bluuebunny/crossref_metadata_2025 huggingface dataset:
What does my patient's coronary artery calcium score mean? Combining information from the coronary artery calcium score with information from conventional risk factors to estimate coronary heart disease risk
Authors: Pletcher Mark J , Tice Jeffrey A , Pignone Michael , McCulloch Charles , Callister Tracy Q , Browner Warren S
Published: August 2004

Background

The coronary artery calcium (CAC) score is an independent predictor of coronary heart disease. We sought to combine information from the CAC score with information from conventional cardiac risk factors to produce post-test risk estimates, and to determine whether the score may add clinically useful information.

Methods

We measured the independent cross-sectional associations between conventional cardiac risk factors and the CAC score among asymptomatic persons referred for non-contrast electron beam computed tomography. Using the resulting multivariable models and published CAC score-specific relative risk estimates, we estimated post-test coronary heart disease risk in a number of different scenarios.

Results

Among 9341 asymptomatic study participants (age 35–88 years, 40% female), we found that conventional coronary heart disease risk factors including age, male sex, self-reported hypertension, diabetes and high cholesterol were independent predictors of the CAC score, and we used the resulting multivariable models for predicting post-test risk in a variety of scenarios. Our models predicted, for example, that a 60-year-old non-smoking non-diabetic women with hypertension and high cholesterol would have a 47% chance of having a CAC score of zero, reducing her 10-year risk estimate from 15% (per Framingham) to 6–9%; if her score were over 100, however (a 17% chance), her risk estimate would be markedly higher (25–51% in 10 years). In low risk scenarios, the CAC score is very likely to be zero or low, and unlikely to change management.

Conclusion

Combining information from the CAC score with information from conventional risk factors can change assessment of coronary heart disease risk to an extent that may be clinically important, especially when the pre-test 10-year risk estimate is intermediate. The attached spreadsheet makes these calculations easy.
Continuous Time Discounted Jump Markov Decision Processes: A Discrete-Event Approach
Authors: Feinberg Eugene A.
Published: August 2004

This paper introduces and develops a new approach to the theory of continuous time jump Markov decision processes (CTJMDP). This approach reduces discounted CTJMDPs to discounted semi-Markov decision processes (SMDPs) and eventually to discrete-time Markov decision processes (MDPs). The reduction is based on the equivalence of strategies that change actions between jumps and the randomized strategies that change actions only at jump epochs. This holds both for one-criterion problems and for multiple-objective problems with constraints. In particular, this paper introduces the theory for multiple-objective problems with expected total discounted rewards and constraints. If a problem is feasible, there exist three types of optimal policies: (i) nonrandomized switching stationary policies, (ii) randomized stationary policies for the CTJMDP, and (iii) randomized stationary policies for the corresponding SMDP with exponentially distributed sojourn times, and these policies can be implemented as randomized strategies in the CTJMDP.
Regulation of inflammatory responses by activated protein C: the molecular mechanism(s) and therapeutic implications
Authors: Okajima Kenji
Published: August 2004

Activated protein C (APC), a natural anticoagulant, is formed from protein C by the action of the thrombinthrombomodulin (TM) complex on the endothelial cell surface. Endothelial protein C receptor augments the activation of protein C by the thrombin/TM system. APC inactivates the activated form of coagulation factors V and VIII in the presence of protein S. Administration of APC reduced the pulmonary vascular injury and hypotension as well as the coagulation abnormalities by inhibiting production of the tumor necrosis factor-α (TNF-α) in rats given endotoxin (ET). These therapeutic effects of APC could not be attributed to its anticoagulant effects. APC inhibited ET-induced TNF-α production in human monocytes by inhibiting activation of nuclear factor k-B and activator protein-1 in vitro. Administration of the human plasma-derived APC ameliorated coagulation abnormalities without any adverse effects in patients with disseminated intravascular coagulation (DIC). Recombinant APC was reported to reduce the mortality of patients with severe sepsis, and the therapeutic effect was more marked in such patients with overt DIC than those without it.

These observations strongly suggest that APC plays important roles in the regulation of inflammation as well as coagulation. Both anti-inflammatory and anticoagulant properties of APC might contribute to the therapeutic usefulness in patients with severe sepsis.
Autoantibodies against oxidized low-density lipoprotein (ox-LDL) and LDL oxidation status
Authors: Brizzi Patrizia , Tonolo Giancarlo , Bertrand Graziano , Carusillo Francesca , Severino Cristiana , Maioli Mario , Malaguarnera Lucia , Musumeci Salvatore
Published: August 2004

Oxidized low-density lipoproteins (ox-LDLs) and their autoantibodies (OLAB) are involved in the development of atherosclerosis in animal models, but their role in humans is still not clear. For this reason we studied 54 patients with β-thalassemia major (TM), as a model of chronically low circulating LDLs with a high level of oxidation; 44 patients with primary hypercholesterolemia, as model of chronically high circulating LDLs; 24 type 2 diabetic mellitus patients (T2DM) before and after 3 months of atorvastatin treatment (20 mg/day), as a model of acute changes in circulating LDLs; and 41 normolipidemic subjects as a control group. ox-LDLs were measured by the determination of baseline diene concentration in the plasma LDL lipidic fraction after 12 hours fasting and were expressed as the amount of conjugated dienes/liter (BDC/l) or BDC/LDL-cholesterol (LDL-C), which indicate respectively LDL oxidation degree and status. OLABwere determined using an enzyme immunoassay and related to LDL oxidation degree (BDC/l). In TM, BDC/l was lower, while BDC/LDL-C was significantly higher, compared to both hypercholesterolemia and normolipidemic subjects. Patients with hypercholesterolemia had higher BDC/l, but lower BDC/LDL-C and OLAB/BDC-l, than normolipidemic subjects. In T2DM patients at diet, BDC/LDL-C and OLAB/BDC-l were lower than in normolipidemic subjects. After 3 months of atorvastatin treatment, BDC/LDL-C and OLAB/BDC-l ratios increased. When all patients were evaluated together, a significant inverse correlation was evident between OLABand either LDL or BDC/l. Our findings suggest that a relationship between OLABtiter and oxidation indices (BDC/l and BDC/LDL-C) does exist and we may speculate that an increase in OLAB/BDC-l ratio might be protective against the risk of atherosclerosis.
Environmental dichlorodiphenyltrichlorethane or hexachlorobenzene exposure and breast cancer: is there a risk?
Authors: Charlier Corinne , Foidart Jean-Michel , Pitance François , Herman Philippe , Gaspard Ulysse , Meurisse Michel , Plomteux Guy
Published: August 2004

The carcinogenic potential of environmental xenoestrogens (i.e., organochlorines) is a matter of controversy. Their pathogenic role as promoters in breast cancer has been previously suggested. In Europe, despite their prohibition since the ’70s, residues persist in soil and rivers resulting in a widespread contamination of the general population. In this study, we have compared the serum levels of p,p'-1,1-dichloro-2, 2-bis (4-chlorophenyl) ethylene (DDE) and hexachlorobenzene (HCB) in 231 women at the time of breast cancer discovery and in 290 age-matched healthy controls. p,p'-DDE was found in 76.2% of cases and in 71.1% of controls but HCB was present only in 12.6% of cases (29 from 231) and in 8.9% of controls (26 from 290). Even if taking all undetectable results (recorded as “0”) into consideration, mean values were significantly different in cases when compared to controls. The serum level of p,p'-DDE was 3.46±3.48 ppb (0.58±0.58 μg/g lipid) in patients and 1.85±2.09 ppb (0.31±0.35 μg/g lipid) in controls (p<0.0001). The HCB serum level was 0.66±1.25 ppb (0.11±0.21 μg/g lipid) in patients and 0.20±1.02 ppb (0.03±0.17 μg/g lipid) in controls (p<0.0001). When considering p,p'-DDE and HCB as binary variables (1 if higher than the limit of quantification, 0 if lower), the presence of both residues was significantly associated with an increased risk of breast cancer development (OR 2.21, 95% CI 1.41–3.48 for p,p'-DDE and OR 4.99, 95% CI 2.95–8.43 for HCB). No excess was observed among parous women or when familial history of breast cancer was considered. In the cancer group, no differences in serum levels of p,p'-DDE or HCB were found in relation with estrogen-receptor (ER) status, Bloom stage or lymph node metastasis, but the HCB level was moderately correlated with tumor size (p=0.026).
Analytical performance and method comparison study of the total homocysteine fluorescence polarization immunoassay (FPIA) on the AxSYM analyzer
Authors: Lonati Silvia , Novembrino Cristina , Ippolito Silvia , Accinni Roberto , Galli Claudio , Troonen Hugo , Campolo Jonica , Noce Cinzia Della , Lunghi Giovanna , Catena Fabrizia Bamonti
Published: August 2004

A fluorescence polarization immunoassay (FPIA) has been commercially released for routine large-scale testing of total homocysteine (tHcy) on the AxSYM analyzer. We evaluated the analytical performance of the AxSYM tHcy FPIA and compared it with the well established high-performance liquid chromatography (HPLC) and IMx tHcy FPIA methods. Homocysteine concentrations were measured by AxSYM and IMx tHcy FPIA and by a rapid isocratic HPLC method with fluorescence detection. Coefficient of variation (CV) of total imprecision for AxSYM tHcy was ≤5%, mean dilution recovery 102%, analytical sensitivity 0.70 μmol/l and linearity was good up to 1:8 dilution. Spearman rank correlations, rho, were 0.83 (p<0.0001) for AxSYM vs. HPLC, 0.97 (p<0.0001) for AxSYM vs. IMx and 0.83 (p <0.0001) for IMx vs. HPLC. Passing and Bablok regression Y-intercepts and slopes were: 2.944/0.937 (AxSYM vs. HPLC), −0.367/1.142 (AxSYM vs. IMx) and 2.632/0.805 (IMx vs. HPLC). Corresponding mean differences (AxSYM-Comparison Assay) recorded over a 5–50 μmol/l measured range were 1.80, −0.73 and 2.53 μmol/l. AxSYM tHcy FPIA's first rate precision, supported by the complete automation of the AxSYM analyzer, makes it fit for routine use and suitable for laboratories requiring homocysteine high-throughput testing capabilities.
Intravenous immunoglobulin (IVIG): modes of action in the clinical management of recurrent pregnancy loss (RPL) and selected autoimmune disorders
Authors: Omwandho Charles O. A. , Gruessner Susanne E. M. , Roberts Timothy K. , Tinneberg Hans Rudolf
Published: August 2004

Recurrent pregnancy loss has been associated with autoimmune responses to membrane phospholipids and alloimmune reactions against paternally derived molecules on the trophoblast. The problem is psychologically and economically stressful as it undermines the capacity of some couples to reproduce and participate effectively in the day-to-day economic activities. This article reviews the adoption of intravenous immunoglobulin as a form of therapy for the clinical management of recurrent pregnancy loss and of selected autoimmune disorders. Side effects, contraindications and safety of use are discussed.
Abnormalities in apolipoprotein and lipid levels in an HIV-infected Brazilian population under different treatment profiles: the relevance of apolipoprotein E genotypes and immunological status
Authors: Malavazi Iran , Abrão Emiliana P. , Mikawa Angela Y. , Landgraf Viviane O. , Costa Paulo I. da
Published: August 2004

HIV infection is associated with disturbances in lipid metabolism due to a host's response mechanism and the current antiretroviral therapy. The pathological appearance and progression of atherosclerosis is dependent on the presence of injurious agents in the vascular endothelium and variations in different subsets of candidate genes. Therefore, the
Amphetamines and 3,4-methylendioxymetamphetamine (MDMA): evaluation of KIMS (kinetic interaction of microparticles in solution) assay at two cut-off levels
Authors: Marchioro Lucio , Bassetto Flavia , Dall'Olio Giuliano , Tedeschi Luciano , Castagna Franca , Plebani Mario
Published: August 2004

Two screening methods for the assay of amphetamines and their derivatives have been applied to the same analytical instrument for their evaluation. In addition to an assay at a cut-off of 1000 μg/l, a new specific reagent was evaluated for an ultra-sensitive assay of amphetamines and 3,4-methylendioxyme-tamphetamine with a cut-off of 300 μg/l. The assay confirmation was performed using high-performance liquid chromatography and gas chromatography/mass spectrometry techniques. The results were positive for both screening methods, confirming the efficacy of two simultaneous methods with different cut-off levels.
Emergency department triage of patients with acute chest pain: definition of cardiac troponin I decisional value to manage patients without electrocardiographic evidence of ischemia
Authors: Beyne Pascale , Bouvier Erik , Werner Patrick , Bourgoin Pierre , Logeart Damien , Alliot Laurent , Daïkha Habiba , Vidaud Michel
Published: August 2004

The aim of this study was to define the use of a new cardiac troponin I (cTnI) assay for emergency patients with chest pain and no specific electrocardiographic changes consistent with the presence of ischemia. Patients (n=106) admitted in Emergency/Cardiology Departments for chest pain and suspicion of acute coronary syndrome (ACS) were randomized into two diagnosis groups (ACS or non-ACS) by two independent cardiologists. cTnI measurements were performed at admission, and 6 hours and 12 hours later with a new generation assay (Access AccuTnI, Beckman Coulter). Using an upper reference limit of 0.04 μg/l, 27 patients had a cTnI elevation not related to the final diagnosis of ischemia; the positive predictive value (PPV) was 67% with specificity 48%. The decisional value was re-defined and set at 0.16 μg/l, a concentration corresponding to the 99th percentile of the non-ACS patient group. Precision (coefficient of variation) was 8% at this level, PPV 97% and specificity 98%. This new decisional value is now used in our institution and could be included in standard care guidelines to improve the management of patients presenting chest pain in emergency departments.
Quality indicators and specifications for the extra-analytical phases in clinical laboratory management
Authors: Ricós Carmen , García-Victoria Montserrat , Fuente Blanca de la
Published: August 2004

Examples of indicators and specifications for the post-analytical process:
Normality: the unreachable star?
Authors: Petitclerc Claude
Published: August 2004

The concept of reference values is widely accepted, but their application has been quite lax over the years. This is due primarily to the difficulty of properly selecting and documenting samples from a reference population. In the absence of a clear description of reference individuals, reference values lose their meaning, are ambiguous at best, and are often confused with decision limits. The clinical medicine perspective of reference values is to rule out diseases and to define health, while that of preventive medicine is to appreciate the state of health. Defining reference limits and normality in this context is a great challenge. Advances in the fields of genomics and proteomics and the rapid pace of technological advances help highlight the biological diversity among individuals. However, there is a great need for reference values that are representative of healthy humans and presented in a manner that they can be utilized by all laboratories. In addition, as secure information technology becomes available, the goal of using an individual as their own reference during a lifetime is now possible, provided that consistency of databases is ensured.
The IFCC recommendation on estimation of reference intervals. The RefVal Program
Authors: Solberg Helge Erik
Published: August 2004

The International Federation of Clinical Chemistry (IFCC) published between 1987–91 a series of six recommendations on reference values in laboratory medicine. This paper reviews the history and scope of the fifth part of these recommendations. This fifth recommendation deals with statistical methods used for analysis of reference values and estimation of reference intervals. The RefVal program, which implements the recommended method, is also described.
Parametric methods for estimating covariate-dependent reference limits
Authors: Virtanen Arja , Kairisto Veli , Uusipaikka Esa
Published: August 2004

Age-specific reference limits are required for many clinical laboratory measurements. Statistical assessment of calculated intervals must be performed to obtain reliable reference limits. When parametric, covariate-dependent limits are derived, normal distribution theory usually is applied due to its mathematical simplicity and relative ease of fitting. However, it is not always possible to transform data and achieve a normal distribution. Therefore, models other than those based on normal distribution theory are needed. Generalized linear model theory offers one such alternative. Regardless of the statistical model used, the assumptions behind the model should always be examined.
Reference regions of two or more dimensions
Authors: Boyd James C.
Published: August 2004

Despite being proposed over 30 years ago, the multivariate reference region (MRR) remains an interpretive tool with uncertain value in clinical practice. This paper reviews the mathematical theory of the MRR, presents topics in the clinical application of MRRs, and examines the advantages and disadvantages of MRRs. Finally, some thoughts are offered regarding future directions for work in this field.
Guideline for the production of multicentre physiological reference values using the same measurement system. A proposal of the Catalan Association for Clinical Laboratory Sciences
Authors: Fuentes-Arderiu Xavier , Mas-Serra Roser , Alumà-Trullàs Alba , Martí-Marcet Maria Isabel , Dot-Bach Dolors
Published: August 2004

This article is intended as a guide for the production of biological reference values of healthy people (physiological reference values) by several clinical laboratories using the same measurement system. This guide is a proposal from the Catalan Association of Clinical Laboratory Sciences to be applied worldwide at a regional level. This guide makes it possible for all clinical laboratories in a region using the same measurement system to adopt the same physiological reference limits. The model presented here is based on the assumption that the production of physiological reference values is a professional task that should be shared by both clinical laboratories and the in vitro diagnostics industry.
Reference intervals for plasma proteins: similarities and differences between adult Caucasian and Asian Indian males in Yorkshire, UK
Authors: Johnson A. Myron , Petersen Per Hyltoft , Whicher John T. , Carlström Anders , MacLennan Sheila
Published: August 2004

The aim of this study was to investigate similarities and differences in the distribution of serum concentrations of nine proteins in two racial groups (Caucasian and Asian Indian) of adult males living in the same geographical area (Leeds, Bradford, UK) for at least two generations. This is part of a larger study to determine the need for separating reference intervals for racial and ethnic groups worldwide. The distributions of concentrations for all proteins evaluated in the Indians fit ln-Gaussian distributions, indicating probable homogeneity. However, for the Caucasians, the distributions for α
Diagnostic and epidemiological implications of regional differences in serum concentrations of proteins observed in six Asian cities
Authors: Ichihara Kiyoshi , Itoh Yoshihisa , Min Won-Ki , Yap Sook Fan , Lam Christopher W. K. , Kong Xian Tao , Chou Chiung-Tei , Nakamura Haruo
Published: August 2004

The IFCC Committee on Plasma Proteins has been investigating regional differences for commonly assayed plasma proteins to determine whether universal reference intervals can be applied. As a part of this study, we launched an Asian project analyzing the concentrations of 13 serum proteins whose values are standardized to CRM470, and five newer analytes: retinol-binding protein (RBP), cystatin C (CysC), lightchain-κ (L-κ), and light-chain-λ (L-λ). In Tokyo, Seoul, Kuala Lumpur, Hong Kong, Taipei and Shanghai, serum samples were collected from 146 to 415 apparently healthy individuals with nearly equal gender ratios. All assays were performed in Tokyo on a Behring Nephelometer II (BN II). Seven chemical analytes (aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyltransferase (γGT), creatinine, total cholesterol (TC), triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C)) were also measured. These results were used for excluding individuals with possible latent clinical disorders.

Positive acute phase reactants were consistently lower, and negative ones were higher, in Tokyo than those in other cities. The most conspicuous difference was observed in C-reactive protein (CRP). There were no regional differences in transferrin, albumin, or CysC. Creatinine was much lower in Tokyo despite comparable CysC levels. ALT and γGT were higher in Shanghai, Taipei and Seoul; γGT and TG were higher in Shanghai; and HDL-C was higher in Tokyo.

Gender-related differences in reference intervals were observed for immunoglobulin (Ig)M, haptoglobin, RBP, transferrin, α

Environmental factors and lifestyle seem to have a great influence on many commonly measured analytes.
Establishment of a serum thyroid stimulating hormone (TSH) reference interval in healthy adults. The importance of environmental factors, including thyroid antibodies
Authors: Jensen Esther , Petersen Per Hyltoft , Blaabjerg Ole , Hansen Pia Skov , Brix Thomas H. , Kyvik Kirsten Ohm , Hegedüs Laszlo
Published: August 2004

It has previously been shown that thyroid antibodies affect thyroid stimulating hormone (TSH) concentrations in men and women and that TSH levels are predictive of future thyroid disease. We investigated the validity of the National Academy of Clinical Biochemistry (NACB) guidelines regarding the TSH reference interval by studying 1512 individuals. Two hundred and fifty had at least one thyroid antibody, 121 were taking medications other than estrogens and occasional analgesics, and 105 reported a family history of thyroid disease. Serum TSH, thyroid peroxidase antibodies (TPOab) and thyroglobulin antibodies (Tgab) were determined on AutoDELFIA and TSHRab by a radioreceptor assay (RRA) from Brahms Diagnostica.

For individuals without thyroid antibodies and other risk factors, no effect of age and gender was seen for serum TSH. Neither medication nor the presence of Tgab alone had any influence on serum TSH. TPOab alone or in combination with Tgab were associated with an increased serum TSH level.

The ‘cumulative percentage distributions’ of subgroups, as well as the combined population, was ln-Gaussian distributed. The central 95% of the population was within the 95% CI in rankit-plots. Consequently, a common reference interval for serum TSH of 0.58–4.07 mIU/l for all adults between 17 and 66 years of age was established. This reference interval is much higher than expected from the NACB-guidelines.
Gunshot Residue Particle Velocity and Deceleration
Authors: De Forest PR , Martir K , Pizzola PA
Published: August 2004

The velocity of over 800 gunshot residue particles from eight different sources was determined using high speed stroboscopic photography (spark gap light source). These particles were found to have an average velocity of 500 to 600 ft per second. Many particles acquired considerably higher velocities. Thus, the particles have sufficient energy to embed themselves within certain nearby targets like skin or fabric. The relatively high velocity that the particles acquire explain the formation of stippling on skin in close proximity to a muzzle discharge. These findings also indicate little influence of air currents on particle behavior near the muzzle. The deceleration of less than 100 particles during a 100-microsecond interval was also calculated. The particles experienced rapid rates of deceleration which would explain why few particles are found in test firings beyond 3 ft from the muzzle of a discharged firearm. Because of their relatively high velocity, normal wind velocity would not be expected to significantly influence their motion near the muzzle.
Genetic Data of Two STR Loci D4S2367, D20S601 in Chinese Population
Authors: Zhou XP , Bai P , Zhang WJ , Jia ZJ , Wu J , Li YB , Hou YP
Published: August 2004

Healthy unrelated individuals from Chinese Han ethnic group in Chengdu, Sichuan of China.
Oxycodone Intoxication in an Infant: Accidental or Intentional Exposure?
Authors: Levine B , Moore KA , Aronica-Pollak P , Fowler DF
Published: August 2004

A case is presented of a 10 month old male who went into cardiac arrest at a local store. The infant subsequently expired and was autopsied at the Office of the Chief Medical Examiner, State of Maryland. The only remarkable finding was the detection of oxycodone in the postmortem specimens; the blood and liver oxycodone concentrations were 0.6 mg/L and 1.6 mg/kg, respectively. Oxycodone was identified and quantitated by gas chromatography-nitrogen-phosphorus detection and confirmed by full scan electron ionization gas chromatography-mass spectrometry. The medical examiner ruled that the cause of death was oxycodone intoxication, and the manner of death was homicide. The key toxicologic question in this case was whether or not it was reasonable for the infant to be exposed to oxycodone exclusively through breast milk or through an alternate source. It was concluded that, at best, there were serious concerns about the likelihood of drug exposure through consumption of breast milk.
A Neuronal Isoform of Protein Kinase G Couples Mitogen-Activated Protein Kinase Nuclear Import to Axotomy-Induced Long-Term Hyperexcitability inAplysiaSensory Neurons
Authors: Sung Ying-Ju , Walters Edgar T. , Ambron Richard T.
Published: August 2004

The induction of a long-term hyperexcitability (LTH) in vertebrate nociceptive sensory neurons (SNs) after nerve injury is an important contributor to neuropathic pain in humans, but the signaling cascades that induce this LTH have not been identified. In particular, it is not known how injuring an axon far from the cell soma elicits changes in gene expression in the nucleus that underlie LTH. The nociceptive SNs ofAplysia(ap) develop an LTH with electrophysiological properties after axotomy similar to those of mammalian neurons and are an experimentally useful model to examine these issues. We cloned anAplysiaPKG (cGMP-dependent protein kinase; protein kinase G) that is homologous to vertebrate type-I PKGs and found that apPKG is activated at the site of injury in the axon after peripheral nerve crush. The active apPKG is subsequently retrogradely transported to the somata of the SNs, but apPKG activity does not appear in other neurons whose axons are injured. In the soma, apPKG phosphorylates apMAPK (Aplysiamitogen-activated protein kinase), resulting in its entry into the nucleus. Surprisingly, studies using recombinant proteinsin vivoandin vitroindicate that apPKG directly phosphorylates the threonine moiety in the T-E-Y activation site of apMAPK when the -Y- site contains a phosphate. We used inhibitors of nitric oxide synthase, soluble guanyl cyclase, or PKG after nerve injury, and found that each prevented the appearance of the LTH. Moreover, blocking apPKG activation prevented the nuclear import of apMAPK. Consequently, the nitric oxide-PKG-MAPK pathway is a potential target for treatment of neuropathic pain.
Substance P-Mediated Modulation of Pacemaker Properties in the Mammalian Respiratory Network
Authors: Peña Fernando , Ramirez Jan-Marino
Published: August 2004

Neuromodulators are integral parts of a neuronal network, and unraveling how these substances alter neuronal activity is critical for understanding how networks generate patterned activity and, ultimately, behavior. In this study, we examined the cellular mechanisms underlying the excitatory action of substance P (SP) on the respiratory network isolated in spontaneously active transverse slice preparation of mice. SP produced a slow depolarization in all recorded inspiratory pacemaker and non-pacemaker neurons. Ion exchange experiments and blockers for different ion channels suggest that the slow depolarization is caused by the activation of a low-threshold TTX-insensitive cationic current that carries mostly Na+. The SP-induced slow depolarization increased tonic discharge in non-pacemaker neurons and primarily enhanced the frequency of bursting in Cd2+-insensitive pacemaker neurons. In the Cd2+-sensitive pacemaker neuron, the burst frequency was not significantly affected, whereas burst duration and amplitude were more enhanced than in Cd2+-insensitive pacemaker neurons. In a subset of non-pacemaker neurons that produced NMDA-dependent subthreshold oscillations, SP caused the production of bursts of action potentials. We conclude that the degree of pacemaker activity in the respiratory network is not fixed but dynamically regulated by neuromodulators such as SP. This finding may have clinical implications for Rett syndrome in which SP levels along with other neuromodulators are decreased in the brainstem.
Viral-Induced Spinal Motor Neuron Death Is Non-Cell-Autonomous and Involves Glutamate Excitotoxicity
Authors: Darman Jessica , Backovic Stephanie , Dike Sonny , Maragakis Nicholas J. , Krishnan Chitra , Rothstein Jeffrey D. , Irani David N. , Kerr Douglas A.
Published: August 2004

Neuroadapted Sindbis virus (NSV) is a neurotropic virus capable of inducing the death of spinal motor neurons in mice and rats. In this study we investigated the mechanisms that underlie NSV-induced motor neuron death. We found that many degenerating spinal motor neurons were not infected directly with NSV, suggesting that bystander cell death occurs. An excitotoxic mechanism was confirmed when blockade of calcium-permeable AMPA receptors attenuated motor neuron death bothin vitroandin vivo. Blockade of astroglial glutamate reuptake potentiated NSV-induced motor neuron lossin vivo, suggesting that astrocyte-mediated removal of perisynaptic glutamate is important in limiting NSV-induced excitotoxic injury. Astroglial glutamate transport was reduced markedly in the spinal cord during NSV infection, in advance of motor neuron injury in susceptible mice. In contrast, we found 5.6-fold elevated glutamate uptake in the spinal cords of mice resistant to NSV-induced paralysis. Likewise, minocycline markedly increased spinal cord glutamate transport and protected mice from NSV-induced motor neuron death. These studies suggest that NSV infection triggers a cascade of events in the spinal cord resulting in impaired astrocytic glutamate transport and excitotoxic injury of motor neurons mediated via calciumpermeable AMPA receptors. Similar changes may occur in other motor neuron disorders such as amyotrophic lateral sclerosis or West Nile Virus-induced poliomyelitis, suggesting a common tissue injury pathway.
Insulin-like growth factors-I and -II and insulin-like growth factor-binding protein-2 in dominant equine follicles during spring transition and the ovulatory season
Authors: Watson E D , Bae S-E , Thomassen R , Thomson S R M , Woad K , Armstrong D G
Published: August 2004

The period between seasonal anoestrus and cyclicity is characterized in many mares by cyclical growth and regression of large dominant follicles. The insulin-like growth factor (IGF) system plays a key role in follicular growth and regression; therefore, we hypothesized that changes in the IGF system and its binding proteins would modulate onset of cyclicity in mares. Ovaries were obtained from pony mares on the day after detection of an actively growing 30 mm transitional anovulatory follicle, and also at the second or third oestrus of the breeding season on the day after the preovulatory follicle reached 30 mm in diameter. Size of dominant follicles at the time of removal was similar in transition (32 ± 0.8 mm) and at oestrus (34 ± 0.6 mm). IGF-I mRNA was present in granulosa cells, with low thecal expression, whereas IGF-II mRNA was confined to the theca layer. Expression of IGF-I and -II mRNAs, and intrafollicular concentrations of oestradiol, were lower (P < 0.01; paired t test) in transitional anovulatory follicles than in preovulatory follicles. Messenger RNA encoding IGFBP-2 was present in both theca and granulosa layers. Steady-state concentrations of mRNA encoding IGFBP-2 mRNA increased (P < 0.001) in theca in preovulatory follicles. Intrafollicular concentrations of IGFBP-2 were higher (P < 0.001) in transitional than in preovulatory follicles. The similarity in circulating concentrations of IGF-I in transitional and cyclic mares, suggested that the somatotrophic axis is not involved in transition from anovulatory to ovulatory cycles. The results suggest that the increased expression of IGF-I and -II mRNAs in preovulatory follicles, along with the decrease in IGFBP-2 concentrations, could increase the bioavailability of intrafollicular IGF in large follicles during the breeding season, and support our hypothesis that intrafollicular IGF bioavailability must exceed a threshold level before ovulation can occur.
Effects of embryo culture on global pattern of gene expression in preimplantation mouse embryos
Authors: Rinaudo Paolo , Schultz Richard M
Published: August 2004

Culture of preimplantation embryos affects gene expression. The magnitude of the effect on the global pattern of gene expression, however, is not known. We compared global patterns of gene expression in blastocysts cultured from the one-cell stage in either Whitten’s medium or KSOM + amino acids (KSOM/AA) with that of blastocysts that developedin vivo, using the Affymetrix MOE430A chip. The analysis revealed that expression of 114 genes was affected after culture in Whitten’s medium, whereas only 29 genes were mis-expressed after culture in KSOM/AA. Expression Analysis Systematic Explorer was used to identify biological and molecular processes that are perturbed after culture and indicated that genes involved in protein synthesis, cell proliferation and transporter function were down-regulated after culture in Whitten’s medium. A common set of genes involved in transporter function was also down-regulated after culture in KSOM/AA. These results provide insights as to why embryos develop better in KSOM/AA than in Whitten’s medium, and highlight the power of microarray analysis to assess global patterns of gene expression.
Paramoebiasis Associated with Mass Mortality of American Lobster Homarus americanus in Long Island Sound, USA
Authors: Mullen Thomas E. , Russell Spencer , Tucker Meghan T. , Maratea Jennifer L. , Koerting Claudia , Hinckley Lynn , De Guise Sylvain , Frasca Salvatore , French Richard A. , Burrage Thomas G. , Perkins Christopher
Published: August 2004

In the autumn of 1999, a mass mortality of American lobster Homarus americanus was reported by lobster fishermen from western Long Island Sound (LIS). At the conclusion of the 1999 season, dead lobsters were estimated at 11 million, resulting in a 90– 99% reduction of landings in western LIS and failure of the natural lobster fishery. Fishermen described moribund lobsters that were “limp,” interpreted clinically as paretic or flaccidly paralyzed. Necropsies were performed on dead or dying limp lobsters, and tissue samples were collected for histopathological, ultrastructural, microbiological, and toxicological analysis. Microbiological cultures of hemolymph and hepatopancreas failed to isolate a bacterium or group of bacteria in any significant frequency or pattern. Toxicological analyses of hepatopancreas and skeletal muscle did not identify significant amounts of trace elements, polycyclic aromatic hydrocarbons, polychlorinated biphenyl congeners, or pesticides. Microscopic analyses of hemocoelomic viscera and nervous tissues revealed a protozoan parasite in foci of hemocytic infiltration of nerves, in cytoplasm of neurons, and between nerve fibers without attendant hemocytic infiltrates as well as in micronodular aggregates of hemocytes in the subcuticular interstitium and tegumental glands. Histologic and ultrastructural features of this parasite were characteristic of protozoa of the genus Paramoeba (Schaudinn, 1896), and contact transmission experiments involving lobsters from uninfected, geographically distant sites and infected lobsters from western LIS resulted in transmission of paramoebiasis. This report represents the first description of a proximate cause of lobster mortality from the 1999 epizootic, along with additional evidence supporting the assertion that this parasitic paramoeba may be the primary cause of the 1999 lobster mass mortality.
Effects of Supplemental Amino Acid-Chelated Trace Elements on the Immune Response of Rainbow Trout Subjected to Bacterial Challenge
Authors: Apines-Amar M. J. S. , Satoh S. , Kiron V. , Watanabe T.
Published: August 2004

This study examined whether supplemental amino acid-chelated trace elements were effective in improving disease resistance in rainbow trout Oncorhynchus mykiss. Four semipurified diets containing trace elements from either sulfates or an amino acid chelate source were fed to the fish for 18 weeks. Subsequently, fish weighing about 20–40 g were challenged with β-hemolytic Streptococcus sp. The cumulative mortality was less in the chelate-supplemented groups but not significantly different from that of the sulfate groups. Antibody titer was significantly higher in the chelate-fed fish. Lysozyme activity and total immunoglobulin content were slightly more enhanced in the chelate-fed than in the sulfate-fed groups. Despite the increased antibody production, no distinct improvement in disease resistance against Streptococcus sp. was achieved by supplementing rainbow trout diets with amino acid-chelated trace elements. Further confirmatory studies focusing on the amounts of the trace elements used are needed to shed light on the influence of amino acid chelates on disease resistance.
Detection of Flavobacterium psychrophilum in Eggs and Sexual Fluids of Pacific Salmonids by a Polymerase Chain Reaction Assay: Implications for Vertical Transmission of Bacterial Coldwater Disease
Authors: Taylor Peter W.
Published: August 2004

Ovarian fluid and eggs were collected from returning salmonid species during normal spawning operations and examined for the presence of Flavobacterium psychrophilum, the causative agent of bacterial coldwater disease (BCWD). A nested polymerase chain reaction assay (PCR) that targets the 16S rRNA gene of F. psychrophilum was used for detection of the pathogen. Samples from coho salmon Oncorhynchus kisutch, chum salmon O. keta, Chinook salmon O. tshawytscha, and steelhead O. mykiss were taken from four fish culture facilities in the Pacific Northwest. Ovarian fluids were pelleted by centrifugation, and yolk material from within the eggs was aseptically removed and prepared for testing by PCR. Flavobacterium psychrophilum was detected in ovarian fluids and unfertilized eggs from species sampled at all facilities. This confirmed the use of PCR as a valid assay for the detection of F. psychrophilum in returning salmonid broodstock of all species tested. More importantly, PCR confirmed the presence of the pathogen within egg contents, not just in the surrounding fluids or on the egg surface.
Prevalence of Walleye Discrete Epidermal Hyperplasia by Age-Class in Walleyes from Oneida Lake, New York
Authors: Getchell R. G. , Wooster G. A. , Rudstam L. G. , Van DeValk A. J. , Brooking T. E. , Bowser P. R.
Published: August 2004

The prevalence of visible proliferative lesions was followed on walleyes Sander vitreus at ages 3 to more than 8 years from 1997 to 2003 in Oneida Lake, New York. Walleye discrete epidermal hyperplasia, the focus of this report, is a seasonally limited skin disease caused by two closely related retroviruses, walleye epidermal hyperplasia virus type 1 and type 2. As with walleye dermal sarcoma, the in-lake transmission patterns of this disease are unknown. The percent of fish developing walleye epidermal hyperplasia lesions increased incrementally with age in this study. It is unlikely that all walleyes of a given year-class will contract discrete epidermal hyperplasia in their lifetimes because fewer than 20% of the fish age 8 and older were affected. In contrast, the prevalence of walleye dermal sarcoma, a disease we believe eventually affects almost all exposed walleyes, changes with age, decreasing after age 6, which suggests that walleyes develop resistance to that disease.
History of the Development of Arsenic Derivatives in Cancer Therapy
Authors: Waxman Samuel , Anderson Kenneth C.
Published: August 2004

Arsenic is a natural substance that has been used medicinally for over 2,400 years. In the 19th century, it was the mainstay of the materia medica. A solution of potassium arsenite (Fowler's solution) was used for a variety of systemic illnesses from the 18th until the 20th century. This multipurpose solution was also primary therapy for the treatment of chronic myelogenous leukemia until replaced by radiation and cytotoxic chemotherapy. The past 100 years have seen a precipitous decline in arsenic use and, by the mid-1990s, the only recognized indication was the treatment of trypanosomiasis. Much of this decline was due to concerns about the toxicity and potential carcinogenicity of chronic arsenic administration. The rebirth of arsenic therapy occurred in the 1970s when physicians in China began using arsenic trioxide as part of a treatment for acute promyelocytic leukemia (APL). Their accumulated experience showed that a stable solution of arsenic trioxide given by intravenous infusion was remarkably safe and effective both in patients with newly diagnosed APL leukemia and in those with refractory and relapsed APL. The mechanisms of action of arsenic derivatives in this disease and other malignancies are many and include induction of apoptosis, partial cytodifferentiation, inhibition of proliferation, and inhibition of angiogenesis. Molecular studies and ongoing clinical trials suggest that, as a chemotherapeutic agent, arsenic trioxide shows great promise in the treatment of malignant disease.
Taxane/Anthracycline Combinations: Setting a New Standard in Breast Cancer?
Authors: Nabholtz Jean-Marc , Riva Alessandro
Published: August 2004

Among the novel chemotherapeutic drugs introduced in the 1990s, the taxanes have emerged as the most powerful compounds in breast cancer. Both compounds, paclitaxel and docetaxel, have been evaluated in metastatic settings before adjuvant trials proceeded. Docetaxel was shown in several phase III trials to be superior, particularly in terms of survival, for salvaging polychemotherapies after failure of prior chemotherapy, including that with anthracyclines. A benefit of docetaxel was also reported when compared with doxorubicin after failure of alkylating agents. In phase III trials paclitaxel was reported to be as efficacious over 24 hours as doxorubicin 60 mg/m2, while paclitaxel was significantly inferior to doxorubicin 75 mg/m2 over 3 hours and was close to CMF in another trial. The role of taxanes in combination with anthracyclines in first-line therapy of advanced breast cancer is emerging. Following several phase II studies, a phase III trial showed the significant superiority of docetaxel/doxorubicin (AT) versus doxorubicin/cyclophosphamide (AC) in terms of response and time to progression. In several phase II studies with paclitaxel (3 hours), anthracyclines in the metastatic setting showed high efficacy but produced cardiac toxicity related to a pharmacokinetic interaction between the two agents. This finding led to the implementation of metastatic strategies (phase III trials) aimed at avoiding the pharmacokinetic interaction, while the adjuvant strategies with paclitaxel focused primarily on the sequential approach (AC followed by paclitaxel). In contrast, adjuvant strategies with docetaxel/anthracycline-based programs were implemented following both sequential and combination approaches.
Vision of the Future: Capecitabine
Authors: Twelves Chris
Published: August 2004

Capecitabine is a thymidine phosphorylase (TP)-activated oral fluoropyrimidine, rationally designed to generate 5-fluorouracil (5-FU) preferentially within tumors. This tumor selectivity is achieved through exploitation of the significantly higher activity of TP in tumor compared with healthy tissue. The high single-agent activity of capecitabine in breast and colorectal cancer suggests that capecitabine may have a role in the treatment of other tumor types that are sensitive to 5-FU, such as pancreatic cancer. Tumor types known to have a high level of TP activity, such as renal cancer, are especially attractive targets for capecitabine therapy. Capecitabine has potential as monotherapy in these tumor types, or as a combination partner for other cytotoxic agents with different mechanisms of action and little overlap of key toxicities. In particular, some cytotoxic drugs, such as the taxanes and cyclophosphamide, are known to upregulate TP activity in tumor tissue, offering the potential for synergistic action. The combination of capecitabine and docetaxel has demonstrated significant activity in women with anthracycline-pretreated breast cancer, and is the only cytotoxic combination to significantly increase survival compared with standard therapy in this setting. In addition, capecitabine as monotherapy or in combination with other cytotoxic agents has shown encouraging activity in pancreatic, ovarian, and renal cell cancers. This article discusses recent data from clinical trials investigating capecitabine in a range of tumor types, highlighting the potential future role of capecitabine as an alternative to traditional i.v. chemotherapy.
A Staff Dialogue on Caring for an Intensely Spiritual Patient: Psychosocial Issues Faced By Patients, Their Families, and Caregivers
Authors: Lintz Kathleen C. , Penson Richard T. , Chabner Bruce A. , Lynch Thomas J.
Published: August 2004

The Schwartz Center Rounds are a monthly multidisciplinary forum, at Massachusetts General Hospital (MGH), in which caregivers discuss a specific patient with cancer and the important psychosocial issues faced by the patient, family, and caregivers. This forum allows caregivers to reflect on their experiences with patients and to gain support and insight from their fellow staff members.

The following case discussion was addressed at the September 1997 Schwartz Center Rounds. M.R. was a 45-year-old woman who developed ovarian carcinoma and was subsequently treated at MGH. She was a deeply religious woman and believed that God would cure her cancer. Her religious views profoundly influenced her decisions related to further care and her ability to accept what staff felt to be a realistic assessment of her condition and progress. At the rounds, staff members struggled with many issues, including whether M.R. should continue her treatment at MGH or return home to Puerto Rico. Staff found it challenging to discuss a sensitive topic—such as spirituality—with a patient, especially when the patient was from a different cultural background. One of the most striking outcomes of the rounds was the diversity of staff views regarding how they advocated addressing spirituality with a patient. Staff concluded that discussion of spirituality—while challenging—can meaningfully enhance the caregiver-patient relationship.