bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Patient Outcomes with Bivalirudin versus Unfractionated Heparin in Percutaneous Coronary Intervention
Authors: Watson Kristin , Seybert Amy L. , Saul Melissa I. , Lee Joon Sup , Kane‐Gill Sandra L.
Published: April 2007

Objective. To compare clinical outcomes and glycoprotein IIb‐IIIa inhibitor use in patients undergoing percutaneous coronary intervention (PCI) who received bivalirudin or unfractionated heparin (UFH) in a real‐world setting.

Design. Retrospective cohort analysis.

Setting. University‐affiliated medical center.

Patients. One thousand seventy‐five adult patients who underwent PCI and received either bivalirudin (539 patients) or UFH (536 patients) from April 1, 2003–April 1, 2004.

Measurement and Main Results. Patient data on demographics, comorbidities, laboratory values, and reports of radiologic examinations, cardiac catheterizations, and discharge summaries were obtained. Outcomes evaluated included rates of in‐hospital mortality, myocardial infarction, revascularization, and length of stay (LOS), as well as Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events (REPLACE‐2) and Thrombosis in Myocardial Infarction (TIMI) bleeding categorization. Bivalirudin use was associated with a significant reduction in TIMI major (5.0% vs 9.7%, p=0.003), REPLACE‐2 major (5.4% vs 12.9%, p<0.001), and TIMI minor (1.7% vs 6%, p<0.001) bleeding complications compared with UFH use. Significantly fewer patients in the bivalirudin group received glycoprotein IIb‐IIIa inhibitors (27.3% vs 62.7%, p<0.001). Patients receiving bivalirudin had significantly fewer myocardial infarctions after catheterization (10.7% [40/375] vs 18.0% [51/284], p=0.007). No differences were noted in mortality and revascularization rates between groups. A shortened LOS was observed in the bivalirudin group.

Conclusions. This real‐world analysis that included high‐risk patients provides further evidence that bivalirudin is an attractive alternative to UFH because of a decrease in bleeding events without compromising efficacy.
Low‐Dose Botulinum Toxin Type A for the Treatment of Refractory Piriformis Syndrome
Authors: Yoon Se Jin , Ho Jin , Kang Ho Yeong , Lee Sang Ho , Kim Kyung Im , Shin Wan Gyoon , Oh Jung Mi
Published: April 2007

Study Objectives. To evaluate the efficacy of a single, low‐dose injection of botulinum toxin type A in relieving pain in Korean patients with piriformis syndrome resistant to conventional therapy, and to assess the drug's influence on these patients' quality of life.

Design. Prospective, single‐site, open‐label trial.

Setting. Rehabilitation medicine clinic in Seoul, Korea.

Patients. Twenty‐nine patients with a confirmed diagnosis of chronic piriformis syndrome and 82 age‐ and sex‐matched healthy subjects were enrolled from April 1, 2003–February 28, 2004.

Intervention. In 20 of the patients, botulinum toxin type A 150 U was injected using computed tomographic guidance into the affected unilateral piriformis muscle. The other nine patients served as active controls and received an injection of dexamethasone 5 mg and 1% lidocaine. The healthy subjects did not receive any injection.

Measurements and Main Results. The patients' pain at baseline and at 4, 8, and 12 weeks after treatment was rated by using a numeric rating scale. Health‐related quality of life was assessed by using the validated Korean version of the Medical Outcomes Study 36‐Item Short Form Health Survey (SF‐36) at baseline and at 4 weeks of treatment. Healthy subjects also completed the SF‐36 at baseline. Pain intensity scores were significantly lower at 4, 8, and 12 weeks after treatment than at baseline (p<0.0001). Baseline scores from the SF‐36 subscales, including those for physical functioning (p<0.0001), role physical (p<0.0001), bodily pain (p<0.0001), general health (p<0.0001), vitality (p<0.0001), and social functioning (p<0.002), were significantly lower in the patients than in the healthy subjects. Four weeks after treatment, physical functioning (p=0.003), role physical (p=0.021), bodily pain (p=0.016), general health (p=0.013), vitality (p=0.031) and social functioning (p=0.035) improved significantly from baseline in the patients. However, at 4 weeks, patients in the active control group were withdrawn from the study because their pain did not improve, and continuation without further medical care was considered unethical.

Conclusion. A low dose of botulinum toxin type A relieved pain and improved quality of life in patients with refractory piriformis syndrome.
The Effect of Acetaminophen on the International Normalized Ratio in Patients Stabilized on Warfarin Therapy
Authors: Parra David , Beckey Nick P. , Stevens Gary R.
Published: April 2007

Study Objective. To determine whether an interaction exists between acetaminophen and warfarin that alters the international normalized ratio (INR).

Design. Prospective, randomized, double‐blind, placebo‐controlled trial.

Setting. Anticoagulation clinic at a Veterans Affairs Medical Center.

Patients. Thirty‐six adult patients receiving warfarin with stable INRs, defined as two consecutive INRs at least 3 weeks apart that were within the therapeutic range.

Intervention. Patients were randomly assigned to receive acetaminophen 1 g twice/day along with matching placebo twice/day (12 patients), acetaminophen 1 g 4 times/day (12 patients), or matching placebo 4 times/day (12 patients) for 4 weeks.

Measurements and Main Results. The primary end point was the difference in mean INR between groups at weekly intervals. Secondary end points were the percentages of patients in each group with supratherapeutic (INR ≥ 0.3 above the upper limit of their therapeutic range) or subtherapeutic (INR ≥ 0.2 or 0.3 below the lower limit of their respective therapeutic range of 2.0–3.0 or 2.5–3.5) INRs, and the difference in mean serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels between groups at biweekly intervals. Slow enrollment and a preliminary observation that 15 patients experienced an elevated INR prompted early termination of the study. At week 2, the group receiving acetaminophen 2 g/day had a significantly higher mean INR versus the placebo group (p=0.01). At weeks 1, 2, and 3, the acetaminophen 4‐g/day group had significantly higher mean INRs compared with those in the placebo group (p=0.04, p=0.01, p=0.01, respectively). In addition, 13 (54%) of 24 patients in the acetaminophen groups combined exceeded the upper limit of their therapeutic range by 0.3 or greater compared with only 2 (17%) of 12 patients in the placebo group. No statistically significant differences in serum ALT or AST levels between either acetaminophen group versus the placebo group were found at week 4; however, there was a statistically significant increase in mean ALT level at week 2 in the acetaminophen 4‐g/day group versus the placebo group.

Conclusion. These findings support the existence of a clinically significant interaction between warfarin and daily use of acetaminophen 2–4 g, necessitating close monitoring of patients who receive this drug combination. Whether this interaction occurs when acetaminophen is taken in lower doses or is used sporadically requires further study.
Rates of Hospitalizations and Emergency Department Visits in Patients with Asthma and Chronic Obstructive Pulmonary Disease Taking β‐Blockers
Authors: Brooks Tyson W. A. , Creekmore Freddy M. , Young David C. , Asche Carl V. , Oberg Brian , Samuelson Wayne M.
Published: April 2007

Study Objective. To determine the rates of hospitalizations and emergency department (ED) visits during cardioselective and nonselective β‐blocker therapy in patients with asthma and/or chronic obstructive pulmonary disease (COPD).

Design. Retrospective, observational cohort study.

Data Source. Electronic medical records database.

Patients. A total of 11,592 adult patients with asthma and/or COPD, identified from August 1, 1997‐December 31, 2005, who were taking β‐blockers for at least 30 days or had never received a β‐blocker (controls).

Measurements and Main Results. Of these patients, 3062 were taking cardioselective and 690 nonselective β‐blockers; 7840 were controls. The primary end point for the β‐blocker groups was the rate of hospitalizations and ED visits/patient‐year of β‐blocker therapy relative to the control group. In patients with asthma with or without concomitant COPD, cardioselective β‐blockers were associated with a relative risk of 0.89 (95% confidence interval [CI] 0.53‐1.50) for hospitalizations and 1.40 (95% CI 1.20‐1.62) for ED visits compared with controls. Nonselective β‐blockers were associated with a relative risk of 2.47 (95% CI 1.37‐4.48) for hospitalizations and 1.21 (95% CI 0.91‐1.62) for ED visits. In patients with COPD only, cardioselective β‐blockers were associated with a relative risk of 0.64 (95% CI 0.43‐0.96) for hospitalizations and 1.19 (95% CI 1.02‐1.39) for ED visits. Nonselective β‐blockers were associated with a relative risk of 1.02 (95% CI 0.52‐2.02) for hospitalizations and 0.51 (95% CI 0.33‐0.80) for ED visits.

Conclusion. In patients with asthma with or without COPD, both cardioselective and nonselective β‐blocker use increased hospitalizations and ED visits compared with controls. Thus, these patients should receive β‐blocker therapy only if their cardiac risk exceeds their pulmonary risk and if they have concomitant cardiac disease for which β‐blockers decrease mortality, such as previous acute myocardial infarction or chronic heart failure. In patients with COPD only, cardioselective β‐blockers slightly increased the risk of ED visits but reduced the risk of hospitalizations. Nonselective β‐blocker therapy in these patients reduced the rate of ED visits and total visits. These findings suggest a larger safety margin with β‐blocker therapy in patients with COPD only than in those with asthma with or without COPD.
Risk of Major Bleeding with Concomitant Dual Antiplatelet Therapy After Percutaneous Coronary Intervention in Patients Receiving Long‐Term Warfarin Therapy
Authors: DeEugenio Deborah , Kolman Louis , DeCaro Matthew , Andrel Jocelyn , Chervoneva Inna , Duong Phu , Lam Linh , McGowan Christopher , Lee Grace , DeCaro Mark , Ruggiero Nicholas , Singhal Shalabh , Greenspon Arnold
Published: April 2007

Study Objectives. To characterize the safety of concomitant aspirin, clopidogrel, and warfarin therapy after percutaneous coronary intervention (PCI), and to identify patient characteristics that increase the risk of hemorrhage.

Design. Retrospective, matched cohort study.

Setting. Academic medical center and affiliated outpatient offices.

Patients. The active group consisted of 97 patients who underwent PCI from January 1, 2000–September 30, 2005, and received warfarin, aspirin, and clopidogrel; the control group consisted of 97 patients who were individually matched to patients in the active group by procedure type, procedure year, age, and sex. Control patients received aspirin and clopidogrel.

Measurements and Main Results. Clinical data were collected from inpatient records, outpatient physician office records, and telephone surveys administered to patients or caregivers. The primary end point was major bleeding. The median duration of follow‐up after index procedure was 182 days (range 0–191 days) in the active group and 182 days (range 0–213 days) in the control group. Fifty‐seven (59%) of the 97 patients in the active group received warfarin for atrial fibrillation. There were 14 major bleeds in the active group (including 1 death) and 3 major bleeds in the control group during the study period. Mean international normalized ratio at the time of bleeding was 3.4. Hazard ratio for major bleeding was 5.0 in patients receiving warfarin therapy (95% confidence interval 1.4–17.8, p=0.012). Aspirin dose, age, sex, body mass index, history of hypertension, diabetes mellitus, intraprocedural glycoprotein IIb‐IIIa or anticoagulant type, and postprocedural anticoagulant use did not have a significant effect on the risk of major bleeding.

Conclusion. Warfarin was an independent predictor of major bleeding after PCI in patients receiving dual antiplatelet therapy. Prospective data to further characterize the safety of concomitant warfarin and dual antiplatelet therapy after PCI are needed.
Tolerability of β‐Blockers in Outpatients with Refractory Heart Failure Who Were Receiving Continuous Milrinone
Authors: Earl Grace L. , Verbos‐Kazanas Marybeth A. , Fitzpatrick Jane M. , Narula Jagat
Published: April 2007

Study Objective. To investigate the dosing, tolerability, and outcomes associated with the use of concomitant β‐blockers and inotropic therapy in patients with refractory heart failure during the first 6 months of their therapy.

Design. Retrospective review.

Setting. University‐based, tertiary care heart failure and transplant center.

Patients. Sixteen inotrope‐dependent outpatients with end‐stage refractory heart failure who were receiving continuous intravenous milrinone. Of these patients, 12 also received an oral β‐blocker; the remaining four patients who did not receive β‐blockers served as the comparator group.

Measurements and Main Results. For each patient, the initial and final study drug doses of continuous intravenous milrinone and oral β‐blocker treatment, when applicable, were recorded over the 6‐month period. Mean heart rate, blood pressure, ejection fraction, and oxygen consumption were measured, and 95% confidence intervals were calculated. Serum sodium and creatinine concentrations, as well as the creatinine clearance, were measured. In the 12 patients who received concomitant milrinone and β‐blockers, the mean baseline ejection fraction was approximately 18%, and they received milrinone for 18.6 weeks. Seven patients received carvedilol for 16.1 weeks, and five received metoprolol tartrate for 17.6 weeks. Dosages of the β‐blockers were titrated. Final daily doses were carvedilol 42.8 mg (95% confidence interval 20.3–65.4) and metoprolol 42.5 mg (95% confidence interval 28.0–57.2). Patients continued to receive other standard oral drug therapy for heart failure. One patient discontinued metoprolol and one discontinued carvedilol because of hypotension and/or worsening heart failure. Cardiac adverse events in the concomitant milrinone plus β‐blocker group were heart failure requiring hospitalization in 10 patients and ventricular arrhythmias in one.

Conclusion. Inotrope‐dependent patients with refractory end‐stage heart failure tolerated continuous intravenous milrinone plus β‐blockers in addition to diuretics and vasodilators for the 6‐month observation period. β‐Blocker dosages were titrated, and three patients achieved the target β‐blocker dosage established for stage A‐C heart failure. Additional studies are needed to determine the optimal selection and dosing of drug combinations in this population.
Prevalence of Anemia in Clinic Patients with Heart Failure and Cost Analysis of Epoetin Treatment
Authors: Choy Christine K. , Spencer Anne P. , Nappi Jean M.
Published: April 2007

Study Objectives. To determine the prevalence of anemia in an outpatient heart failure clinic, describe the type of anemia in patients treated there, and evaluate the potential costs associated with epoetin therapy in this cohort.

Design. Single‐center, retrospective cohort analysis (part 1) and a literature‐based economic decision analysis (part 2).

Data Source. Medical records from a multidisciplinary, outpatient, heart failure clinic, and published hospitalization and drug‐use data.

Patients. We evaluated 170 adults with chronic heart failure who were enrolled in the clinic and for whom at least one complete blood count was recorded between January 1, 2003, and April 15, 2006.

Measurements and Main Results. In part 1, demographic and clinical data were extracted from electronic medical records. The overall prevalence of anemia was 47.6% or 47.1%, as based on World Health Organization or National Kidney Foundation definitions, respectively. Normocytic anemia was characterized in 75.0% of patients. In part 2, heart failure hospitalization rates and costs, drug acquisition, and drug administration were estimated by using the published literature. In a hypothetical cohort of 100 patients with heart failure and comorbid anemia, the costs associated with outpatient epoetin and intravenous iron therapy exceeded savings in hospitalization costs by $83,070. Results of 1‐way sensitivity analyses generally confirmed robustness of the model.

Conclusion. Anemia is a common comorbidity in patients with chronic heart failure treated in the outpatient clinic. Although the current evidence is insufficient to support the use of epoetin in this population, initial findings indicate that epoetin and intravenous iron therapy may be associated with positive clinical outcomes. From a pharmacoeconomic standpoint, however, a reduction in the cost of heart failure–related hospitalization does not offset the cost of epoetin and intravenous iron therapy.
Pharmacist‐Managed Vaccination Program Increased Influenza Vaccination Rates in Cardiovascular Patients Enrolled in a Secondary Prevention Lipid Clinic
Authors: Loughlin Susan M. , Mortazavi Ali , Garey Kevin W. , Rice Gary K. , Birtcher Kim K.
Published: April 2007

Study Objectives. To determine whether a vaccination program in a pharmacist‐managed secondary prevention lipid clinic increased influenza immunization rates in a high‐risk population, and whether age or gender disparity existed among those vaccinated.

Design. Retrospective chart review.

Setting. Large, multispecialty group practice.

Patients. A total of 476 and 266 patients seen at clinic visits during the 2003–2004 and 2004–2005 influenza seasons, respectively.

Measurements and Main Results. Immunization rates were compared before (2003–2004 influenza season) and after (2004–2005 influenza season) the implementation of the influenza vaccination program; χ2 analysis was used for all statistical inferences. Vaccination rates increased significantly from 39% to 76% (p<0.0001) after program implementation. No before‐after difference in rates was noted based on gender. Before implementation, patients younger than 65 years were less likely versus those aged 65 years or older to receive the influenza vaccine (29% vs 58%, p<0.0001). Age disparity in vaccination rates was eliminated after initiation of the program.

Conclusion. The pharmacist‐managed program increased influenza vaccination rates in high‐risk patients with cardiovascular disease in advance of the newly published secondary prevention guidelines. Age‐related differences in the vaccination rates were eliminated after program implementation.
Severe Anaphylactic Reaction After Repeated Intermittent Exposure to Lepirudin
Authors: Veach Sidney A. , Franks Amy M. , Allan Michael C.
Published: April 2007

Lepirudin, a recombinant DNA derivative of hirudin, is used to prevent thromboembolic complications caused by heparin‐induced thrombocytopenia type II. Anaphylactic and anaphylactoid reactions have been reported with its use in patients both with and without known previous exposure to lepirudin. We describe the case of a 57‐year‐old woman who received five uneventful courses of lepirudin therapy before having a severe anaphylactic reaction during administration of the intravenous bolus dose that began her sixth course. The patient experienced cardiorespiratory arrest but recovered from the reaction. The decision to administer lepirudin to a patient who has previously received it should be reached with due consideration of the risk:benefit ratio and strategies to manage risk resulting from readministration. Risk factors for an anaphylactic reaction to lepirudin may include use of an initial bolus dose, intravenous rather than subcutaneous administration, length of any single course of therapy beyond 3 days, and repeat administration of lepirudin within 100 days.
Emphysematous Cholecystitis in a Patient with Gastrointestinal Stromal Tumor Treated with Sunitinib
Authors: de Lopes Gilberto Lima , Lima Caio Max Rocha
Published: April 2007

A 50‐year‐old man had a metastatic gastrointestinal stromal tumor that was refractory to imatinib. He was prescribed a 6‐week course of treatment with oral sunitinib 50 mg/day. During the fourth week of his first cycle of treatment with the drug, the patient developed acute‐onset, right upper quadrant pain associated with nausea, vomiting, and fever; laboratory tests revealed leukocytosis and mild hyperbilirubinemia. He was diagnosed with acute emphysematous cholecystitis, which was treated with broad‐spectrum antibiotics and percutaneous cholecystostomy. His symptoms resolved, and he successfully completed his course of therapy with sunitinib. Using the Naranjo adverse drug reaction probability scale, a score of 5 was derived, which indicates that the likelihood was probable that this adverse event was caused by sunitinib.
Evaluation of Inaccuracies in the Measurement of Glycemia in the Laboratory, by Glucose Meters, and Through Measurement of Hemoglobin A1c
Authors: Schrot Richard J. , Patel Kirit T. , Foulis Philip
Published: April 2007

IN BRIEF

The accurate measurement of glucose is extremely important in the diagnosis of diabetes and pre-diabetes, where the laboratory values are crucial; in the management of diabetes, where glucose meter values are crucial; and in attainment of goals in diabetes, where hemoglobin A1c measurement is crucial. This article reviews pitfalls that may interfere with accuracy of glucose measurement in each of these three areas and how this inaccuracy may be evaluated and managed in the primary care setting. Three case presentations of disparity are discussed.
Electrospinning of the hydrophilic poly (2-hydroxyethyl methacrylate) and its copolymers with 2-ethoxyethyl methacrylate
Authors: Přádný Martin , Martinová Lenka , Michálek Jiří , Fenclová Tat’ána , Krumbholcová Eva
Published: April 2007

The goal was to electrospin 2-hydroxyethyl methacrylate — based biocompatible polymers and prepare submicron fibres (nanofibers) for biomedicinal applications. Syntheses of poly(2-hydroxyethyl methacrylate) (HEMA) and its copolymer with 2-ethoxyethyl methacrylate (EOEMA), and their characterization by viscometry and molecular weight are described. Their relation to electrospinning is discussed. Electrospinning of HEMA homopolymer from water-ethanol is successful for molecular weights 6.31 × 105 and 1.80 × 106 g/mol. Electrospinning of HEMA/EOEMA copolymers is feasible from ethanol.
Electron rectification through donor-acceptor-heterocyclics connected to cumulenic bridge: a computational study
Authors: Laxmikanth Rao J.
Published: April 2007

Density Functional Theory (DFT) calculations and Frontier Molecular Orbital (FMO) analysis have been carried out at B3LYP/6-31G(d,p) level of theory on some Donor-Bridge-Acceptor (D-B-A) molecules for their electrical rectification behavior. The donor-acceptor-heterocyclics (D/A-heterocyclics) (namely thiophene, furan and pyrrole rings) are attached as donor and acceptors to the two ends of cumulenic bridge. FMO analysis indicates that the molecules having even number of double bonds in the bridge, possess a complete localization of the MOs i.e., the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) are localized on the donor and the acceptor side of the molecules respectively, and LUMO+1 is localized on the donor side, where as in case of odd number of double bonds in the bridge, both the HOMO and LUMOs are delocalized all over the molecule. The Potential Drop (PD) in the former case decreases as the number of double bonds increases in the bridge and due to the presence of the mutually orthogonal and noninteracting π-clouds, they can act as molecular rectifiers. For the molecules with the odd number of double bonds due to the low-lying LUMO delocalized all over the molecule, may find application as molecular wires in molecular electronics circuits.
Flame dynamics and structure within sub‐millimeter combustors
Authors: Prakash Shaurya , Armijo Adrian D. , Masel Richard I. , Shannon Mark A.
Published: April 2007

Non‐premixed methane‐oxygen flame dynamics and structures confined within an alumina combustor are described. Non‐stabilized, transient flame dynamics and phenomena leading to the formation of a stable edge‐like flame and distinct cellular structures that take place within combustor channels of dimensions 35 mm long, 5 mm wide, and 0.75 mm high (combustor volume ∼ 130 mm3) are discussed. These confined flames are surveyed by measuring the external wall temperatures, high‐speed and still‐frame visual flame imaging, recordings of emitted acoustics from the combustor, and capturing visible, CH*, and OH* chemiluminescence through a sapphire window. The observed dynamic flame structure is an oscillating edge‐like flame accompanied by ignition‐extinction events that precede the formation of a stable edge‐like flame and flame cells in the reaction channel. The cellular flame structures in all cases exhibit a confined tribrachial structure with a folded or extinguished rich branch while the lean branch survives. © 2007 American Institute of Chemical Engineers AIChE J, 2007
Additional clinical manifestations in children with sensorineural hearing loss and biallelicGJB2mutations: Who should be offeredGJB2testing?
Authors: Kenna Margaret A. , Rehm Heidi L. , Robson Caroline D. , Frangulov Anna , McCallum Jennifer , Yaeger Dinah , Krantz Ian D.
Published: April 2007

Sensorineural hearing loss (SNHL), the most common sensory impairment noted at birth, occurs in 3 out of every 1,000 births live births. At least half of congenital SNHL is genetic in origin, with nonsyndromic, or isolated hearing loss, accounting for approximately 70% of the total genetic causes. Syndromic hearing loss (hearing loss associated with other clinical findings) makes up the remaining 30%. Worldwide, mutations in the gap junction beta 2 (GJB2) gene, encoding the connexin 26 (Cx26) protein, are responsible for approximately 30% of all cases of childhood SNHL.GJB2mutations have been primarily associated with nonsyndromic forms of bilateral SNHL although rare syndromic forms involving dermatologic manifestations have also been reported. In general, unless skin findings are present, children with bilateral SNHL and other structural or developmental abnormalities are not generally thought of as candidates forGJB2testing. We evaluated 163 individuals with biallelicGJB2mutations and SNHL for the presence of other clinical findings. Twenty‐nine of the 163 (18%) were found to have structural and/or developmental abnormalities in addition to the SNHL and four subjects had diagnoses that were felt to account for their hearing loss prior to being screened forGJB2mutations. Although theGJB2mutations are likely not responsible for these additional clinical manifestations, this study underscores the importance of consideringGJB2mutational analysis in individuals with more than just isolated SNHL given the high prevalence ofGJB2‐related hearing loss. © 2007 Wiley‐Liss, Inc.
Genome‐wide scan of bipolar disorder and investigation of population stratification effects on linkage: Support for susceptibility loci at 4q21, 7q36, 9p21, 12q24, 14q24, and 16p13
Authors: Cassidy F. , Zhao C. , Badger J. , Claffey E. , Dobrin S. , Roche S. , McKeon P.
Published: April 2007

Bipolar disorder (BPD) is a complex genetic disorder with cycling symptoms of depression and mania. Despite the extreme complexity of this psychiatric disorder, attempts to localize genes which confer vulnerability to the disorder have had some success. Chromosomal regions including 4p16, 12q24, 18p11, 18q22, and 21q21 have been repeatedly linked to BPD in different populations. Here we present the results of a whole genome scan for linkage to BPD in an Irish population. Our most significant result was at 14q24 which yielded a non‐parametric LOD (NPL) score of 3.27 at the D14S588 marker with a nominal P‐value of 0.0006 under a narrow (bipolar type I only) model of affection. We previously reported linkage to 14q22‐24 in a subset of the families tested in this analysis. We also obtained suggestive evidence for linkage at 4q21, 9p21, 12q24, and 16p13, chromosomal regions that have all been previously linked to BPD. Additionally, we report on a novel approach to linkage analysis, STRUCTURE‐Guided Linkage Analysis (SGLA), which is designed to reduce genetic heterogeneity and increase the power to detect linkage. Application of this technique resulted in more highly significant evidence for linkage of BPD to three regions including 16p13, a locus that has been repeatedly linked to numerous psychiatric disorders. © 2007 Wiley‐Liss, Inc.
Relationship of 5‐HTTLPR genotypes and depression risk in the presence of trauma in a female twin sample
Authors: Chorbov Vesselin M. , Lobos Elizabeth A. , Todorov Alexandre A. , Heath Andrew C. , Botteron Kelly N. , Todd Richard D.
Published: April 2007

Several studies have implicated an insertion/deletion polymorphism in the promoter region of the serotonin transporter gene (SLC6A4; 5‐HTT) in the development of mood disorders. In the present study of a sample of 247 young adult female twins from Missouri, we examine whether this polymorphism interacts with the effect of adverse life events to increase risk for developing depression. We found a significant interaction between the number of high‐activity LA alleles and exposure to trauma (OR = 1.70, P < 0.0001). This differs from previous reports, in that the higher activity genotypes (LA/LA, LA/S, LA/LG), rather than the low activity genotypes (S/S, S/LG, LG/LG), are associated with an increased incidence of major depressive disease (MDD) in the presence of environmental trauma. © 2007 Wiley‐Liss, Inc.
Polymorphisms in dopamine receptor DRD1 and DRD2 genes and psychopathological and extrapyramidal symptoms in patients on long‐term antipsychotic treatment
Authors: Dolžan Vita , Plesničar Blanka Kores , Serretti Alessandro , Mandelli Laura , Zalar Bojan , Koprivšek Jure , Breskvar Katja
Published: April 2007

DRD1and DRD2receptor gene variants have been associated with clinical aspects of schizophrenia; however only specific features were analyzed in different samples. To assess the complex interaction between genetic and clinical factors, we studied the possible cross‐interactions between DRD1 and DRD2 dopamine receptor gene polymorphisms, symptomatology of schizophrenia and schizoaffective disorders, and the occurrence of treatment induced side effects taking into consideration possible clinical confounding variables. One hundred thirty one outpatients in stable remission meeting the DSMIV criteria for schizophrenia spectrum disorders and receiving long‐term maintenance therapy with haloperidol, fluphenazine, zuclopenthixole, or risperidone were genotyped for DRD1 A‐48G, DRD2 Ins‐141CDel, and DRD2 Ser311Cys polymorphisms. Psychopathological symptoms were assessed with the positive and negative syndrome scale for schizophrenia (PANSS). Extrapyramidal side effects were assessed with the Simpson–Angus extrapyramidal side effects scale (EPS), the Barnes Akathisia scale (BARS), and the abnormal involuntary movement scale (AIMS). Drug dosage was included as covariant because it was associated with the severity of symptomatology, akathisia, and parkinsonism. No association was observed for DRD1 and DRD2 polymorphisms and extrapyramidal side effects, or with the other clinical variables considered. Our study suggests that DRD1 and DRD2 variants are not liability factors for tardive dyskinesia. © 2007 Wiley‐Liss, Inc.
Mitochondrial DNA hypervariable region‐1 sequence variation and phylogeny of the concolor gibbons, Nomascus
Authors: Monda Keri , Simmons Rachel E. , Kressirer Philipp , Su Bing , Woodruff David S.
Published: April 2007

The still little known concolor gibbons are represented by 14 taxa (five species, nine subspecies) distributed parapatrically in China, Myanmar, Vietnam, Laos and Cambodia. To set the stage for a phylogeographic study of the genus we examined DNA sequences from the highly variable mitochondrial hypervariable region‐1 (HVR‐1 or control region) in 51 animals, mostly of unknown geographic provenance. We developed gibbon‐specific primers to amplify mtDNA noninvasively and obtained >477 bp sequences from 38 gibbons in North American and European zoos and >159 bp sequences from ten Chinese museum skins. In hindsight, we believe these animals represent eight of the nine nominal subspecies and four of the five nominal species. Bayesian, maximum likelihood and maximum parsimony haplotype network analyses gave concordant results and show Nomascus to be monophyletic. Significant intraspecific variation within N. leucogenys (17 haplotypes) is comparable with that reported earlier in Hylobates lar and less than half the known interspecific pairwise distances in gibbons. Sequence data support the recognition of five species (concolor, leucogenys, nasutus, gabriellae and probably hainanus) and suggest that nasutus is the oldest and leucogenys, the youngest taxon. In contrast, the subspecies N. c. furvogaster, N. c. jingdongensis, and N. leucogenys siki, are not recognizable at this otherwise informative genetic locus. These results show that HVR‐1 sequence is variable enough to define evolutionarily significant units in Nomascus and, if coupled with multilocus microsatellite or SNP genotyping, more than adequate to characterize their phylogeographic history. There is an urgent need to obtain DNA from gibbons of known geographic provenance before they are extirpated to facilitate the conservation genetic management of the surviving animals. Am. J. Primatol. 69:1285–1306, 2007. © 2007 Wiley‐Liss, Inc.
Intraspecific variation in hair δ13C and δ15N values of ring‐tailed lemurs (Lemur catta) with known individual histories, behavior, and feeding ecology
Authors: Loudon James E. , Sponheimer Matt , Sauther Michelle L. , Cuozzo Frank P.
Published: April 2007

Stable carbon and nitrogen isotope compositions were analyzed from hair samples of 30 sympatric ring‐tailed lemurs (Lemur catta) inhabiting the Beza Mahafaly Special Reserve, Madagascar. All lemurs were known individuals involved in a longitudinal study, which allowed us to explore the degree to which group membership, sex, health status, and migration influenced their stable isotope compositions. The differences in δ13C and δ15N values between groups were small (<1.5‰) but highly significant. In fact, each group was tightly clustered, and discriminant function analysis of the stable isotope data assigned individuals to the group in which they were originally collared with over 90% accuracy. In general, the differences between groups reflected the degree to which they utilized forested versus open habitats. As open habitats at Beza Mahafaly often correspond to areas of anthropogenic disturbance, these data suggest that isotopic data can be useful for addressing questions of lemur conservation. There were few sex differences, but significant differences did occur between individuals of normal and suboptimal health, with those in poor health (especially those in the worst condition) being enriched in 15N and to a lesser degree 13C compared with healthy individuals. Moreover, lemurs that had emigrated between 2003 and 2004 had different δ13C and δ15N compositions than their original groups. Am J Phys Anthropol, 2007. © 2007 Wiley‐Liss, Inc.
Rethinking incisor size and diet in anthropoids: Diet, incisor wear and incisor breadth in the African apes
Authors: McCollum Melanie A.
Published: April 2007

In a seminal study Hylander (1975) concluded that the length of the incisor row in catarrhines considered frugivores is longer relative to body mass than in those classified as folivores. Assuming that large fruits require greater incisal processing than do leaves, stems, berries, and seeds, he argued that the larger incisors of frugivores increased their resistance to wear. The present analysis examines diet, incisor wear, and incisor crown breadth in cranial samples of western lowland gorillas and chimpanzees. Incisor wear rate was assessed on the basis of the extent of incisor crown reduction observed at sequential stages of first molar wear. Incisor metrics were obtained from the unworn teeth of juveniles. Results suggest that incisor wear is greater in the more folivorous western lowland gorillas than in more frugivorous chimpanzees. Moreover, incisor crown dimensions do not differ appreciably among African apes. These findings fail to support the hypothesis that slower wear rates are associated with broader incisor crowns, and raise new questions regarding the significance of incisor row length in anthropoids. Am J Phys Anthropol, 2007. © 2007 Wiley‐Liss, Inc.
Origins and spread of agriculture in Italy: A nonmetric dental analysis
Authors: Coppa A. , Cucina A. , Lucci M. , Mancinelli D. , Vargiu R.
Published: April 2007

Dental morphological traits were employed in this study as direct indicators of biological affinities among the populations that inhabited the Italian peninsula from the Upper Paleolithic‐Mesolithic to Medieval times. Our analysis aims at contributing to the ongoing debate regarding the origin and spread of agriculture in the peninsula by contrasting the dental evidence of archaeological and modern molecular samples. It is not possible to generalize given the complex and dynamic nature of these populations. However, the results from the principal component analysis, maximum likelihood, mean measure of divergence, and multidimensional scaling do indicate a net separation of the Paleo‐Mesolithic sample from the other groups that is not related to dental reduction. This suggests that the shift in dental morphology was the product of Neolithic populations migrating into the peninsula from other areas. Nonetheless, the Paleo‐Mesolithic populations share several discriminative traits with the Neolithic group. The biological relevance of such evidence suggests that, to some minor extent, the spread of agriculture did not occur by total population replacement. Because of regional small sample sizes, this hypothesis cannot be tested on a micro‐regional scale. It is, however, feasible to depict a scenario where processes of genetic mixture or replacement probably took place at different rates on a macro‐regional level. Am J Phys Anthropol, 2007. © 2007 Wiley‐Liss, Inc.
A specific viral cause of multiple sclerosis: One virus, one disease
Authors: Lipton Howard L. , Liang Zhiguo , Hertzler Shannon , Son Kyung‐No
Published: April 2007

“Multiple sclerosis is an autoimmune disease,” is heard so often that it is widely accepted as fact by the current generation of students and physicians. Yet, although it is undisputed that multiple sclerosis (MS) is immune mediated, an autoimmune mechanism remains unproven. Immune‐mediated tissue damage can also result from viral infections in which the host immune response is directed to viral rather than self proteins, or as a consequence of nonspecific or bystander immune responses that change the local cytokine environment. Increasing evidence suggests that poorly controlled host immune responses account for much of the tissue damage in chronic infections, and it has been postulated that a similar mechanism may underlie many chronic diseases with features suggestive of an infectious causative factor, including MS. A recent study suggesting that oligodendrocyte death accompanied by microglial activation is the primary event in new MS lesion formation, rather than lymphocyte infiltration, could change the current mindset almost exclusively focused on autoimmunity. This review presents the rationale for considering MS a single disease caused by one virus, as well as the anticipated pattern of a persistent central nervous system infection, the application of Koch's postulates to viral discovery in MS as the causative agent, and tissue culture‐independent genotypic approaches to viral discovery in MS. Ann Neurol 2007
Mutation of a potassium channel–related gene in progressive myoclonic epilepsy
Authors: Van Bogaert Patrick , Azizieh Regis , Désir Julie , Aeby Alec , De Meirleir Linda , Laes Jean‐François , Christiaens Florence , Abramowicz Marc J.
Published: April 2007

Objective

We investigated a large consanguineous Moroccan family with progressive myoclonic epilepsy (PME) consistent with autosomal recessive inheritance, to describe the phenotype and identify the causal gene.

Methods

We recorded the clinical course of the disease and the response to drug therapy, whereas carefully excluding known causes of progressive myoclonic epilepsy. We then linked the disease by homozygosity mapping using microsatellite markers and single nucleotide polymorphism microarrays (11K GeneChip), and studied candidate genes in the critical linkage region.

Results

Epilepsy started between 16 and 24 months of age after normal initial development. Seizures were multifocal myoclonus aggravated by movements, and generalized tonic‐clonic seizures were experienced by two patients. Electroencephalogram showed slow dysrhythmia, multifocal and occasionally generalized epileptiform discharges, and photosensitivity. Brain magnetic resonance images were normal. All patients were demented. Two had refractory epilepsy and a severe course. Seizures were controlled in the third patient, whose disease course was less severe. Linkage analyses identified a new locus on 7q11.2, with a maximum multipoint logarithm of odds of 4.0 at D7S663. In the critical linkage region, we found a C to T mutation in exon 2 of the potassium channel tetramerization domain containing 7 gene (KCTD7). The mutation affected a highly conserved segment of the predicted protein, changing an arginine codon into a stop codon (R99X).

Interpretation

Neurodegeneration in progressive myoclonic epilepsy presented by our patients paralleled the refractoriness of epilepsy. The disease was transmitted as an autosomal recessive trait linked to a novel locus at 7q11.2, where we identified a mutation in KCTD7. Ann Neurol 2007
Muscle Nogo‐a expression is a prognostic marker in lower motor neuron syndromes
Authors: Pradat Pierre‐François , Bruneteau Gaelle , Gonzalez de Aguilar Jose‐Luis , Dupuis Luc , Jokic Natasa , Salachas François , Le Forestier Nadine , Echaniz‐Laguna Andoni , Dubourg Odile , Hauw Jean‐Jacques , Tranchant Christine , Loeffler Jean‐Philippe , Meininger Vincent
Published: April 2007

Objective

A proportion of patients with pure lower motor neuron syndrome (LMNS) progress to amyotrophic lateral sclerosis (ALS). Early detection of this progression is impossible, which delays the patient's access to treatment. Muscle expression of Nogo‐A is a new candidate marker of ALS. We tested whether detection of Nogo‐A in a muscle biopsy from patients with LMNS predicts progression to ALS.

Methods

Thirty‐three patients who had undergone a muscle biopsy during the diagnostic workup of spinal LMNS were observed for 12 months. Nogo‐A expression was measured by Western blot in muscle biopsy samples and compared with the final diagnosis.

Results

Nogo‐A expression was detected in 17 patients and was absent in 16 patients. The detection of Nogo‐A in muscle biopsy samples from LMNS patients correctly identified patients who further progressed to ALS with 91% accuracy, 94% sensitivity, and 88% specificity. In patients who later developed typical ALS, Nogo‐A may be detected as early as 3 months after the onset of symptoms.

Interpretation

Nogo‐A test is able to identify ALS early in the course of the disease when diagnosis is difficult, requiring further progression. Use of the test in clinical practice may shorten the delay before introduction of neuroprotective drugs or inclusion in clinical trials. Ann Neurol 2007
Minimale Umgestaltung aktiver Enzymtaschen – wie man alten Enzymen neue Kunststücke beibringt
Authors: Toscano Miguel D. , Woycechowsky Kenneth J. , Hilvert Donald
Published: April 2007

Während die Natur ihre Katalysatoren über Millionen von Jahren entwickelt hat, versuchen Enzymingenieure, dies ein wenig schneller zu bewerkstelligen. Die aktive Tasche eines Enzyms bildet eine stark optimierte Mikroumgebung für die Katalyse chemischer Transformationen in biologischen Systemen – folglich können Änderungen in diesen Zentren die Enzymaktivität stark beeinflussen. Daher bietet die Voraussage und Kontrolle solcher Effekte einen vielversprechenden Weg, um zu neuen Funktionen zu gelangen. Der Ansatz, bei dem minimale Modifikationen in den aktiven Taschen von Enzymen (z. B. durch gezielte Mutagenese und Hinzufügen neuer reaktiver Funktionalitäten) deren katalytisches Repertoire erweitern sollen, ist der Schwerpunkt dieses Aufsatzes. Dabei kann eine neue Aktivität oft schon durch eine einzige Mutation erreicht werden. Die vielen erfolgreichen Beispiele für die Umgestaltung von aktiven Taschen durch minimale Mutationen geben wertvolle Einblicke in die Evolution von Enzymen und bahnen neue Wege in der Erforschung der Biokatalysatoren.
Titelbild: Duftvorhersage: das Computermodell des hOR17‐4‐Rezeptors auf dem Prüfstand mit Silicium‐Analoga von Bourgeonal und Lilial (Angew. Chem. 18/2007)
Authors: Doszczak Leszek , Kraft Philip , Weber Hans‐Peter , Bertermann Rüdiger , Triller Annika , Hatt Hanns , Tacke Reinhold
Published: April 2007

Riechen Sie selbst durch Rubbeln des Titelbildes (und Riechen am Finger): ein Maiglöckchen‐Akkord um Sila‐Bourgeonal passend zum Wonnemonat. Der C/Si‐Austausch in Bourgeonal und Lilial hat einen kleinen, aber charakteristischen Einfluss auf Geruch und Schwellenwert, der sich über die elektronische Moleküloberflächenform korrekt vorhersagen ließ (siehe die Zuschrift von P. Kraft, H. Hatt und R. Tacke auf S. 3431 ff). Akkord von Caroline Gaillardot, mit Serenolid (Moschus) und Azurone (Salzeffekt).
Innentitelbild: Einzelmolekülfluoreszenzspektroskopische Beobachtung der Bildung und des Zerfalls individueller Metallkomplexe (Angew. Chem. 18/2007)
Authors: Kiel Alexander , Kovacs Janos , Mokhir Andriy , Krämer Roland , Herten Dirk‐Peter
Published: April 2007

Die Einzelmolekülspektroskopie wird für viele Aufgaben in der Biochemie und der Molekularbiologie eingesetzt. D. P. Herten et al. beschreiben in ihrer Zuschrift auf S. 3427 ff. mit der direkten Beobachtung der Assoziation und Dissoziation von Kupfer(II)‐Komplexen in Echtzeit nun die erste Anwendung der Einzelmolekülfluoreszenzspektroskopie auf chemische Reaktionen kleiner Moleküle. Mit konfokaler Mikroskopie und einem immobilisierbaren fluoreszierenden Metallsensor bestimmten sie die Reaktionskinetik einzelner Komplexe im thermodynamischen Gleichgewicht.
Cover Picture: Prediction of Perception: Probing the hOR17‐4 Olfactory Receptor Model with Silicon Analogues of Bourgeonal and Lilial (Angew. Chem. Int. Ed. 18/2007)
Authors: Doszczak Leszek , Kraft Philip , Weber Hans‐Peter , Bertermann Rüdiger , Triller Annika , Hatt Hanns , Tacke Reinhold
Published: April 2007

Smell for yourself by rubbing the cover (and smelling your finger): A lily‐of‐the‐valley accord around sila‐bourgeonal is appropriate for the merry month of May. The C/Si exchange in lilial and bourgeonal has only a slight, but distinct influence on the odor and threshold, which was predicted in the electronic surface structures (see the Communication by P. Kraft, H. Hatt, R. Tacke, and co‐workers on page 3367 ff). The accord was composed by Caroline Gaillardot, with serenolide (musk) and azurone (salty effect).
Inside Cover: Direct Monitoring of Formation and Dissociation of Individual Metal Complexes by Single‐Molecule Fluorescence Spectroscopy (Angew. Chem. Int. Ed. 18/2007)
Authors: Kiel Alexander , Kovacs Janos , Mokhir Andriy , Krämer Roland , Herten Dirk‐Peter
Published: April 2007

Single‐molecule spectroscopy has proven a versatile tool in biochemistry and molecular biology. In their Communication on page 3363 ff., D. P. Herten et al. describe the first application of this technique to chemical reactions of small molecules by observing the association and dissociation of a Cu2+ complex in real time. By the use of confocal microscopy and by designing a fluorescent metal sensor that can be immobilized on glass slides, they were able to obtain the kinetics of individual complexes in thermodynamic equilibrium.