proteolysis in fourth instar larvae of C. maculatus were purified by chromatography on activated thiol‐Sepharose. These purified proteases were unable to digest TEL after a 15‐h incubation. These results suggest that the insecticidal activity of TEL involves a specific carbohydrate‐lectin interaction with glycoconjugates on the surface of digestive tract epithelial cells, as well as binding to assimilatory glycoproteins present in midgut extracts and resistance to enzymatic digestion by cysteine proteinases. Arch. Insect Biochem. Physiol. 56:84–96, 2004. © 2004 Wiley‐Liss, Inc.
On‐line monitoring of human prostate cancer cells in a perfusion rotating wall vessel by near‐infrared spectroscopy
Authors: Rhiel Martin H. , Cohen Michael B. , Arnold Mark A. , Murhammer David W.
Published: May 2004

PC‐3 human prostate cancer cells have been cultivated in a rotating wall vessel in which glucose, lactate, and glutamine profiles were monitored noninvasively and in real time by near‐infrared (NIR) spectroscopy. The calibration models were based on off‐line spectra from tissue culture experiments described previously (Rhiel et al., Biotechnol Bioeng 77:73–82). Monitoring performance was improved by Fourier filtering of the spectra and initial off‐set adjustment. The resulting standard errors of predictions were 0.95, 0.74, and 0.39 mM for glucose, lactate, and glutamine, respectively. The concentration of ammonia could not be accurately measured from the same spectra. In addition, metabolite uptake and production rates were determined for PC‐3 prostate cancer cells during exponential growth in batch‐mode cultivation. Cells grew with a doubling time of 21 h and consumed glucose and glutamine at rates of 6.8 and 1.8 × 10−17 mol/cell·s, respectively. This resulted in lactate and ammonia production rates of 11.9 and 1.3 × 10−17 mol/cell·s, respectively. Compared with other monitoring technologies, this technology has many advantages for spaceflights and stand‐alone units; for instance, calibration can be performed at one time and then applied in a reagentless, low‐maintenance way at a later time. The resulting concentration information can be incorporated into closed‐loop control schemes, thereby leading to better in vitro models of in vivo behavior. © 2004 Wiley Periodicals, Inc.
A study on application of impregnated synthetic peptide TLC stationary phases for the screening of 5‐HT1A ligands. Part 2
Authors: Zajdel Paweł , Bojarski Andrzej J. , Bugno Ryszard , Jurczyk Sławomir , Kołaczkowski Marcin , Nowak Mateusz , Subra Gilles , Martinez Jean , Pawłowski Maciej
Published: May 2004

Six extended analogues of the recently described peptides (LDVL, ADVL) were designed and synthesized on a solid support, and then impregnated on TLC stationary phases. The impact of the impregnated peptide sequence modiﬁcations on the chromatographic retard, ΔRf (difference in the migration of tested compound on control and impregnated plates), of 42 arylpiperazine 5‐HT1A receptor ligands was studied. None of the new models tested made a better prediction of 5‐HT1A afﬁnity than that utilizing ADVL tetrapeptide. Further validation of the ADVL model on a set of 22 structurally differentiated 2‐methoxy‐phenylpiperazine derivatives conﬁrmed its effectiveness in the afﬁnity discrimination of a coherent group of 5‐HT1A receptor ligands. Copyright © 2004 John Wiley & Sons, Ltd.
LC/MS/MS identiﬁcation of glycosides produced by biotransformation of cinnamyl alcohol in Rhodiola rosea compact callus aggregates
Authors: Tolonen Ari , György Zsuzsanna , Jalonen Jorma , Neubauer Peter , Hohtola Anja
Published: May 2004

Cinnamyl alcohol was added to the media of compact callus aggregates (CCA) of Rhodiola rosea for stimulating the production of cinnamyl glycosides. The biotransformation reaction produced high amounts of rosin, while only a very low amount of rosavin was produced. As the consumption rate of cinnamyl alcohol was much higher than production of rosin, the aqueous methanol extracts of compact callus aggregates were studied by liquid chromatography–mass spectrometric methods and four new unexpected biotransformation products of cinnamyl alcohol were identiﬁed. Copyright © 2004 John Wiley & Sons, Ltd.
Simplicity and typical rank of three‐way arrays, with applications to Tucker‐3 analysis with simple cores
Authors: ten Berge Jos M. F.
Published: May 2004

In chemometric applications of Tucker three‐way principal component analysis, core arrays are often constrained to have a large majority of zero elements. This gives rise to questions of non‐triviality (are the constraints active, or can any core of a given format be transformed to satisfy the constraints?) and uniqueness (can we transform the components in one or more directions without losing the given pattern of zero elements in the core?). Rather than deciding such questions on an ad hoc basis, general principles are to be preferred. This paper gives an overview of simplicity transformations on the one hand, and typical rank results on the other, which are suitable to determine whether or not certain constrained cores are trivial. Copyright © 2004 John Wiley & Sons, Ltd.
A dedicated generalized Procrustes algorithm for consensus molecular alignment
Authors: Commandeur Jacques J. F. , Kroonenberg Pieter M. , Dunn William J.
Published: May 2004

Recently the idea of using generalized Procrustes analysis for aligning sets of molecules was introduced using standard algorithms. In this paper it is shown that, by tailoring the algorithm to this specific problem, a great gain in computational speed and memory efficiency can be obtained, but even more importantly, by using rotations without reflection, changes in chirality of molecules can be prevented, which was not previously possible. Copyright © 2004 John Wiley & Sons, Ltd.
C2C12 Co‐culture on a fibroblast substratum enables sustained survival of contractile, highly differentiated myotubes with peripheral nuclei and adult fast myosin expression
Authors: Cooper S.T. , Maxwell A.L. , Kizana E. , Ghoddusi M. , Hardeman E.C. , Alexander I.E. , Allen D.G. , North K.N.
Published: May 2004

We describe a simple culture method for obtaining highly differentiated clonal C2C12 myotubes using a feeder layer of confluent fibroblasts, and document the expression of contractile protein expression and aspects of myofibre morphology using this system. Traditional culture methods using collagen‐ or laminin‐coated tissue‐culture plastic typically results in a cyclic pattern of detachment and reformation of myotubes, rarely producing myotubes of a mature adult phenotype. C2C12 co‐culture on a fibroblast substratum facilitates the sustained culture of contractile myotubes, resulting in a mature sarcomeric register with evidence for peripherally migrating nuclei. Immunoblot analysis demonstrates that desmin, tropomyosin, sarcomeric actin, α‐actinin‐2 and slow myosin are detected throughout myogenic differentiation, whereas adult fast myosin heavy chain isoforms, members of the dystrophin‐associated complex, and α‐actinin‐3 are not expressed at significant levels until >6 days of differentiation, coincident with the onset of contractile activity. Electrical stimulation of mature myotubes reveals typical and reproducible calcium transients, demonstrating functional maturation with respect to calcium handling proteins. Immunocytochemical staining demonstrates a well‐defined sarcomeric register throughout the majority of myotubes (70–80%) and a striated staining pattern is observed for desmin, indicating alignment of the intermediate filament network with the sarcomeric register. We report that culture volume affects the fusion index and rate of sarcomeric development in developing myotubes and propose that a fibroblast feeder layer provides an elastic substratum to support contractile activity and likely secretes growth factors and extracellular matrix proteins that assist myotube development. Cell Motil. Cytoskeleton 58:200–211, 2004. © 2004 Wiley‐Liss, Inc.
Comparison of high‐dose melphalan with a more intensive regimen of thiotepa, busulfan, and cyclophosphamide for patients with multiple myeloma
Authors: Anagnostopoulos Athanasios , Aleman Ana , Ayers Gregory , Donato Michele , Champlin Richard , Weber Donna , Alexanian Raymond , Giralt Sergio
Published: May 2004

BACKGROUND

High‐dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) as part of the initial treatment regimen improves progression‐free survival (PFS) and overall survival (OS) for patients with multiple myeloma. The optimal preparative regimen for patients with multiple myeloma has yet to be defined. In the current study, the authors compared the outcomes associated with high‐dose melphalan (HDM) and a more intensive regimen of thiotepa, busulfan, and cyclophosphamide (TBC) in patients with multiple myeloma.

METHODS

One hundred eighty‐six patients with newly diagnosed multiple myeloma (median age, 51 years) received HDC with ASCT for consolidation of first remission (n = 108) or for treatment of primary refractory disease (n = 78). Seventy patients had a large tumor mass at the time of diagnosis. The preparative regimen consisted of TBC for 97 patients and HDM for 89 patients. Patients in the TBC group were younger and had more advanced disease stage at diagnosis and at the time of ASCT compared with patients in the HDM group.

RESULTS

The response rates (complete response [CR] and partial response [PR]) were similar in the TBC group (overall response rate, 66%; CR rate, 17%; PR rate, 49%) and the HDM group (overall response rate, 69%; CR rate, 28%; PR rate, 41%). PFS and OS were similar in both groups. A proportional hazards regression model revealed that Durie–Salmon disease stage at diagnosis and having received three or more previous treatment regimens were the only factors that predicted PFS; the type of preparative regimen did not influence outcome.

CONCLUSIONS

The results of the current study indicate that the use of a more intensive regimen did not improve results compared with HDM in patients with multiple myeloma. HDM should continue to be considered the standard preparative regimen for patients with myeloma. Cancer 2004. © 2004 American Cancer Society.
Prospective evaluation of a novel approach for the use of a quantitative galactose oxidase–Schiff reaction in ductal fluid samples from women with breast carcinoma
Authors: Chagpar Anees , Evelegh Michael , Fritsche Herbert A. , Krishnamurthy Savitri , Hunt Kelly K. , Kuerer Henry M.
Published: May 2004

BACKGROUND

The galactose oxidase–Schiff reaction (GOS) yields positive findings in a number of malignant solid tumors. The goals of the current study were to develop a novel technique for quantifying GOS reactivity in nipple aspirate fluid (NAF) samples from women with invasive breast carcinoma and to assess the clinical utility of the technique in this setting.

METHODS

Patients with biopsy‐proven unilateral invasive breast carcinoma were eligible for study entry. Before definitive surgery, NAF samples were obtained from healthy breast tissue and malignant breast tissue from 23 women with breast carcinoma. Under blind conditions with respect to clinical data, 10 μL NAF samples were applied to a glass fiber membrane and incubated with 100 μL galactose oxidase and 1 mL Schiff reagent. The stain was developed and the color reaction quantitated by measuring hue (shade) and chroma (intensity) using a spectrophotometer.

RESULTS

GOS reactivity was quantitated using two color parameters, hue and chroma. Because chroma varies with concentration, this measurement was adjusted for the concentration of NAF in each sample. After adjustment for NAF concentration, chroma was found to be statistically significantly different in the affected breast tissue sample and the healthy contralateral internal control sample (P = 0.001).

CONCLUSIONS

A quantitative measure of GOS reactivity based on spectrophotometric measurement of intensity of color has been developed and was found to be significantly different in the affected breast compared with the unaffected breast in the current population of patients with breast carcinoma. The preliminary results support further exploration of this novel quantitative test in patients with breast carcinoma. Cancer 2004. © 2004 American Cancer Society.
Time to disease progression to evaluate a novel protein kinase C inhibitor, UCN‐01, in renal cell carcinoma
Authors: Rini Brian I. , Weinberg Vivian , Shaw Vanessa , Scott Janet , Bok Robert , Park John W. , Small Eric J.
Published: May 2004

BACKGROUND

Renal cell carcinoma (RCC) is characterized by von Hippel‐Lindau gene inactivation and vascular endothelial growth factor (VEGF) overproduction. The mechanism of VEGF overproduction may involve protein kinase C (PKC) delta and zeta isoforms. UCN‐01 (7‐hydroxystaurosporine) is a selective inhibitor of PKC. Given the historically low objective response rate in RCC, time to disease progression (TTP) as an alternative endpoint was employed to evaluate the antitumor activity of UCN‐01 in RCC.

METHODS

Patients with progressive, metastatic RCC received UCN‐01 intravenously on Day 1 of each 21‐day cycle. The initial dose was 90 mg/m2 and all subsequent doses were 45 mg/m2 unless modified for toxicity. TTP was the primary endpoint, defined as the period from the first day of treatment until disease progression. Detection of circulating EpCAM‐positive renal carcinoma cells was undertaken for predictive or prognostic potential.

RESULTS

Twenty‐one patients were enrolled in this Phase II study. Accrual was halted after failure to reach a predetermined efficacy requirement with 7 patients remaining disease progression free after 4 months (6 cycles). The median TTP for all patients was 2.67 months (range, 0.4–7.6 months). There were no objective responses. Therapy was generally well tolerated. Thirteen patients had < 0.6 EpCAM‐positive cells/mL (considered negative) at all time points measured. Two patients had detectable EpCAM‐positive cells at a single time point with other measurements being negative.

CONCLUSIONS

TTP is a novel endpoint for the evaluation of agents in RCC. UCN‐01 did not demonstrate significant antitumor activity. No evidence for significant circulating EpCAM‐positive cells was found in this study cohort. Cancer 2004. © 2004 American Cancer Society.
Dermatofibrosarcoma protuberans: A report on 29 patients treated by Mohs micrographic surgery with long‐term follow‐up and review of the literature
Authors: Snow Stephen N. , Gordon Ellen M. , Larson Paul O. , Bagheri Mohammed M. , Bentz Michael L. , Sable David B.
Published: May 2004

BACKGROUND

Dermatofibrosarcoma protuberans (DFSP) is an uncommon tumor of the skin. Clinically, it often masquerades as a benign, indolent tumor on the trunk and extremities. Microscopically, it extends far beyond assessed clinical margins, spreading locally in the dermis, subcutaneous tissue, and muscle. The local recurrence rate in patients with DFSP who undergo wide local excision ranges from 0% to 21%. Recent preliminary reports indicate more consistently favorable cure rates with Mohs micrographic surgery (MMS). However, to date only a few scattered reports have documented long‐term 5‐year follow‐up. The authors present data on 29 patients with DFSP who underwent MMS. In addition, they reviewed the medical literature to summarize the accumulated experience of MMS treatment in the management of DFSP.

METHODS

The authors conducted a retrospective review of a series of 40 consecutive patients with DFSP who underwent MMS over the last 20 years. Of these, there were 29 patients with > 5 years of follow‐up who formed the basis of the current review. The literature also was searched for patients with DFSP who underwent MMS with > 5 years of follow‐up

RESULTS

At the University of Wisconsin Mohs Surgery Clinic, 29 patients with > 5 years of follow‐up were treated. There were 16 women and 13 men. Eight patients developed recurrent disease after previous non‐Mohs treatment. Site distribution was 45% head and neck and 55% trunk and extremities. In the current series, there were no local recurrences, with a local 5‐year cure rate of 100%. In the literature review, which included the current series, there were 136 patients with DFSP who underwent Mohs surgery with > 5 years of follow‐up. Nine patients in the current series developed local recurrences, including five patients who underwent a second Mohs procedure. The local cure rates after the first and second Mohs surgeries were 93.4% and 98.5%, respectively. The rate (percent) and time to local recurrence was 50% at 3 years and 75% at 5 years. However, 25% of local recurrences appeared late, after the usual 5‐year recommendation.

CONCLUSIONS

In a series of 29 patients with of DFSP and in an accompanying update of the medical literature, 136 patients with DFSP underwent MMS with > 5 years of follow‐up. There were no regional and/or distant metastases. However, late recurrences beyond the usual recommended 5‐year follow‐up may occur. Therefore, all patients with DFSP, especially those with recurrent tumors, should be followed for an extended period. The accumulated data continue to confirm that, when DFSP is discovered early and is accessible readily to excision by MMS, a favorable outcome can be expected with minimal trauma or sacrifice of adjacent normal structures and with a low recurrence rate. Cancer 2004. © 2004 American Cancer Society.
The role of preoperative endorectal magnetic resonance imaging in the decision regarding whether to preserve or resect neurovascular bundles during radical retropubic prostatectomy
Authors: Hricak Hedvig , Wang Liang , Wei David C. , Coakley Fergus V. , Akin Oguz , Reuter Victor E. , Gonen Mithat , Kattan Michael W. , Onyebuchi Chinyere N. , Scardino Peter T.
Published: May 2004

BACKGROUND

Because the recovery of erectile function and the avoidance of positive surgical margins are important but competing outcomes, the decision to preserve or resect a neurovascular bundle (NVB) during radical prostatectomy (RP) should be based on the most accurate information concerning the location and extent of the tumor. In the current study, the authors determined the incremental value of endorectal magnetic resonance imaging (eMRI) in making this decision.

METHODS

eMRI was performed in 135 patients preoperatively. For each NVB, tumor extension to the NVB and the need for NVB resection was judged by a surgeon on a scale from 1 (definite preservation) to 5 (definite resection) before and after reviewing eMRI with a radiologist. Histopathologic findings were used as the standard of reference. The value of eMRI was assessed using binormal receiver operating characteristic (ROC) analysis adjusted for multiple observations per patient, and a mixed effects ordinal regression model was used for risk stratification.

RESULTS

Histopathologic examination determined that NVB resection was warranted in 44 of 270 NVBs (16%) because of posterolateral extracapsular extension (n = 29), positive surgical margins (n = 7), or both (n = 8). The areas under the ROC curves (AUC) were 0.741 for pre‐MRI and 0.832 for post‐MRI surgical planning (P < 0.01). MRI findings suggested altering the surgical plan in 39% of NVBs (106 of 270 NVBs). When the surgeon judged that the NVB resection was definitely not necessary (165 NVBs), MRI confirmed that decision in 138 NVBs (84%); the concordant decision was correct in 96% of the cases (133 of 138 NVBs). In 36 high‐risk patients (≥ 75% probability of extracapsular extension), MRI findings changed the surgical plan for 28 NVBs (78%); the change was found to be appropriate in 26 cases (93%).

CONCLUSIONS

MRI was found to significantly improve the surgeon's decision to preserve or resect the NVB during radical prostatectomy. Cancer 2004. © 2004 American Cancer Society.
Characterization of novel antigens recognized by serum autoantibodies from anti‐CD1 TCR‐transgenic lupus mice
Authors: Hueber Wolfgang , Zeng Defu , Sharpe Orr , Robinson William H. , Strober Samuel , Utz Paul J.
Published: May 2004

In this study, we further characterize the humoral autoimmune response in the recently described anti‐CD1 autoreactive T cell receptor‐transgenic mouse lupus model (CD1 lupus model). We discovered and characterized novel autoantigens, comprising a protein of 105 kDa (p105) and a novel RNA molecule of 140 base pairs (bp) that is likely associated with p105, and several additional factors with distinct biochemical properties. In the CD1 lupus model, lethally irradiated BALB/c/nu/nu mice were injected intravenously with sorted bone marrow cells and sorted splenic T cells from donor BALB/c mice expressing TCR α and β transgenes that encode autoreactivity for CD1d. Adoptive hosts injected with the single‐positive (CD4+ and CD8+) subset of transgenic cellsdeveloped anti‐double‐stranded DNA antibodies and a lupus‐like illness. Sera were analyzed by Western blotting and immunoprecipitation. Antigens were characterized by biochemical and serological methods. Serum autoantibodies from 5 of 12 (42%) CD1 lupus mice immunoprecipitated a 105‐kDa protein, termed p105. p105 was associated with a small RNA of ∼140 bp. Anti‐p105 autoantibodies appeared early in the course of disease. Serological and biochemical characterization suggested that p105 was distinct from known lupus autoantigens of similar molecular masses, indicating that p105 represents anovel autoantigen in lupus.