bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiple Antipsychotic Medication Prescribing Patterns
Authors: Schumacher Jennifer E , Makela Eugene H , Griffin Holly R
Published: May 2003

OBJECTIVE:

To assess current prescribing practices regarding concomitant use of antipsychotic medications and summarize the reasons clinicians may prescribe >1 scheduled agent.

METHODS:

The pharmacy identified patients at William R Sharpe Jr Hospital currently receiving antipsychotic therapy. All patients receiving ≥2 scheduled antipsychotic agents concomitantly were included in the study. Data regarding the demographics, current medication combinations used, history of therapeutic regimens tried, and prescriber rationale were prospectively evaluated for a 60-day period beginning December 13, 2000, and ending February 10, 2001. Prescriber rationale for using >1 antipsychotic simultaneously and other drug therapy regimens that had been tried were compared with chart documentation and published therapeutic guidelines for schizophrenia.

RESULTS:

Over a 60-day surveillance period, 206 patients were placed on scheduled antipsychotic medications, with 85 (41%) receiving at least 2 agents. Responders to a prescriber questionnaire (59%) indicated the most common rationale for combination therapy was augmentation; the least likely rationale was cross-titration. Survey responses also indicated a belief that there was questionable therapeutic benefit in more than half of the patients being treated with multiple antipsychotic combinations. Additionally, chart documentation showed that the majority of these patients did not receive an adequate trial of monotherapy with other atypical or typical agents, or clozapine prior to the combination antipsychotic regimen. Fifty-one percent of medical records did not document the rationale for concomitant therapy.

CONCLUSIONS:

Due to the lack of published data, the practice of using multiple antipsychotic agents is considered to be a gray area that requires the prescriber to be at a heightened level of awareness in assessing effectiveness and safety. Documentation of rationale, adverse effects, and response to the treatment regimen is essential in providing optimal care for the patient.
Direct-to-Consumer Marketing of Osteoporosis Drugs and Bone Densitometry
Authors: Hollon Matthew F , Larson Eric B , Koepsell Thomas D , Downer Ann E
Published: May 2003

OBJECTIVE:

To determine whether there is an association between a woman's exposure to direct-to-consumer (DTC) advertisements for 2 osteoporosis drugs and presentation for bone densitometry.

METHODS:

A matched case–control study was conducted between October and December 1998 at an academic primary care clinic in Seattle, WA. Seventeen women from the study population (aged ≥18 y, seen in the previous 2 y at the academic primary care clinic) presented for bone densitometry. All 51 women completed a self-administered questionnaire.

RESULTS:

Women familiar with 1 of 2 osteoporosis drugs due to exposure to advertisements had 9 times the odds of densitometry (unadjusted OR 9.3, 95% CI 1.0 to 86). Multivariate analysis, including confounders such as education level and whether a woman had previously had 3 screening tests (mammography, Pap smear, serum cholesterol), revealed a significant and strong association between exposure to advertisements and densitometry (adjusted OR 29, 95% CI 1.6 to 511).

CONCLUSIONS:

DTC marketing may increase health services utilization. Further independent evaluation of DTC marketing based on available observational evidence is feasible and warranted.
Peripheral Neuropathy Associated with Fluoroquinolones
Authors: Cohen Jay S
Published: June 2003

OBJECTIVE:

To survey cases of fluoroquinolone-associated adverse events that included peripheral nervous system (PNS) symptoms posted on Internet Web sites.

METHODS:

Cases were obtained with the assistance of members of Web sites formed by people sustaining fluoroquinolone-related events. Information obtained met the standards of MedWatch, and each reported case was assessed using the Naranjo probability scale.

RESULTS:

In contrast to previous reports suggesting that fluoroquinolone-associated PNS events are mild and short-term, 36 of the 45 cases reported severe events that typically involved multiple organ systems. Although many newer cases are still evolving, symptoms had lasted more than three months in 71% of cases and more than one year in 58%. Onset of adverse events was usually rapid, with 15 (33%) events beginning within 24 hours of initiating treatment, 26 (58%) within 72 hours, and 38 (84%) within one week. Sixty courses of fluoroquinolones were prescribed: levofloxacin (n = 33 cases), ciprofloxacin (n = 11), ofloxacin (n = 6), lomefloxacin (n = 1), trovafloxacin (n = 1); in eight cases the same antibiotic was prescribed twice.

CONCLUSIONS:

These cases suggest a possible association between fluoroquinolone antibiotics and severe, long-term adverse effects involving the PNS as well as other organ systems. The severity of these cases may reflect a different population than typically reported to drug companies or MedWatch, which often originate from healthcare providers. In contrast, Internet Web sites may provide a forum for patients experiencing adverse effects that have not resolved promptly. Further study is warranted. Meanwhile, the occurrence of PNS symptoms during fluoroquinolone therapy should prompt immediate discontinuation of the agent used.
Sertraline-Induced Hypoglycemia
Authors: Pollak P Timothy , Mukherjee Som D , Fraser Albert D
Published: June 2003

OBJECTIVE:

To report a case of hypoglycemia that occurred in a patient treated with the selective serotonin-reuptake inhibitor, sertraline.

CASE SUMMARY:

An 82-year-old white woman with mild cardiovascular disease and no history of glucose intolerance was seen in the emergency department for a presyncopal episode associated with a blood glucose of 32 mg/dL as measured by the ambulance attendant. She had similar symptoms the day before. Despite repeated administration of oral and intravenous glucose, the patient had recurrent episodes of hypoglycemia and was hospitalized for four days. She had started taking sertraline 50 mg once daily for mild depression 25 days prior to presentation. Other medications included furosemide 20 mg/d, ramipril 5 mg/d, clopidogrel 75 mg/d, nitroglycerin patch 0.4 mg/h, and lorazepam 1 mg taken occasionally for agitation. She had never been prescribed any oral hypoglycemic agents. Serum sertraline and desmethylsertraline concentrations measured two, three, and four days after discontinuing sertraline were within the expected range, but the rate of decline was consistent with a moderately prolonged half-life.

DISCUSSION:

Sertraline has been shown to blunt postprandial hyperglycemia in rats and to potentiate the hypoglycemic effects of sulfonylurea agents in humans. It has not been reported to cause hypoglycemia independently, but in this case, a nondiabetic patient experienced multiple episodes of hypoglycemia that resolved after discontinuation of sertraline.

CONCLUSIONS:

This report and another implicating fluoxetine in a case of hypoglycemia suggest that healthcare professionals should consider these medications among the possible causes of hypoglycemia occurring in patients receiving selective serotonin-reuptake inhibitors.
Effects of Risperidone on Gonadal Axis Hormones in Schizophrenia
Authors: Kaneda Yasuhiro
Published: June 2003

OBJECTIVE:

To investigate the effects of risperidone on the hypothalamo—pituitary—gonadal (HPG) axis of chronic schizophrenic male inpatients medicated regularly.

METHODS:

Subjects included six inpatients who were diagnosed according to the Diagnostic and Statistical Manual, Fourth Edition, criteria for schizophrenia, and were termed treatment-refractory. Each patient gave informed consent for the research involved in this study. The neuroendocrine studies were done before and during risperidone administration. Patients took a mean dose of risperidone 9.5 mg/d for a mean period of 64.2 days. Psychotic symptoms were assessed using the Brief Psychiatric Rating Scale (BPRS).

RESULTS:

Prolactin (PRL) increased significantly during risperidone administration. However, luteinizing hormone, follicle-stimulating hormone, and testosterone did not show significant difference between blood concentrations before and during risperidone administration. Scores of the BPRS total, thought disturbance factor, and tension decreased significantly during risperidone administration. Throughout the study, none of the patients experienced clinically significant problems associated with elevated PRL concentrations including gynecomastia and/or sexual dysfunction.

CONCLUSIONS:

Addition of risperidone produced significant improvement of psychotic symptoms in treatment-resistant schizophrenic patients, and an increase in basal blood PRL concentrations, but not in basal blood HPG axis hormone concentrations. This preliminary result warrants further double-blind evaluation with a larger sample.
Ofloxacin: A Probable Cause of Toxic Epidermal Necrolysis
Authors: Melde Stephen L
Published: June 2003

OBJECTIVE:

To report a fatal case of toxic epidermal necrolysis in a man who was treated with oral ofloxacin for epididymitis.

CASE SUMMARY:

A 75-year-old white man received 23.6 grams of ofloxacin over a 51-day period for epididymitis. He experienced a severe skin reaction diagnosed as toxic epidermal necrolysis. The man died from complications related to toxic epidermal necrolysis.

DISCUSSION:

Toxic epidermal necrolysis is an infrequent, yet often fatal, severe, systemic, cutaneous disease most often the result of an adverse drug reaction. Fluoroquinolones have rarely been implicated in cases of toxic epidermal necrolysis. A MEDLINE search from 1966 to December 2000 revealed no reports of toxic epidermal necrolysis, erythema multiforme, or Stevens—Johnson syndrome due to ofloxacin therapy. However, a large case-control study included three cases of either Stevens—Johnson syndrome or toxic epidermal necrolysis associated with ofloxacin use, but no details of the cases were given. This report rules out other causes of toxic epidermal necrolysis and implicates ofloxacin in what appears to be an atypical presentation of drug-induced toxic epidermal necrolysis.

CONCLUSIONS:

There is very little published information regarding ofloxacin-induced toxic epidermal necrolysis. There are a few case reports of other fluoroquinolones that have been associated with toxic epidermal necrolysis. It is hoped that this case report creates awareness that ofloxacin-induced toxic epidermal necrolysis is possible.
Aggravation of Glaucoma with Fluvoxamine
Authors: Jiménez-Jiménez Félix Javier , Ortí-Pareja Miguel , Zurdo José Martín
Published: June 2003

OBJECTIVE:

To report a case of aggravation of glaucoma associated with the use of fluvoxamine.

CASE SUMMARY:

A 66-year-old white woman diagnosed with narrow-angle glaucoma showed an increase in intraocular pressure and experienced orbital pain and blurred vision after the initiation of fluvoxamine for tension-type headache. These symptoms disappeared and intraocular pressure normalized after withdrawal of this drug.

DISCUSSION:

Aggravation of narrow-angle glaucoma is a well-known adverse effect of tricyclic antidepressants. Because this adverse effect had been rarely reported to date with selective serotonin-reuptake inhibitors (paroxetine and fluoxetine), we used fluvoxamine in our patient. The disappearance of ocular symptoms and the normalization of intraocular pressure two days after stopping fluvoxamine suggest a possible relationship between fluvoxamine and aggravation of glaucoma.

CONCLUSIONS:

Fluvoxamine should be considered as a drug that can induce or aggravate narrow-angle glaucoma.
Possible Interaction between Warfarin and Lycium Barbarum L.
Authors: Lam Annie Y , Elmer Gary W , Mohutsky Michael A
Published: June 2003

OBJECTIVE:

To describe a patient who was stabilized on warfarin and developed an elevated international normalized ratio (INR) after drinking a concentrated Chinese herbal tea. Additionally, to determine the effect of the tea on CYP2C9, the isoenzyme responsible for the metabolism of S-warfarin.

CASE SUMMARY:

An elevated INR of 4.1 was observed in a 61-year-old Chinese woman, previously stabilized on anticoagulation therapy (INR 2–3). With no changes in her other medications or lifestyle, a review of her dietary habits revealed four days of drinking a concentrated Chinese herbal tea made from Lycium barbarum L. fruits (3–4 glasses daily) prior to her clinic visit. Warfarin was withheld for one day and then resumed at a lower weekly dose. She discontinued the tea, while maintaining consistency with medications and dietary habits. A follow-up INR seven days later was 2.4, and seven subsequent INR values were in the 2.0–2.5 range.

DISCUSSION:

L. barbarum L. (family Solanaceae) is a commonly used Chinese herb considered to have a tonic effect on various organs. Any impact of an herbal product on the metabolism of S-warfarin, the enantiomer responsible for most of the anticoagulant activity, could alter the INR values. An herbal—drug interaction was suspected in this case. In vitro evaluation showed inhibition of S-warfarin metabolism by CYP2C9 by the tea of L. barbarum L.; however, the inhibition observed was weak, with a dissociation constant (Ki) value of 3.4 mg/mL, suggesting that the observed interaction may be caused by factors other than the CYP450 system.

CONCLUSIONS:

There is a potential herbal—drug interaction between warfarin and L. barbarum L., based on an increased INR value noted with concurrent use. Thus, combination of L. barbarum L. and warfarin should be avoided. Vigilance is needed with other herbal combinations taken with drugs of narrow therapeutic indices.
Efficacy of the Dietary Supplement S-Adenosyl-L-Methionine
Authors: Fetrow CW , Avila Juan R
Published: June 2003

OBJECTIVE:

To review existing published clinical evidence surrounding the dietary supplement SAMe ( S-adenosyl-L-methionine).

DATA SOURCES:

The majority of information was obtained from primary published literature identified through MEDLINE search (1966–February 2001). Information was also obtained through secondary and tertiary sources when available.

STUDY SELECTION AND DATA EXTRACTION:

All articles identified from data sources were evaluated and all relevant information included in this review.

DATA SYNTHESIS:

The majority of clinical trial evidence surrounds the application of SAMe for various depressive disorders, osteoarthritis, and fibromyalgia. Sample sizes of these trials and the dose employed have varied considerably. Several reviews and at least two meta-analyses have examined the available evidence surrounding SAMe in the therapy of depression for trials completed prior to 1994 and concluded that SAMe was superior to placebo in treating depressive disorders and approximately as effective as standard tricyclic antidepressants. Much of this information exists in the form of isolated case reports or solitary clinical trials. SAMe appears to be well tolerated, with the majority of adverse effects presenting as mild to moderate gastrointestinal complaints. However, it is apparent that this agent is not without risk of more significant psychiatric and cardiovascular adverse events. Information documenting drug or food interactions with SAMe is very limited.

CONCLUSIONS:

Consumers should be instructed to avoid unmonitored consumption of this dietary supplement until sufficient discussion has taken place with their primary healthcare provider. Although there exists significant potential for therapeutic application of SAMe, its uncertain risk profile precludes definitive recommendation at this time. Healthcare providers and consumers should likely temper their enthusiasm for this dietary supplement until sufficient information becomes available.
Assemblies of Metal Nanoparticles and Self‐Assembled Peptide Fibrils—Formation of Double Helical and Single‐Chain Arrays of Metal Nanoparticles
Authors: Fu X. , Wang Y. , Huang L. , Sha Y. , Gui L. , Lai L. , Tang Y.
Published: June 2003

Double helical and single‐chain arrays of Au and Pd metal nanoclusters have been achieved by assembling the corresponding metal nanoparticles on peptide nanofibril templates at different pH values. The assembled metal nanoparticles are useful for studying the superstructures of the peptide nanofibrils. Pd nanowires of different shapes have also been prepared by varying the amount of metal deposition.
Carbon‐Nanotube‐Templated Assembly of Rare‐Earth Phthalocyanine Nanowires
Authors: Cao L. , Chen H.‐Z. , Zhou H.‐B. , Zhu L. , Sun J.‐Z. , Zhang X.‐B. , Xu J.‐M. , Wang M.
Published: June 2003

Multi‐walled carbon nanotubes are used for the templated assembly of HErPc2 nanowires via the phase‐separation method. When the solvent is evaporated gradually, HErPc2 nanoparticles and nanowires are found to self‐assemble on the exterior walls of CNTs, as shown in the Figure. The CNT–HErPc2 hybrid materials exhibit improved photoconductivity owing to the contribution from the photoinduced charge transfer from HErPc2 to CNTs.
Charge Density and Film Morphology Dependence of Charge Mobility in Polymer Field‐Effect Transistors
Authors: Shaked S. , Tal S. , Roichman Y. , Razin A. , Xiao S. , Eichen Y. , Tessler N.
Published: June 2003

A qualitative comparison between the extended disorder model for charge transport and the measured charge density dependence of the field‐effect mobility is presented for field‐effect transistors (see Figure) using a poly(phenylenevinylene) layer. By varying the film morphology through the use of polymers of different molecular weights, further insight into the role of morphology is gained.
Relationship Between Molecular Structure and Electrical Performance of Oligothiophene Organic Thin Film Transistors
Authors: Halik M. , Klauk H. , Zschieschang U. , Schmid G. , Ponomarenko S. , Kirchmeyer S. , Weber W.
Published: June 2003

Organic thin film transistors (TFTs) based on alkyl‐substituted oligothiophenes with varying chromophore and alkyl side‐chain length have been fabricated. The TFT performance is shown to depend on side‐chain length and contact configuration, but is found to be relatively insensitive to chromophore length. Mobilities as large as 1.1 cm2/V s were obtained. TFTs with ultra‐thin self‐assembled monolayer gate dielectrics have also been prepared and investigated.
Large‐Scale Synthesis of Ultralong Bi2S3 Nanoribbons via a Solvothermal Process
Authors: Liu Z. , Peng S. , Xie Q. , Hu Z. , Yang Y. , Zhang S. , Qian Y.
Published: June 2003

Ultralong Bi2S3 nanoribbons have been synthesized by a solvothermal process, using a mixture of aqueous NaOH solution and glycerol as the solvent. These nanoribbons (see Figure) are 50–300 nm wide, 20–80 nm thick, and up to several millimeters long, and the initial formation of the precursor polycrystalline NaBiS2 phase is crucial to their formation. The nucleation and growth process was interpreted as a solid–solution–solid transformation.
Nanoparticle Actuators
Authors: Raguse B. , Müller K.‐H. , Wieczorek L.
Published: June 2003

The actuator response of a thin porous film of functionalized gold nanoparticles is found to be fast (< 0 .5 s) and require low voltages (< 0.6 V, see Figure), relative to other comparable systems. The mechanism of reaction is based on non‐Faradaic double‐layer charging of the films in electrolyte solution. Response can be controlled by varying the nature of the molecules coating the nanoparticles, the thickness of the film, and the electrolyte.
Severe musculoskeletal phenotype associated with an unbalanced t(6;10) translocation: Clarification of the locus for this phenotype on distal 6p
Authors: James Paul A. , Aftimos Salim , Oei Paul
Published: May 2003

Larsen syndrome is a congenital condition consisting of multiple large joint dislocations associated with a distinctive facial appearance and frequently other abnormalities. The syndrome is probably genetically heterogeneous, with both dominant and recessive inheritance reported. Previously two cases have been reported where a Larsen‐like syndrome was associated with unbalanced chromosomal translocations resulting in partial trisomy 1q and monosomy distal 6p. We now report a child with an unbalanced translocation resulting in a distal 6p deletion and partial trisomy 10q, who has Larsen‐like features and has also severe developmental delay. A G‐banded preparation revealed a karyotype 46,XX,der(6),t(6:10)(p25;q25.2) and the breakpoint at 6p25 was confirmed by FISH using YAC probes (between 6p25 at D6s477/F13A1 and 6p24 at 6WI13606). Our case provides further evidence for a Larsen‐like locus at distal 6p and reduces the potential critical region. © 2003 Wiley‐Liss, Inc.
A new autosomal recessive syndrome with Zellweger‐like manifestations
Authors: Ahn Joe K. , Lev Dorit , Leshinsky‐Silver Esther , Ginzberg Mira , Lerman‐Sagie Tally
Published: May 2003

A son and daughter of consanguineous Ashkenazi Jewish parents presented with phenotypic features that are typically seen in Zellweger syndrome: high forehead, broad nasal bridge, epicanthal fold, upslanting palpebral fissures, and micrognathia. In addition to the physical anomalies, they also have severe psychomotor retardation and hypotonia. However, results of peroxisomal studies including very long chain fatty acids and plasmalogen functions, were normal. There was partial deficiency of respiratory chain complexes. We suggest that this is a new autosomal recessive syndrome that could be due to a nuclear‐encoded mitochondrial defect. © 2003 Wiley‐Liss, Inc.
Epidemiology of triploidy in a population‐based birth defects registry, Hawaii, 1986–1999
Authors: Forrester Mathias B. , Merz Ruth D.
Published: May 2003

Triploidy is a highly lethal chromosomal abnormality with few fetuses surviving to term. Triploidy has not been extensively studied using data from a population‐based birth defect registry. This investigation examined the epidemiology of triploidy using data from the Hawaii Birth Defects Program (HBDP) and compared its findings with the literature. Of the 38 identified cases of triploidy delivered in Hawaii during 1986–1999, 31 (82%) were early fetal deaths, 3 (8%) late fetal deaths, and 4 (11%) elective terminations. The distribution of cases by sex chromosome combination was 15 (39%) XXX, 22 (58%) XXY, and 1 (3%) XYY. Triploidy was prenatally diagnosed in eight (21%) of the cases, of which four were electively terminated, two resulted in early fetal death, and two resulted in late fetal death. The detected triploidy prevalence in 1993–1999 was higher than the prevalence in 1986–1992, although the difference was not statistically significant (rate ratio (RR) 1.20, 95% confidence interval (CI) 0.73–1.86). The detected triploidy prevalence for maternal age of 35 years or greater was significantly higher than the prevalence for maternal age less than 35 years (RR 4.07, 95% CI 2.22–6.83). In spite of under detection of cases, many aspects of the epidemiology of triploidy identified in a population‐based birth defects registry were consistent with that reported in the literature. © 2003 Wiley‐Liss, Inc.
Prevalence of myotonic dystrophy in Israeli Jewish communities: Inter‐community variation and founder premutations
Authors: Segel Reeval , Silverstein Shira , Lerer Israela , Kahana Esther , Meir Rachel , Sagi Michal , Zilber Nelly , Korczyn Amos D. , Shapira Yehuda , Argov Zohar , Abeliovich Dvorah
Published: May 2003

In a comprehensive epidemiological survey among Jews living in Israel, the average prevalence of myotonic dystrophy (DM) was 15.7/105 (1 case in 6,369) with intercommunity variations; the Ashkenazi Jews had the lowest rate, 5.7/105 (1 case in 17,544) as compared to the rate in the Sephardim/Oriental Jews 20/105 (1 case in 5,000) and the in the Yemenite Jews 47.3/105 (1 case in 2,114). The rate of unrelated DM‐sibships per 106 people of each community was used as an estimate of the transition rate from stable to unstable DMPK‐(CTG)n alleles assuming that each transition is a beginning of a new DM sibship. This study indicated that the difference in the incidence of DM is a result of higher mutation rate in the non‐Ashkenazi Jews (>50/106) as compared to the rate in the Ashkenazi Jews (16.3/106). The intragenic haplotype of the DM alleles was the same as that of the DM in many populations all over the world. However, two DM closely linked markers D19S207 and D19S112 were in linkage disequilibrium with the DM mutation in patients of Yemenite and Moroccan (the largest subgroup in the Sephardim Jews) extractions and not in the Ashkenazi patients. This observation indicated a common ancestral origin for the DM premutation in patients of the same ethnic origin. We concluded that the difference in the prevalence of DM among the Jewish communities is a consequence of founder premutations in the non‐Ashkenazi Jewish communities. © 2003 Wiley‐Liss, Inc.
Inv(X)(p21.1;q22.1) in a man with mental retardation, short stature, general muscle wasting, and facial dysmorphism: Clinical study and mutation analysis of the NXF5 Gene
Authors: Frints Suzanna G.M. , Jun Lin , Fryns Jean‐Pierre , Devriendt Koen , Teulingkx Rudi , Berghe Lut Van den , Vos Bernice De , Borghgraef Martine , Chelly Jamel , Portes Vincent Des , Bokhoven Hans Van , Hamel Ben , Ropers Hans‐Hilger , Kalscheuer Vera , Raynaud Martine , Moraine Claude , Marynen Peter , Froyen Guy
Published: May 2003

We describe a 59‐year‐old male (patient A059) with moderate to severe mental retardation (MR) and a pericentric inversion of the X‐chromosome: inv(X)(p21.1;q22.1). He had short stature, pectus excavatum, general muscle wasting, and facial dysmorphism. Until now, no other patients with similar clinical features have been described in the literature. Molecular analysis of both breakpoints led to the identification of a novel “Nuclear RNA export factor” (NXF) gene cluster on Xq22.1. Within this cluster, the NXF5 gene was interrupted with subsequent loss of gene expression. Hence, mutation analysis of the NXF5 and its neighboring homologue, the NXF2 gene was performed in 45 men with various forms of syndromic X‐linked MR (XLMR) and in 70 patients with nonspecific XLMR. In the NXF5 gene four nucleotide changes: one intronic, two silent, and one missense (K23E), were identified. In the NXF2 gene two changes (one intronic and one silent) were found. Although none of these changes were causative mutations, we propose that NXF5 is a good candidate gene for this syndromic form of XLMR, given the suspected role of NXF proteins is within mRNA export/transport in neurons. Therefore, mutation screening of the NXF gene family in phenotypically identical patients is recommended. © 2003 Wiley‐Liss, Inc.
Noninvasive technique for the repeated sampling of salivary free cortisol in awake, unrestrained squirrel monkeys
Authors: TIEFENBACHER S. , LEE B. , MEYER J.S. , SPEALMAN R.D.
Published: May 2003

The use of noninvasive measures of hypothalamic‐pituitary‐adrenal (HPA) axis function is of growing interest among preclinical and clinical investigators. This report describes a method for the repeated assessment of salivary free cortisol in awake, unrestrained squirrel monkeys (Saimiri sciureus) based on a saliva sampling technique previously developed for rhesus monkeys. Individually housed adult male squirrel monkeys were trained to chew on dental rope attached to a pole, from which saliva was extracted by centrifugation and analyzed for cortisol by radioimmunoassay (RIA). Eight of nine monkeys readily acquired the task, reliably providing adequate saliva samples for the assay. Salivary free cortisol levels were examined in these subjects under basal conditions and in response to two types of neuroendocrine challenge. Levels of salivary free cortisol showed relatively low intra‐ and interindividual variability, with mean individual morning levels ranging between 17.1 and 37.9 µg/dl. Squirrel monkeys demonstrated a consistent daily rhythm in salivary free cortisol ranging from a high of 27.4 ± 5.2 µg/dl (mean ± SEM) at 12 P.M. to a low of 7.5 ± 1.6 µg/dl at 6 P.M.. Intravenous (IV) challenges with 1 µg/kg ACTH, or 10 and 50 µg/kg CRF resulted in significant increases in salivary free cortisol. The described sampling technique provides a reliable and sensitive means for repeated measurement of HPA activity in unrestrained, awake squirrel monkeys. In addition, our findings illustrate several features of HPA system rhythmicity and reactivity using salivary cortisol instead of blood plasma or serum. Am. J. Primatol. 60:69–75, 2003. © 2003 Wiley‐Liss, Inc.
Mitochondrial uncoupling protein‐2 protects the immature brain from excitotoxic neuronal death
Authors: Sullivan Patrick G. , Dubé Celine , Dorenbos Kristina , Steward Oswald , Baram Tallie Z.
Published: May 2003

Excitotoxic cell death is the fundamental process responsible for many human neurodegenerative disorders, yet the basic mechanisms involved are not fully understood. Here, we exploited the fact that the immature brain is remarkably resistant to seizure‐induced excitotoxic cell death and examined the underlying protective mechanisms. We found that, unlike in the adult, seizures do not increase the formation of reactive oxygen species or result in mitochondrial dysfunction in neonatal brain, because of high levels of the mitochondrial uncoupling protein (UCP2). UCP2 expression and function were basally increased in neonatal brain by the fat‐rich diet of maternal milk, and substituting a low‐fat diet reduced UCP2, restored mitochondrial coupling, and permitted seizure‐induced neuronal injury. Thus, modulation of UCP2 expression and function by dietary fat protects neonatal neurons from excitotoxicity by preventing mitochondrial dysfunction. This mechanism offers novel neuroprotective strategies for individuals, greater than 1% of the world's population, who are affected by seizures. Ann Neurol 2003
Functional organization of the brain with malformations of cortical development
Authors: Janszky Jozsef , Ebner Alois , Kruse Bernd , Mertens Markus , Jokeit Hennric , Seitz Ruediger J. , Witte Otto W. , Tuxhorn Ingrid , Woermann Friedrich G.
Published: May 2003

We examined the localization of cerebral functions in 28 patients with focal epilepsy and malformations of cortical development (MCDs). Polymicrogyria occurred in nine, hemimegalencephaly in four, heterotopia in eight, and focal cortical dysplasia (FCD) in nine cases. We used simple (sensomotor, visual) or complex (language, memory) functional magnetic resonance imaging (fMRI) paradigms. Two thirds of MCDs were activated by simple fMRI paradigms, whereas they less frequently showed activity during complex cognitive fMRI paradigms. During simple paradigms, all disturbances of cortical organization (polymicrogyria, schizencephaly, and mild‐type FCD) showed activity, whereas other MCDs (disturbances of earlier steps of cortical development: hemimegalencephaly, Taylor‐type FCD, and heterotopia) showed activity in only 44% (p < 0.01). The association between the pathophysiology and morphology of MCDs confirms the recently proposed classification system. Both focal neurological signs (p < 0.05) and focal electroencephalogram slowing (p < 0.05) independently correlated with MCD inactivity, confirming that fMRI showed neuronal functions of MCDs. Conclusively, fMRI visualizes the MCD functions and their relationship to the eloquent cortex, providing useful information before epilepsy surgery. Surgery of cortical organization disturbances should be cautiously performed because these malformations may participate to some degree in brain functions. Ann Neurol 2003;53:759–767
Cortical anomalies associated with visuospatial processing deficits
Authors: Isaacs Elizabeth B. , Edmonds Caroline J. , Chong Wui K. , Lucas Alan , Gadian David G.
Published: May 2003

Children born preterm provide a fruitful population for studying structure–function relationships because they often have specific functional deficits in the context of normal neurological status. We selected a group of preterm adolescents with deficits in judgment of line orientation. Despite their very low birth weight, all were neurologically normal with no consistent abnormalities on conventional magnetic resonance imaging. However, voxel‐based morphometric analysis of their magnetic resonance imaging scans showed areas of decreased gray matter and increased white matter most prominently in right ventral extrastriate cortex, close to an area previously implicated in the line orientation task. We suggest that these anomalies of cortical architecture relate to impaired performance on the line orientation task. Ann Neurol 2003;53:768–773
Slowing of electroencephalogram in rapid eye movement sleep behavior disorder
Authors: Livia Fantini Maria , Gagnon Jean‐François , Petit Dominique , Rompré Sylvie , Décary Anne , Carrier Julie , Montplaisir Jacques
Published: May 2003

Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by a loss of atonia and an increase in phasic muscle activity during REM sleep, leading to complex nocturnal motor behaviors. Brainstem structures responsible for the pathogenesis of RBD are also implicated in cortical activation. To verify the hypothesis that electroencephalogram (EEG) activation will be impaired in RBD, we performed quantitative analyses of waking and REM sleep EEG in 15 idiopathic RBD patients and 15 age‐ and gender‐matched healthy subjects. During wakefulness, RBD patients showed a considerably higher θ power in frontal, temporal, and occipital regions with a lower β power in the occipital region. The dominant occipital frequency was significantly lower in RBD. During REM sleep, β power in the occipital region was lower in RBD. This study shows for the first time an impaired cortical activation during both wakefulness and REM sleep in idiopathic RBD, despite an absence of changes on sleep architecture compared with controls. EEG slowing in these patients may represent an early sign of central nervous system dysfunction, perhaps paralleled by subclinical cognitive deficits. The topographical distribution of EEG slowing and possible pathophysiological mechanisms are discussed in light of the known association between RBD and neurodegenerative disorders. Ann Neurol 2003;53:774–780
Toward therapy for DYT1 dystonia: Allele‐specific silencing of mutant TorsinA
Authors: Gonzalez‐Alegre Pedro , Miller Victor M. , Davidson Beverly L. , Paulson Henry L.
Published: May 2003

A three‐nucleotide (GAG) deletion in the TOR1A gene is the most common cause of inherited dystonia, DYT1. Because the mutant protein, TorsinA (TA), is thought to act in a dominant manner to cause disease, inhibiting expression from the mutant gene represents a potentially powerful therapeutic strategy. In an effort to develop therapy for this disease, we tested whether small interfering RNA (siRNA) could selectively silence expression of mutant TA. Exploiting the three–base pair difference between wild‐type and mutant alleles, we designed siRNAs to silence expression of mutant, wild‐type, or both forms of TA. In transfected cells, siRNA successfully suppressed wild‐type or mutant TA in an allele‐specific manner: for example, mutant‐specific siRNA reduced the levels of mutant TA to less than 1% of controls with minimal effect on wild‐type TA expression. In cells expressing both alleles, thus simulating the heterozygous state, siRNA‐mediated suppression remained robust and allele specific. Our siRNA studies demonstrate allele‐specific targeting of a dominant neurogenetic disease gene and suggest the broad therapeutic potential of siRNA for DYT1 dystonia and other dominantly inherited neurological diseases. Ann Neurol 2003;53:781–787
Validation of diagnostic magnetic resonance imaging criteria for multiple sclerosis and response to interferon β1a
Authors: Barkhof Frederik , Rocca Mara , Francis Gordon , van Waesberghe Jan‐Hein T. M. , Uitdehaag Bernard M. J. , Hommes Otto R. , Hartung Hans‐Peter , Durelli Luca , Edan Gilles , Fernández Oscar , Seeldrayers Pierette , Sørensen Per , Margrie Simon , Rovaris Marco , Comi Giancarlo , Filippi Massimo ,   for the Early Treatment of Multiple Sclerosis Study Group
Published: May 2003

In the recently proposed diagnostic criteria for multiple sclerosis (MS) by McDonald, the modified magnetic resonance imaging (MRI) Barkhof criteria have been incorporated. We examined the validity of this implementation in the Early Treatment of MS study, a randomized, double‐blind, placebo‐controlled study of 22μg interferon β1a given subcutaneously once weekly in 309 patients with a first episode consistent with demyelinating disease (and abnormal MRI). Conversion to clinically definite MS (CDMS) within 2 years of follow‐up, as evidenced by a new clinical episode, occurred in 41% of patients (independent of treatment) with gadolinium enhancement or nine or more T2 lesions versus 11% of those without either finding (p = 0.017); similarly, proportions converting were 44% versus 31% for infratentorial lesions (p = 0.026), 40% versus 35% for juxtacortical lesions (p = 0.413), and 41% versus 17% for three or more periventricular lesions (p = 0.034). The rate of conversion to CDMS based on the number of modified Barkhof criteria was 22% for two or fewer positive criteria, increasing to 47% with four positive criteria. For a cutoff of three positive criteria, the hazard ratio for time to CDMS was 2.3 (95% confidence interval, 1.17–4.55; p = 0.016). Treatment effect seemed more evident as the number of positive criteria increased, and the number of patients needed to avoid one patient converting to CDMS decreased from 50 in patients with one or two positive criteria to 5.6 in patients with four positive criteria. However, the study was not powered to detect statistically significant treatment by variable interaction, and this remains an important issue for further study.Ann Neurol 2003;53:718–724
Endothelial dysfunction precedes C‐fiber abnormalities in primary (AL) amyloidosis
Authors: Berghoff Martin , Kathpal Madeera , Khan Faisal , Skinner Martha , Falk Rodney , Freeman Roy
Published: May 2003

Primary (AL; immunoglobulin light‐chain associated) amyloidosis is characterized by the deposition of pathological proteins in the extracellular matrix of tissues and organs. Autonomic and sensory peripheral neuropathy is a common feature of this disorder. The pathogenesis of the neuropathy is poorly defined. The aims of this study were to investigate vascular and neural function in the cutaneous microcirculation of AL amyloidosis patients. Seven patients with AL amyloidosis and controls were studied. Acetylcholine and sodium nitroprusside were iontophoresed into the forearm skin. Endothelial, smooth muscle, and C‐fiber–mediated cutaneous blood flow (CuBF) were recorded by laser Doppler flowmetry. Endothelial vasodilation in the forearm skin was attenuated in AL amyloidosis patients (p = 0.007). Maximum endothelium‐mediated CuBF in the patient group was reduced (p = 0.047). No group differences could be detected in the C‐fiber response or smooth muscle vasodilation (p value not significant). Maximum C‐fiber and endothelium‐independent CuBF did not differ between the two groups (p value not significant). Early in the disease, AL amyloidosis patients present with impaired endothelial function. At this stage, C‐fiber and smooth muscle function are still preserved. These data suggest that endothelial abnormalities precede and may contribute to the pathogenesis of the neuropathy associated with AL amyloidosis. Ann Neurol 2003;53:725–730
Intracerebral hemorrhage induces macrophage activation and matrix metalloproteinases
Authors: Power Christopher , Henry Scot , Del Bigio Marc R. , Larsen Peter H. , Corbett Dale , Imai Yumi , Yong Voon Wee , Peeling James
Published: May 2003

Intracerebral hemorrhage (ICH) is characterized by parenchymal hematoma formation with surrounding inflammation. Matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of neurological diseases defined by inflammation and cell death. To investigate the expression profile and pathogenic aspects of MMPs in ICH, we examined MMP expression in vivo using a collagenase‐induced rat model of ICH. ICH increased brain MMP‐2, ‐3, ‐7, and ‐9 mRNA levels relative to sham‐injected (control) animals in the vicinity of the hematoma, but MMP‐12 (macrophage metalloelastase) was the most highly induced MMP (>80‐fold). Immunohistochemistry showed MMP‐12 to be localized in activated monocytoid cells surrounding the hematoma. In vitro studies showed that thrombin, released during ICH, induced MMP‐12 expression in monocytoid cells, which was reduced by minocycline application. Similarly, in vivo minocycline treatment significantly reduced MMP‐12 levels in brain. Neuropathological studies disclosed marked glial activation and apoptosis after ICH that was reduced by minocycline treatment. Neurobehavioral outcomes also were improved with minocycline treatment compared with untreated ICH controls. Thus, select MMPs exhibit increased expression after ICH, whereas minocycline is neuroprotective after ICH by suppressing monocytoid cell activation and downregulating MMP‐12 expression.Ann Neurol 2003;53:731–742
Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke
Authors: Chen Jieli , Zhang Zheng Gang , Li Yi , Wang Ying , Wang Lei , Jiang Hao , Zhang Chenling , Lu Mei , Katakowski Mark , Feldkamp Carolyn S. , Chopp Michael
Published: May 2003

We demonstrate that the 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme A (HMG‐CoA) reductase inhibitors atorvastatin and simvastatin enhance functional outcome and induce brain plasticity when administered after stroke to rats. With atorvastatin treatment initiated 1 day after stroke, animals exhibited significant increases in vascular endothelial growth factor, cyclic guanosine monophosphate, angiogenesis, endogenous cell proliferation and neurogenesis, and an increase in the synaptic protein, synaptophysin. Atorvastatin‐induced angiogenesis in a tube formation assay was reduced by an antibody against the vascular endothelial growth factor receptor 2 (FIK‐1) and by the nitric oxide synthase inhibitor, N‐mono‐methyl‐L‐arginine (L‐NAME). Atorvastatin also induced phosphorylation of Akt and Erk in cultured primary cortical neurons. These data indicate that atorvastatin induced brain plasticity and has neurorestorative activity after experimental stroke. Ann Neurol 2003
The spectrum of autoimmune autonomic neuropathies
Authors: Klein Caroline M. , Vernino Steven , Lennon Vanda A. , Sandroni Paola , Fealey Robert D. , Benrud‐Larson Lisa , Sletten David , Low Phillip A.
Published: May 2003

We analyzed the clinical characteristics of 18 patients (13 female, 5 male) who had autoimmune autonomic neuropathy (AAN) and ganglionic acetylcholine receptor (AChR) autoantibodies. Mean age was 61.4 years (standard deviation, 12.0 years). Ten patients had subacute symptom onset, six with an antecedent event. Eight patients had chronic AAN, characterized by insidious symptom onset, without antecedent event, and gradual progression. A majority of patients with high antibody values (>1.00 nmol/L) had a combination of sicca complex (marked dry eyes and dry mouth), abnormal pupillary light response, upper gastrointestinal symptoms, and neurogenic bladder. Chronic AAN segregated into two subgroups. One subgroup (N = 4) had low antibody titer (0.09 ± 0.01 nmol/L) and a paucity of cholinergic symptoms. It was indistinguishable from pure autonomic failure. The other subgroup (N = 4) had high antibody titer (11.6 ± 2.08 nmol/L), sicca complex, abnormal pupils, and neurogenic bladder; three had severe upper gastrointestinal dysfunction. Higher antibody titers correlated with greater autonomic dysfunction and more frequent cholinergic dysautonomia. These observations expand the clinical spectrum of AAN to include chronic cases, some being indistinguishable from pure autonomic failure, and support the concept that ganglionic AChR antibodies are important diagnostically and pathophysiologically in acquired dysautonomia.Ann Neurol 2003;53:752–758
Asymmetric flaccid paralysis: A neuromuscular presentation of West Nile virus infection
Authors: Li Jun , Loeb Jeffrey A. , Shy Michael E. , Shah Aashit K. , Tselis Alex C. , Kupski William J. , Lewis Richard A.
Published: May 2003

The neuromuscular aspects of West Nile virus (WNV) infection have not been characterized in detail. We have studied a group of six patients with proven WNV infection. All cases presented with acute, severe, asymmetric, or monolimb weakness, with minimal or no sensory disturbance after a mild flu‐like prodrome. Four cases also had facial weakness. Three of our cases had no encephalitic signs or symptoms despite cerebrospinal fluid pleocytosis. Electrophysiological studies showed severe denervation in paralyzed limb muscles, suggesting either motor neuron or multiple ventral nerve root damage. This localization is supported further by the finding of abnormal signal intensity confined to the anterior horns on a lumbar spine magnetic resonance imaging. Muscle biopsies from three patients showed scattered necrotic fibers, implicating mild direct or indirect muscle damage from the WNV infection. In summary, we describe a group of patients with acute segmental flaccid paralysis with minimal or no encephalitic or sensory signs. We have localized the abnormality to either the spinal motor neurons or their ventral nerve roots. It will be important for physicians to consider WNV infection in patients with acute asymmetric paralysis with or without encephalitic symptoms. Ann Neurol 2003;53:703–710
Altered hippocampal muscarinic receptors in acetylcholinesterase‐deficient mice
Authors: Volpicelli‐Daley Laura A. , Duysen Ellen G. , Lockridge Oksana , Levey Allan I.
Published: May 2003

A primary therapeutic strategy for Alzheimer's disease includes acetylcholinesterase (AChE) inhibitors with the goal of enhancing cholinergic transmission. Stimulation of muscarinic acetylcholine receptors (mAChRs) by elevated levels of ACh plays a role in the effects of AChE inhibitors on cognition and behavior. However, AChE inhibitors only demonstrate modest symptomatic improvements. Chronic treatment with these drugs may cause mAChR downregulation and consequently limit the treatment efficacy. AChE knockout (−/−) mice were utilized in this study as a model for investigating the effects of selective, complete, and chronic diminished AChE activity on mAChR expression and function. In AChE −/− mice, the M1, M2, and M4 mAChRs showed strikingly 50 to 80% decreased expression in brain regions associated with memory. In addition, mAChRs showed decreased presynaptic, cell surface, and dendritic distributions and increased localization to intracellular puncta. Furthermore, mAChR agonist–induced activation of extracellular signal–regulated kinase, a signaling pathway associated with synaptic plasticity and amyloidogenesis, is diminished in the hippocampus and cortex of AChE −/− mice. Therefore, chronic diminished ACh metabolism produces profound effects on mAChR expression and function. The alterations of mAChRs in AChE −/− mice suggest that mAChR downregulation may contribute to the limited efficacy of AChE inhibitors in Alzheimer's disease treatment. Ann Neurol 2003;53:788–796
Effect of ultrasound on thrombolysis of middle cerebral artery occlusion
Authors: Eggers Jürgen , Koch Björn , Meyer Karsten , König Inke , Seidel Günter
Published: May 2003

We studied the effect of transcranial 2MHz Doppler ultrasound (US) on the recanalization and outcome of stroke patients suffering from acute middle cerebral artery occlusion. All patients underwent intravenous recombinant tissue‐type plasminogen activator thrombolysis. Eleven patients were randomly selected for continuous US monitoring (C‐US) over 1 hour; 14 patients were selected for the control group. The C‐US group showed a higher grade of recanalization after 1 hour but also a higher number of intraparenchymal bleedings. Overall, a favorable functional outcome occurred more frequently in the C‐US group (Barthel index, p = 0.037) after 3 months. Ann Neurol 2003;53:797–800