bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative analysis of protein coding sequences from human, mouse and the domesticated pig
Authors: Jørgensen Frank Grønlund , Hobolth Asger , Hornshøj Henrik , Bendixen Christian , Fredholm Merete , Schierup Mikkel Heide
Published: January 2005

Background

The availability of abundant sequence data from key model organisms has made large scale studies of molecular evolution an exciting possibility. Here we use full length cDNA alignments comprising more than 700,000 nucleotides from human, mouse, pig and the Japanese pufferfish Fugu rubrices in order to investigate 1) the relationships between three major lineages of mammals: rodents, artiodactyls and primates, and 2) the rate of evolution and the occurrence of positive Darwinian selection using codon based models of sequence evolution.

Results

We provide evidence that the evolutionary splits among primates, rodents and artiodactyls happened shortly after each other, with most gene trees favouring a topology with rodents as outgroup to primates and artiodactyls. Using an unrooted topology of the three mammalian species we show that since their diversification, the pig and mouse lineages have on average experienced 1.44 and 2.86 times as many synonymous substitutions as humans, respectively, whereas the rates of non-synonymous substitutions are more similar. The analysis shows the highest average dN/dS ratio in the human lineage, followed by the pig and then the mouse lineages. Using codon based models we detect signals of positive Darwinian selection in approximately 5.3%, 4.9% and 6.0% of the genes on the human, pig and mouse lineages respectively. Approximately 16.8% of all the genes studied here are not currently annotated as functional genes in humans. Our analyses indicate that a large fraction of these genes may have lost their function quite recently or may still be functional genes in some or all of the three mammalian species.

Conclusions

We present a comparative analysis of protein coding genes from three major mammalian lineages. Our study demonstrates the usefulness of codon-based likelihood models in detecting selection and it illustrates the value of sequencing organisms at different phylogenetic distances for comparative studies.
Defective CD4+CD25+regulatory T cell functioning in collagen-induced arthritis: an important factor in pathogenesis, counter-regulated by endogenous IFN-γ
Authors: Kelchtermans Hilde , De Klerck Bert , Mitera Tania , Van Balen Maarten , Bullens Dominique , Billiau Alfons , Leclercq Georges , Matthys Patrick
Published: January 2005

Mice with a deficiency in IFN-γ or IFN-γ receptor (IFN-γR) are more susceptible to collagen-induced arthritis (CIA), an experimental autoimmune disease that relies on the use of complete Freund's adjuvant (CFA). Here we report that the heightened susceptibility of IFN-γR knock-out (KO) mice is associated with a functional impairment of CD4+CD25+ Treg cells. Treatment of wild-type mice with depleting anti-CD25 antibody after CFA-assisted immunisation with collagen type II (CII) significantly accelerated the onset of arthritis and increased the severity of CIA. This is an indication of a role of Treg cells in the effector phase of CIA. IFN-γR deficiency did not affect the number of CD4+CD25+ T cells in the central and peripheral lymphoid tissues. In addition, CD4+CD25+ T cells isolated from naive IFN-γR KO mice had a normal potential to suppress T cell proliferation in vitro. However, after immunisation with CII in CFA, the suppressive activity of CD4+CD25+ T cells became significantly more impaired in IFN-γR-deficient mice. Moreover, expression of the mRNA for Foxp3, a highly specific marker for Treg cells, was lower. We further demonstrated that the effect of endogenous IFN-γ, which accounts for more suppressive activity in wild-type mice, concerns both Treg cells and accessory cells. Our results demonstrate that the decrease in Treg cell activity in CIA is counter-regulated by endogenous IFN-γ.
Clonogenic growth of human breast cancer cells co-cultured in direct contact with serum-activated fibroblasts
Authors: Samoszuk Michael , Tan Jenny , Chorn Guillaume
Published: January 2005

Introduction

Accumulating evidence suggests that fibroblasts play a pivotal role in promoting the growth of breast cancer cells. The objective of the present study was to characterize and validate an in vitro model of the interaction between small numbers of human breast cancer cells and human fibroblasts.

Methods

We measured the clonogenic growth of small numbers of human breast cancer cells co-cultured in direct contact with serum-activated, normal human fibroblasts. Using DNA microarrays, we also characterized the gene expression profile of the serum-activated fibroblasts. In order to validate the in vivo relevance of our experiments, we then analyzed clinical samples of metastatic breast cancer for the presence of myofibroblasts expressing α-smooth muscle actin.

Results

Clonogenic growth of human breast cancer cells obtained directly from in situ and invasive tumors was dramatically and consistently enhanced when the tumor cells were co-cultured in direct contact with serum-activated fibroblasts. This effect was abolished when the cells were co-cultured in transwells separated by permeable inserts. The fibroblasts in our experimental model exhibited a gene expression signature characteristic of 'serum response' (i.e. myofibroblasts). Immunostaining of human samples of metastatic breast cancer tissue confirmed that myofibroblasts are in direct contact with breast cancer cells.

Conclusion

Serum-activated fibroblasts promote the clonogenic growth of human breast cancer cells in vitro through a mechanism that involves direct physical contact between the cells. This model shares many important molecular and phenotypic similarities with the fibroblasts that are naturally found in breast cancers.
Preferred analysis methods for Affymetrix GeneChips revealed by a wholly defined control dataset
Authors: Choe Sung E , Boutros Michael , Michelson Alan M , Church George M , Halfon Marc S
Published: January 2005

Background

As more methods are developed to analyze RNA-profiling data, assessing their performance using control datasets becomes increasingly important.

Results

We present a 'spike-in' experiment for Affymetrix GeneChips that provides a defined dataset of 3,860 RNA species, which we use to evaluate analysis options for identifying differentially expressed genes. The experimental design incorporates two novel features. First, to obtain accurate estimates of false-positive and false-negative rates, 100-200 RNAs are spiked in at each fold-change level of interest, ranging from 1.2 to 4-fold. Second, instead of using an uncharacterized background RNA sample, a set of 2,551 RNA species is used as the constant (1x) set, allowing us to know whether any given probe set is truly present or absent. Application of a large number of analysis methods to this dataset reveals clear variation in their ability to identify differentially expressed genes. False-negative and false-positive rates are minimized when the following options are chosen: subtracting nonspecific signal from the PM probe intensities; performing an intensity-dependent normalization at the probe set level; and incorporating a signal intensity-dependent standard deviation in the test statistic.

Conclusions

A best-route combination of analysis methods is presented that allows detection of approximately 70% of true positives before reaching a 10% false-discovery rate. We highlight areas in need of improvement, including better estimate of false-discovery rates and decreased false-negative rates.
Subjective cognitive complaints relate to mild impairment of cognition in multiple sclerosis
Authors: Marrie Ruth Ann , Chelune Gordon J , Miller Deborah M , Cohen Jeffrey A
Published: January 2005

Cognitive impairment is common in multiple sclerosis (MS), but cannot be reliably predicted by physical impairment. The negative impact of cognitive impairment makes early detection important, but subjective cognitive complaints may be attributed to depression. We examined the relationship between subjectively reported and objectively measured cognitive impairment in MS, adjusting for mood. A neuropsychological battery, the Multiple Sclerosis Functional Composite (MSFC), the Mental Health Inventory (MHI), the Modified Fatigue Impact Scale (MFIS), the Perceived Deficits Questionnaire (PDQ) were administered to 136 patients. Demographically-adjusted cognitive scores were calculated. Subjective impairment was defined as PDQ score-2 standard deviations above that for healthy persons. We modeled the relationship of cognitive scores (independent variables) to being subjectively impaired (dependent variable) using logistic regression. Immediate Memory (IM) and Processing Speed Index (PSI) scores were non-linearly related to subjective impairment. Patients were less likely to report subjective impairment if their PSI was normal (OR-0.11; 0.02-0.73) or markedly impaired (OR-0.17; 0.03-0.91), compared to mildly reduced PSI. In young patients decreases in IM were associated with increased subjective impairment (OR-1.25; 1.07-1.47). Subjectively reported impairment reflects subtle declines in PSI and IM independent of mood, fatigue, and physical impairment. Cognitive complaints should not be discounted due to depression.
Multiple sclerosis and nutrition
Authors: Schwarz Stefan , Leweling Hans
Published: January 2005

Benefits from any particular diet in multiple sclerosis (MS) have not yet been proven. It is, however, frequent that malnutrition may potentially exacerbate the symptoms of MS. There is some evidence that a high intake of saturated fat increases the incidence of MS. Epidemiological studies imply that unsaturated fatty acids may have a positive effect on the course of MS. However, the results of controlled studies are ambiguous. A meta-analysis of three small controlled clinical trials suggests a benefit from linoleic acid. Intake of Vitamin D is associated with a lower incidence of MS. In MS, the risk of osteoporosis is high, and prophylactic vitamin D and calcium should be considered at an early stage. The role of minerals, trace elements, antioxidants, vitamins or fish oil is unclear. The possible relationships between diet and MS have not been subjected to adequate study. It seems possible that in the future, diets or dietary supplements may become recommended forms of treatment for MS.
Serum levels of insulin-like growth factor-1 and insulin-like growth factor binding protein-3 in relapsing and primary progressive multiple sclerosis
Authors: Wilczak N , Ramsaransing G SM , Mostert J , Chesik D , De Keyser J
Published: January 2005

Using radioimmunoassay we measured serum levels of insulin-like growth factor (IGF)-1 and IGF binding protein (IGFBP)-3 in patients with relapsing multiple sclerosis (MS) and a benign course (Expanded Disability Status Scale (EDSS)≤ 3 despite > 10 years disease duration), relapsing MS with cumulative disability leading to an EDSS score > 4 within 10 years of disease duration, primary progressive MS and healthy controls. We found no differences in IGF-1 and IGFBP-3 serum levels, and the IGF-1/IGFBP-3 ratio between the four groups. However, there was a significant correlation (P=0.005) between IGFBP-3 serum levels and both the progression index of disability and the Multiple Sclerosis Severity Score in patients with primary progressive MS.
The Paced Auditory Serial Addition Test: to what extent is it performed as instructed, and is it associated with disease course?
Authors: Coo H , Hopman W M , Edgar C M , McBride E V , Brunet D G
Published: January 2005

One commonly used outcome measure in multiple sclerosis (MS) clinical trials is the Multiple Sclerosis Functional Composite, which includes the Paced Auditory Serial Addition Test (PASAT) as a measure of cognitive function. Concerns have been raised about the standard PASAT scoring method, whereby the number of correct responses is summed. This method does not take into account whether the test is performed as intended, which may affect interpretation of the results. Accordingly, another scoring method has been proposed, which examines the number of times a correct response is immediately preceded by another correct response (termed a dyad). We compared the two scoring methods for the PASAT, and found that the mean percentage of correct responses not accounted for by dyads ranged from 27.5% to 49.5%, indicating that much of the time the test is not performed as instructed. We also examined disease course and the PASAT score, as studies have produced conflicting results as to whether disease course is associated with cognitive impairment. Although disease course was significantly associated with the PASAT score, it accounted for little of the variation in scores, even when adjusting for other predictors. Finally, as 14.2% of participants refused to do the PASATor failed to complete it, we also examined whether the Perceived Deficits Questionnaire (PDQ), a self-reported measure of cognitive function, is a potential proxy measure for the PASAT. The correlation between the two tools was low (-0.14), suggesting that the PDQ is not a useful substitute for the PASAT.
Altered cytokine responses to cognitive stress in multiple sclerosis patients with fatigue
Authors: Heesen Christoph , Koehler Gabriele , Gross Rüdiger , Tessmer Wiebke , Schulz Karl-Heinz , Gold Stefan M
Published: January 2005

This study intended to examine if the immune response to a cognitive task as a variant of psychological stress in MS patients is distinct from healthy controls. The experiment was part of a larger study on mechanisms and measurements of MS fatigue. Patients (n=23) and controls (n=25) participated in a cognitive task lasting 40 minutes, in which the heart rate was continuously monitored. Blood samples were taken at baseline and directly after the stress-inducing task. Whole blood stimulated cytokine production representative of the TH-1 (i.e. IFNγ, TNFα) and TH-2 paradigm (i.e. IL-10) was evaluated in relation to disability, fatigue, cognitive deficit, and anxiety. Patients scored high on a disease specific fatigue score compared to controls, whereas baseline cytokine patterns did not differ between the groups. MS patients displayed a blunted response of IFNg (P=0.03) whereas TNFα and IL-10 responses did not change. Additionally MS patients showed a significantly lower heart rate increase after the task (P<0.001). Cognitive impairment was associated with a decreased heart rate reactivity (P=0.02) while depressive symptoms correlated with stronger IL-10 responses (P=0.05). Overall, cognitive stress induces IFNγ production in healthy controls but not in MS patients with fatigue. Furthermore, a reduced cardiac response might indicate an autonomic dysfunction in this group of patients.
Stopping beta-interferon therapy in multiple sclerosis: an analysis of stopping patterns
Authors: O'Rourke K ET , Hutchinson M
Published: January 2005

Estimates of the beta-interferon (IFNB) stopping rate in relapsing-remitting multiple sclerosis (RRMS) and secondary progressive MS (SPMS) vary and have been mainly derived from multicentre studies. This is a retrospective, hospital chart-based study of 394 patients treated by a single neurologist for up to eight years. The aims of the study were to ascertain the frequency and timing of IFNβ discontinuation in a well supported cohort, and to investigate whether the clinical disease type at the initiation of IFNβ or the reason for discontinuation influenced stopping rates. The median follow-up was 49 months. The overall IFNβ stopping rate was 28% over five years; there was a significant difference between the IFNβ stopping rates for RRMS (14%) and SPMS (23%) after three years of follow-up (P=0.0003). Patients stopped IFNβ due to side effects after a median of 13 months, and due to failure of therapy after a median of 35 months (P=0.0004). Significantly more patients with SPMS than with RRMS stopped IFNβ due to treatment failure (P=0.037). Conclusion: IFNβ discontinuation occurred earlier in the treatment course when due to side effects. Stopping IFNβ therapy was more common in SPMS and was more often due to treatment failure than side effects.
Multiple sclerosis diagnostic criteria: three years later
Authors: Polman Chris H , Wolinsky Jerry S , Reingold Stephen C
Published: January 2005

New diagnostic criteria for multiple sclerosis (MS) were developed by an International Panel in 2001 and have had wide distribution and discussion since publication. These provided the first formal incorporation of magnetic resonance imaging (MRI) in a diagnosis work-up for patients suspected of having MS. The so-called McDonald criteria have been studied in retrospective and prospective analyses for sensitivity, specificity and utility, and have been proven to compare favourably or to be an improvement upon prior MS diagnostic criteria. The purpose of the current review is to present and evaluate the key studies that have been performed using the McDonald criteria since 2001 and to set the stage for an upcoming re-evaluation of the new criteria based on data-driven information gathered since their development.
Branch vessel complications are increased in aortic dissection patients with renal insufficiency
Authors: Beckman Joshua A , Mehta Rajendra H , Isselbacher Eric M , Bossone Eduardo , Cooper Jeanna V , Smith Dean E , Fang Jianming , Sechtem Udo , Pape Linda A , Myrmel Truls , Nienaber Christoph A , Eagle Kim A , O'Gara Patrick T
Published: January 2005

Morbidity and mortality from aortic dissection remain high despite advances in diagnosis and treatment. Simple markers to identify patients at high risk for non-aortic complications of dissection are lacking. We investigated the effect of renal insufficiency on the presentation, complications, and outcome of patients with acute aortic dissection. We evaluated 638 patients with type A and 365 patients with type B aortic dissection enrolled in the International Registry of Acute Aortic Dissection (IRAD) between January 1996 and December 2000. Chi-squared and Student’s t testing were performed to identify the effect of renal insufficiency on patient presentation, management, and outcome. Patients with renal insufficiency more often required nitroprusside for blood pressure control (type A: 40.7% vs 31.1%, p 1/4-0.049; type B: 66.7% vs 37.3, p 1/4-0.0001) and had a greater risk of mesenteric ischemia (type A: 10.7% vs 1.4%, p < 0.0001; type B: 17.7% vs 3.0%, p < 0.0001). In conclusion, aortic dissection patients with renal insufficiency are at increased risk for drug-resistant hypertension and aortic branch vessel compromise. Routine measurement of serum creatinine provides a readily accessible clinical marker for important complications. Upon recognition, renal impairment indicates a need for close monitoring, aggressive blood pressure control, and evaluation of aortic branch vessel circulations.
The effect of inhibition of acyl coenzyme A-cholesterol acyltransferase (ACAT) on exercise performance in patients with peripheral arterial disease
Authors: Hiatt William R , Klepack Ellen , Nehler Mark , Regensteiner Judith G , Blue John , Imus James , Criqui Michael H
Published: January 2005

This study tested the hypothesis that avasimibe, an inhibitor of acyl coenzyme A-cholesterol acyltransferase (ACAT), would improve treadmill exercise performance in patients with claudication secondary to peripheral arterial disease (PAD). Four hundred and forty-two patients with PAD (ankle brachial index in the index leg of≤0.90 with a ≥20% reduction post-exercise) were enrolled from 39 centers in the USA. Patients were randomized to receive oral avasimibe 50 mg, 250 mg, 750 mg or placebo for a treatment period of 12 months. Changes from baseline in peak walking time (PWT) using a graded treadmill protocol were compared among groups after 6 and 12 months of treatment. Individual group comparisons were considered statistically significant if p< 0.0245 for the 50 mg and 250 mg groups and p< 0.001 for the 750 mg group. Patients randomized to the 50 mg group experienced a 0.76 min net increase over placebo in PWT, but this did not reach the pre-specified level of statistical significance (Hochberg procedure p=0.027) using ANCOVA after 12 months of treatment after adjusting for multiple comparisons. This trend in PWT was supported by the changes in treadmill initial claudication time (ICT) (p=0.026) and Walking Impairment Questionnaire (WIQ) walking distance score (p=0.058). The 250 mg and 750 mg avasimibe dose groups failed to demonstrate an improvement in PWT over placebo after 6 months of treatment. In conclusion, while the ACAT inhibitor avasimibe did not show clear evidence of benefit on treadmill exercise performance in patients with PAD, the results add to our knowledge of the impact of treatments directed at atherosclerosis on functional endpoints.
Cost-effectiveness of exercise training to improve claudication symptoms in patients with peripheral arterial disease
Authors: Treesak Charoen , Kasemsup Vijj , Treat-Jacobson Diane , Nyman John A , Hirsch Alan T
Published: January 2005

Exercise rehabilitation is a proven, yet poorly available, treatment for intermittent claudication, the primary symptom of peripheral arterial disease (PAD). Exercise rehabilitation is effective, non-invasive, and associated with minimal cardiovascular risk in appropriate patients. Percutaneous transluminal angioplasty (PTA), especially of the iliac segment, is an alternative effective treatment for claudication. There are, however, minimal data currently available to compare the cost-effectiveness of these two interventions. We compared the cost-effectiveness of 3- and 6-month exercise programs with that of iliac PTA without stenting, using the incremental cost-effectiveness ratio [ICER 1/4 (Cost2 Cost1)=(Effectiveness2 Effectiveness1)]. The ICER represented the price of an additional meter walked derived from each treatment based on conservative models of success of each procedure and specific care assumptions. PTA and exercise efficacy data were derived from a literature review and exercise costs were modeled per the current CPT code 93668. Effectiveness was defined as absolute claudication distance (ACD) at 3 and 6 months. Three treatment alternatives were assessed: (1) no treatment, (2) PTA, and (3) exercise rehabilitation. At 3 months, PTA was more effective than exercise therapy and resulted in an additional 38 meters at an additional cost of $6719, for an ICER of $177=meter. At 6 months, however, exercise was more effective than PTA, resulting in an additional 137 meters walked, and costs less ($61 less per meter gained). In conclusion, exercise rehabilitation at 6 months is more effective and costs less than PTA, and is therefore cost-saving. The cost-effectiveness and availability of claudication treatments has national implications for future PAD care; however, data to inform these care choices can best be obtained in prospective clinical trials.
Targeting Amyloid‐Degrading Enzymes as Therapeutic Strategies in Neurodegeneration
Authors: TURNER ANTHONY J. , FISK LILIA , NALIVAEVA NATALIA N.
Published: January 2005

Abstract:The levels of amyloid β‐peptides (Aβ) in the brain represent a dynamic equilibrium state as a result of their biosynthesis from the amyloid precursor protein (APP) by β‐ and γ‐secretases, their degradation by a team of amyloid‐degrading enzymes, their subsequent oligomerization, and deposition into senile plaques. While most therapeutic attention has focused on developing inhibitors of secretases to prevent Aβ formation, enhancing the rate of Aβ degradation represents an alternative and viable strategy. Current evidence bothin vivoandin vitrosuggests that there are three major players in amyloid turnover: neprilysin, endothelin converting enzyme(s), and insulin‐degrading enzyme, all of which are zinc metallopeptidases. Other proteases have also been implicated in amyloid metabolism, including angiotensin‐converting enzyme, and plasmin but for these the evidence is less compelling. Neprilysin and endothelin converting enzyme(s) are homologous membrane proteins of the M13 peptidase family, which normally play roles in the biosynthesis and/or metabolism of regulatory peptides. Insulin‐degrading enzyme is structurally and mechanistically distinct. The regional, cellular, and subcellular localizations of these enzymes differ, providing an efficient and diverse mechanism for protecting the brain against the normal accumulation of toxic Aβ peptides. Reduction in expression levels of some of these proteases following insults (e.g., hypoxia and ischemia) or aging might predispose to the development of Alzheimer's disease. Conversely, enhancement of their levels by gene delivery or pharmacological means could be neuroprotective. Even a relatively small enhancement of Aβ metabolism could slow the inexorable progression of the disease. The relative merits of targeting these enzymes for the treatment of Alzheimer's disease will be reviewed and possible side‐effects of enhancing their activity evaluated.
NSAID and Antioxidant Prevention of Alzheimer's Disease: Lessons from In Vitro and Animal Models
Authors: COLE GREG M. , MORIHARA TAKASHI , LIM GISELLE P. , YANG FUSHENG , BEGUM AYNUN , FRAUTSCHY SALLY A.
Published: January 2005

Abstract: Both oxidative damage and inflammation are elevated in brains of Alzheimer's disease (AD) patients, but their pathogenic significance remains unclear. The reduced AD risk associated with high intake of both nonsteroidal anti‐inflammatory drugs (NSAIDs) and antioxidants suggests causal roles, but clinical trials in AD patients have yielded only limited or negative results. To test the potential efficacy and mechanisms of candidate approaches, we have explored conventional and unconventional NSAIDs, antioxidants, and combined NSAID/antioxidants in cell culture and animal models for AD (including aging APPsw transgenic mice and soluble Aβ rodent infusion models). The conventional NSAID ibuprofen has the strongest epidemiological support. At sustainable doses designed to mimic protective consumption in the epidemiology, ibuprofen reduces amyloid accumulation but suppresses a surprisingly limited subset of inflammatory markers in APPsw transgenic mice. Both Ab production (APP, β‐ and γ‐secretases) and post‐production pathways (those affecting Aβ aggregation or clearance: e.g., IL‐1 or α1ACT) are potentially involved in ibuprofen and other NSAID anti‐AD activities. The post‐production pathways are predictably shared with other seemingly protective NSAIDs, including naproxen that do not lower Aβ42 in vitro. Using clinically feasible dosing, brain levels of NSAIDs appear too low to implicate a number of pharmacological dose targets that have been demonstrated in vitro. Ibuprofen did not suppress microglial markers related to phagocytosis. The putative anti‐inflammatory omega‐3 fatty acid DHA had a profound impact on pathogenesis but did not lower inflammation, while vitamin E was surprisingly ineffective in reducing oxidative damage or amyloid in the aged APPsw mouse. In contrast, the unconventional NSAID/antioxidant curcumin was effective, lowering oxidative damage, cognitive deficits, synaptic marker loss, and amyloid deposition. Curcumin proved to be immunomodulatory, simultaneously inhibiting cytokine and microglial activation indices related to neurotoxicity, but increasing an index of phagocytosis. Curcumin directly targeted Aβ and was also effective in other models, warranting further preclinical and clinical exploration.
Inflammation, Neurodegenerative Diseases, and Environmental Exposures
Authors: CAMPBELL AREZOO
Published: January 2005

Abstract: The etiology of neurodegenerative disorders is multifactorial and consists of an interaction between aging, environmental factors, and genetic predisposition. Neuronal cell loss in specific regions of the central nervous system and the resulting clinical symptoms are used to characterize different neurological syndromes. While the selectivity of neuronal cell death is not clearly understood, it is in part attributed to the physiological role and microenvironment of the impacted cells. In this review, innate immune responses in the central nervous system are described. Chronic upregulation of this pathway, orchestrated mainly by microglial cells, may jeopardize neuronal integrity through the prolonged production of toxic inflammatory mediators. Environmental exposures that further enhance the innate immune response may accelerate microglia‐driven neurodegeneration. Environmental factors that can trigger inflammatory events in the central nervous system are lipopolysaccharide, aluminum, and particulate matter present in air pollution. These factors may enhance existing age‐related inflammation in the central nervous system and thus accelerate neuronal toxicity.
Vaccinia Virus Complement Control Protein Reduces Inflammation and Improves Spinal Cord Integrity Following Spinal Cord Injury
Authors: REYNOLDS DAVID N. , SMITH SCOTT A. , ZHANG YI P. , MENGSHENG QIU , LAHIRI DEBOMOY K. , MORASSUTTI DANTE J. , SHIELDS CHRISTOPHER B. , KOTWAL GIRISH J.
Published: January 2005

Abstract: Traumatic spinal cord injury (SCI) claims approximately 10,000 new victims each year in the United States alone. The injury usually strikes those under the age of 30 years, often leading to a lifetime of pain, suffering, and disability. Therapeutic agents targeting spinal cord injury are sorely lacking, and therefore our laboratory endeavored to evaluate the potential therapeutic benefits of immediate post‐injury administration of the vaccinia virus complement control protein (VCP). VCP is a multifunctional anti‐inflammatory protein that can inhibit both pathways of complement activation and bind heparin. Utilizing a common animal model of contusion SCI, motor function recovery tests, and immunochemical stains, we evaluated the effects of VCP injected into spinal cord tissue following injury. Results demonstrate that VCP administration inhibits macrophage infiltration, reduces spinal cord destruction, and improves hind‐limb function, establishing VCP as a strong candidate for further investigation in the treatment of SCI.
Melatonin Relieves the Neural Oxidative Burden that Contributes to Dementias
Authors: REITER RUSSEL J. , TAN DUN‐XIAN , PAPPOLLA MIGUEL A.
Published: January 2005

Abstract: This report summarizes some of the many publications that document the beneficial actions of melatonin within the central nervous system. Of particular interest are the multiple functions of melatonin and its metabolites as ubiquitously acting direct free radical scavengers and indirect antioxidants. The fact that melatonin and the metabolic progeny that are formed when it scavenges toxic reactants are all effective in neutralizing destructive molecules greatly increases the efficacy of melatonin as a protection against by‐products of oxygen and nitrogen that normally mutilate essential molecules. Of the large number of situations in which oxidative stress may be the cause of disease processes or debilitating conditions, the current review examines melatonin's protection within the central nervous system, particularly in experimental ischemia/reperfusion (stroke) injury, Alzheimer's disease, and parkinsonism. In each of these conditions, melatonin has been found to provide significant neural protection against both the morphophysiological damage and the biobehavioral consequences of these infirmities. The report concludes with the suggestion that melatonin, alone or in combination with other antioxidants, be considered for routine usage to potentially combat some of the neural ravages of aging.
Retardation of Brain Aging by Chronic Treatment with Melatonin
Authors: BONDY S C , LAHIRI D K , PERREAU V M , SHARMAN K Z , CAMPBELL A , ZHOU J , SHARMAN E H
Published: January 2005

Abstract: Slowing the functional decline in the aging brain is not only relevant to nonpathological senescence but also to a broad range of neurodegenerative diseases. Although disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) are not found in the young adult, they gradually manifest with increasing age. AD, in particular, is an increasing major public health concern as the population ages; therapies that delay disease onset will markedly reduce overall disease prevalence. Aging of the brain has been repeatedly associated with cumulative oxidative damage to macromolecules and to abnormal levels of inflammatory activity. Melatonin has attained increasing prominence as a candidate for ameliorating these changes occurring during senescence. Recent research has focused on supplementation with dietary melatonin designed to elucidate the specific key intracellular targets of age‐related inflammatory events, and the optimal means of affording protection of these targets. This report summarizes the progress made in this area.
Blockade of PKCδ Proteolytic Activation by Loss of Function Mutants Rescues Mesencephalic Dopaminergic Neurons from Methylcyclopentadienyl Manganese Tricarbonyl (MMT)‐Induced Apoptotic Cell Death
Authors: ANANTHARAM V , KITAZAWA M , LATCHOUMYCANDANE C , KANTHASAMY A , KANTHASAMY A G
Published: January 2005

Abstract: The use of methylcyclopentadienyl manganese tricarbonyl (MMT) as a gasoline additive has raised health concerns and increased interest in understanding the neurotoxic effects of manganese. Chronic exposure to inorganic manganese causes Manganism, a neurological disorder somewhat similar to Parkinson's disease. However, the cellular mechanism by which MMT, an organic manganese compound, induces neurotoxicity in dopaminergic neuronal cells remains unclear. Therefore, we systematically investigated apoptotic cell‐signaling events following exposure to 3–200 μM MMT in mesencephalic dopaminergic neuronal (N27) cells. MMT treatment resulted in a time‐ and dose‐dependent increase in reactive oxygen species generation and cell death in N27 cells. The cell death was preceded by sequential activation of mitochondrial‐dependent proapoptotic events including cytochrome c release, caspase‐3 activation, and DNA fragmentation, indicating that the mitochondrial‐dependent apoptotic cascade primarily triggers MMT‐induced apoptotic cell death. Importantly, MMT induced proteolytic cleavage of protein kinase Cδ (PKCδ), resulting in persistently increased kinase activity. The proteolytic activation of PKCδ was suppressed by treatment with 100 μM Z‐VAD‐FMK and 100 μM Z‐DEVD‐FMK, suggesting that caspase‐3 mediates the proteolytic activation of PKCδ. Pretreatment with 100 μM Z‐DEVD‐FMK and 5 μM rottlerin (a PKCδ inhibitor) also significantly attenuated MMT‐induced DNA fragmentation. Furthermore, overexpression of either the kinase inactive dominant negative PKCδK376R mutant or the caspase cleavage resistant PKCδD327A mutant rescued N27 cells from MMT‐induced DNA fragmentation. Collectively, these results demonstrate that the mitochondrial‐dependent apoptotic cascade mediates apoptosis via proteolytic activation of PKCδ in MMT‐induced dopaminergic degeneration and suggest that PKCδ may serve as an attractive therapeutic target in Parkinson‐related neurological diseases.
New Therapeutic Strategies and Drug Candidates for Neurodegenerative Diseases: p53 and TNF‐α Inhibitors, and GLP‐1 Receptor Agonists
Authors: GREIG NIGEL H. , MATTSON MARK P. , PERRY TRACYANN , CHAN SIC L. , GIORDANO TONY , SAMBAMURTI KUMAR , ROGERS JACK T. , OVADIA HAIM , LAHIRI DEBOMOY K.
Published: January 2005

Abstract:Owing to improving preventative, diagnostic, and therapeutic measures for cardiovascular disease and a variety of cancers, the average ages of North Americans and Europeans continue to rise. Regrettably, accompanying this increase in life span, there has been an increase in the number of individuals afflicted with age‐related neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and stroke. Although different cell types and brain areas are vulnerable among these, each disorder likely develops from activation of a common final cascade of biochemical and cellular events that eventually lead to neuronal dysfunction and death. In this regard, different triggers, including oxidative damage to DNA, the overactivation of glutamate receptors, and disruption of cellular calcium homeostasis, albeit initiated by different genetic and/or environmental factors, can instigate a cascade of intracellular events that induce apoptosis. To forestall the neurodegenerative process, we have chosen specific targets to inhibit that are at pivotal rate‐limiting steps within the pathological cascade. Such targets include TNF‐α, p53, and GLP‐1 receptor. The cytokine TNF‐α is elevated in Alzheimer's disease, Parkinson's disease, stroke, and amyotrophic lateral sclerosis. Its synthesis can be reduced via posttranscriptional mechanisms with novel analogues of the classic drug, thalidomide. The intracellular protein and transcription factor, p53, is activated by the Alzheimer's disease toxic peptide, Aβ, as well as by excess glutamate and hypoxia to trigger neural cell death. It is inactivated by novel tetrahydrobenzothiazole and ‐oxazole analogues to rescue cells from lethal insults. Stimulation of the glucagon‐like peptide‐1 receptor (GLP‐1R) in brain is associated with neurotrophic functions that, additionally, can protect cells against excess glutamate and other toxic insults.
Nicotinic Receptor Modulation for Neuroprotection and Enhancement of Functional Recovery Following Brain Injury or Disease
Authors: PAULY J R. , CHARRIEZ C M. , GUSEVA M V. , SCHEFF S W.
Published: January 2005

Abstract: Despite the well‐known adverse health effects of tobacco smoking, numerous studies have shown that nicotine, the principal pharmacologically active alkaloid in tobacco smoke, exerts neuroprotective properties in several animal models of neurodegeneration. Furthermore, cigarette smoking appears to significantly reduce the risk of developing Parkinson's disease in human subjects. We review the animal and human studies that investigated possible neuroprotective actions of nicotine and other nicotinic receptor agonists and antagonists. We demonstrate that nicotine is not neuroprotective in all animal models of neurodegenerative disease. In fact, C57Bl/6 mice pretreated with nicotine have an increased sensitivity to 3‐nitropropionic acid, a neurotoxin used in mice to mimic some aspects of Huntington's disease. The actions of nicotine on dopamine release may explain the variable effects of nicotine in animal models of Parkinson's and Huntington's diseases. Finally, we focus on some future directions for studies that evaluate neuroprotective properties of nicotinic agonists and antagonists.
Pharmacological Manipulation of Brain Kynurenine Metabolism
Authors: REINHARD JOHN F.
Published: January 2005

Abstract: The amino acid tryptophan is a precursor for the neurotransmitter serotonin as well as for kynurenic and quinolinic acids. These latter molecules are antagonists and agonists, respectively, of the excitatory amino acid glutamate and arise through the kynurenine pathway of tryptophan metabolism. Significant differences exist in the sites and physiological control of serotonin versus kynurenine. While serotonin is formed within serotonin neurons (in the brain and intestine) and neuroendocrine cells of the intestine, kynurenine is formed by liver cells (as a precursor to nicotinic acid) and in macrophages, activated by inflammatory cytokines. Our studies are based on the hypothesis that inhibition of kynurenine metabolism (at the kynurenine hydroxylase [KH] step) allows the amino acid to be converted to kynurenic acid, a neuroprotective antagonist of excitatory amino acid receptors. Inhibition of KH also prevents formation of the neurotoxic species 3‐hydroxykynurenine and quinolinic acid. To accomplish this end, inhibitors were identified and are described.
Phase I and Pharmacokinetic Study of Oral Irinotecan Given Once Daily for 5 Days Every 3 Weeks in Combination With Capecitabine in Patients With Solid Tumors
Authors: Soepenberg Otto , Dumez Herlinde , Verweij Jaap , Semiond Dorothee , deJonge Maja J.A. , Eskens Ferry A.L.M. , Steeg Judith ter , Selleslach Johan , Assadourian Sylvie , Sanderink Ger-Jan , Sparreboom Alex , van Oosterom A.T.
Published: January 2005

Purpose

To assess the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and preliminary antitumor activity of oral irinotecan given in combination with capecitabine to patients with advanced, refractory solid tumors.

Patients and Methods

Patients were treated from day 1 with irinotecan capsules given once daily for 5 consecutive days (50 to 60 mg/m2/d) concomitantly with capecitabine given twice daily for 14 consecutive days (800 to 1,000 mg/m2); cycles were repeated every 21 days.

Results

Twenty-eight patients were enrolled and received 155 cycles of therapy (median, five cycles; range, one to 18 cycles). With irinotecan 60 mg/m2/d and capecitabine 2 × 800 mg/m2/d, grade 3 delayed diarrhea in combination with grade 2 nausea (despite maximal antiemetic support) and grade 3 anorexia and colitis, were the first-cycle dose-limiting toxicities in two of six patients, respectively. At the recommended doses (irinotecan 50 mg/m2/d; capecitabine 2 × 1,000 mg/m2/d), side effects were mostly mild to moderate and uniformly reversible. Pharmacokinetic analysis showed that there was no interaction between oral irinotecan and capecitabine, and that body-surface area was not significantly contributing to the observed pharmacokinetic variability. Confirmed partial responses were observed in two patients with gallbladder carcinoma and in one patient with melanoma. Disease stabilization was noted in 16 patients.

Conclusion

The recommended phase II doses for oral irinotecan and capecitabine are 50 mg/m2/d for 5 consecutive days, and 2 × 1,000 mg/m2/d for 14 consecutive days repeated every 3 weeks, respectively.
Discussions Regarding Reproductive Health for Young Women With Breast Cancer Undergoing Chemotherapy
Authors: Duffy Christine M. , Allen Susan M. , Clark Melissa A.
Published: January 2005

Purpose

Young women who undergo chemotherapy for breast cancer face serious consequences to their reproductive health. Research in this area has previously focused on men, or on childhood cancer survivors. We sought to explore self-report of reproductive health counseling in young women undergoing chemotherapy for breast cancer.

Patients and Methods

A total of 166 premenopausal women aged ≤ 50 years were recruited from oncology offices in academic and private practices in four northeastern states, as part of a randomized controlled clinical trial aimed at stress reduction. Women were asked a variety of questions regarding diagnosis and treatment, including whether they received any counseling regarding early menopause and fertility issues.

Results

Sixty-eight percent and 34% of women reported recalling a discussion with a physician regarding early menopause or fertility, respectively. In multivariate analysis, hormonal therapy and early stage of disease were associated with significantly increased odds of recall of a discussion regarding menopause. Difficulty communicating with medical team was associated with increased odds of recalling a discussion regarding fertility, whereas older age and anxiety in medical situations were associated with decreased odds.

Conclusion

Many women fail to recall discussions regarding the reproductive health impact of chemotherapy. Demographic, psychological, and disease-related variables are related to recalling such discussions. Counseling about premature menopause and fertility changes is an overlooked aspect of preparation for adjuvant chemotherapy in young premenopausal women with breast cancer. Future research should explore this issue further.
Mortality Risk From Squamous Cell Skin Cancer
Authors: Clayman Gary L. , Lee J. Jack , Holsinger F. Christopher , Zhou Xian , Duvic Madeleine , El-Naggar Adel K. , Prieto Victor G. , Altamirano Evelyn , Tucker Susan L. , Strom Sara S. , Kripke Margaret L. , Lippman Scott M.
Published: January 2005

Purpose

To identify nonmelanoma skin cancer patients with squamous cell carcinoma (SCC) who are at greatest risk of disease-specific mortality.

Patients and Methods

Prospectively enrolled patients with a minimum of one pathologically confirmed skin SCC lesion, definitive treatment of the SCC lesion(s) resulting in no evidence of disease, and at least 2 months of follow-up after definitive treatment were eligible for the present longitudinal analysis. They received comprehensive clinical, pathologic evaluations and follow-up for patterns of failure and mortality.

Results

We enrolled 210 patients (187 men and 23 women) with a total of 277 skin SCC lesions and a median enrollment age of 68 years (range, 34 to 95 years). Median follow-up of surviving patients was 22 months. Three-year overall and disease-specific survival (DSS) rates were 70% and 85%, respectively. In univariate analyses, the clinical-pathologic factors associated with adverse DSS were local recurrence at presentation (P = .05), invasion beyond subcutaneous tissues (P = .009), perineural invasion (P = .002), lesion size (P = .0003), and depth of invasion (P = .05). Statistical models identified a homogeneous high-risk group of patients with lesions ≥ 4 cm, perineural invasion, and deep invasion beyond subcutaneous structures. Three-year DSS was 100% for patients with no risk factors versus 70% for patients with at least one risk factor.

Conclusion

Lesion size ≥ 4 cm and histologic evidence of perineural invasion and deep invasion beyond subcutaneous structures were the clinical-pathologic factors most significantly associated with disease-specific mortality in skin SCC.
Rituximab in Combination With Fludarabine Chemotherapy in Low-Grade or Follicular Lymphoma
Authors: Czuczman M.S. , Koryzna A. , Mohr A. , Stewart C. , Donohue K. , Blumenson L. , Bernstein Z.P. , McCarthy P. , Alam A. , Hernandez-Ilizaliturri F. , Skipper M. , Brown K. , Chanan-Khan A. , Klippenstein D. , Loud P. , Rock M.K. , Benyunes M. , Grillo-Lopez A. , Bernstein S.H.
Published: January 2005

Purpose

To evaluate the safety and efficacy of fludarabine plus rituximab in treatment-naïve or relapsed patients with low-grade and/or follicular non-Hodgkin's lymphoma.

Patients and Methods

This was an open-label, single-arm, single-center phase II study enrolling 40 patients. During the first week of the study, patients received two infusions of rituximab 375 mg/m2 administered 4 days apart. Seventy-two hours after the second infusion of rituximab, patients received the first of six cycles of fludarabine chemotherapy (25 mg/m2/d for 5 days on a 28-day cycle). Single infusions of rituximab were administered 72 hours before the second, fourth, and sixth cycles of fludarabine, and two infusions of rituximab were given 4 weeks after the last cycle of fludarabine. Treatment duration was 26 weeks.

Results

An overall response rate of 90% (80% complete response rate) was achieved in the intent-to-treat population. Similar response rates were seen in treatment-naïve and previously treated patients. The median duration of response has not been reached at 40+ months. The median follow-up time in this study is 44 months (range, 15 to 66 months). In patients positive for the 14;18 translocation in blood and/or marrow at enrollment, molecular remission was achieved in 88% of cases, with patients remaining negative for up to 4 years to date. Hematologic toxicity was manageable, and except for a 15% incidence of herpes simplex/zoster infections, infectious complications were rare. Nonhematologic toxicities were minimal.

Conclusion

Rituximab plus fludarabine was well tolerated and associated with an excellent complete response rate, including molecular remissions, in patients with low-grade or follicular lymphoma.