bluuebunny/crossref_metadata_2025 huggingface dataset:
Reference signal extraction from corrupted ECG using wavelet decomposition for MRI sequence triggering: application to small animals
Authors: Abi-Abdallah Dima , Chauvet Eric , Bouchet-Fakri Latifa , Bataillard Alain , Briguet André , Fokapu Odette
Published: February 2006

Background

Present developments in Nuclear Magnetic Resonance (NMR) imaging techniques strive for improved spatial and temporal resolution performances. However, trying to achieve the shortest gradient rising time with high intensity gradients has its drawbacks: It generates high amplitude noises that get superimposed on the simultaneously recorded electrophysiological signals, needed to synchronize moving organ images. Consequently, new strategies have to be developed for processing these collected signals during Magnetic Resonance Imaging (MRI) examinations. The aim of this work is to extract an efficient reference signal, from an electrocardiogram (ECG) that was contaminated by the NMR artefacts. This may be used for image triggering and/or cardiac rhythm monitoring.

Methods

Our method, based on sub-band decomposition using wavelet filters, is tested on various ECG signals recorded during three imaging sequences: Gradient Echo (GE), Fast Spin Echo (FSE) and Inversion Recovery with Spin Echo (IRSE). In order to define the most adapted wavelet functions to use according to the excitation protocols, noise generated by each imaging sequence is recorded and analysed. After exploring noise models along with information found in the literature, a group of 14 wavelets, members of three families (Daubechies, Coiflets, Symlets), is selected for the study. The extraction process is carried out by decomposing the contaminated ECG signals into 8 scales using a given wavelet function, then combining the sub-bands necessary for cardiac synchronization, i.e. those containing the essential part of the QRS energy, to construct a reference signal.

Results

The efficiency of the presented method has been tested on a group of quite representative signals containing: highly contaminated (mean SNR<-5 dB) simulated ECGs that replicate normal and pathological human heart beats, as well as some pathological and healthy rodents' actual ECG records. Despite the weak SNR of the contaminated ECG, the performances were quite satisfactory. When comparing the wavelet performances, one may notice that for a given sequence, some wavelets are more efficient for processing than others; for GE, FSE and IRSE sequence, good synchronisation condition is accomplished with coif5, sym8, and sym4 respectively.

Conclusion

Sub-band decomposition proved to be very suitable for extracting a reference signal from a corrupted ECG for MRI triggering. An appropriate choice of the wavelet function, in accordance with the image sequence type, could considerably improve the quality of the reference signal for better image synchronization.
Embryonic exposure to the fungicide vinclozolin causes virilization of females and alteration of progesterone receptor expression in vivo: an experimental study in mice
Authors: Buckley Jill , Willingham Emily , Agras Koray , Baskin Laurence S
Published: February 2006

Background

Vinclozolin is a fungicide that has been reported to have anti-androgenic effects in rats. We have found that in utero exposure to natural or synthetic progesterones can induce hypospadias in mice, and that the synthetic progesterone medroxyprogesterone acetate (MPA) feminizes male and virilizes female genital tubercles. In the current work, we selected a relatively low dose of vinclozolin to examine its in utero effects on the development of the genital tubercle, both at the morphological and molecular levels.

Methods

We gave pregnant dams vinclozolin by oral gavage from gestational days 13 through 17. We assessed the fetal genital tubercles from exposed fetuses at E19 to determine location of the urethral opening. After determination of gonadal sex, either genital tubercles were harvested for mRNA quantitation, or urethras were injected with a plastic resin for casting. We analyzed quantified mRNA levels between treated and untreated animals for mRNA levels of estrogen receptors α and β, progesterone receptor, and androgen receptor using nonparametric tests or ANOVA. To determine effects on urethral length (males have long urethras compared to females), we measured the lengths of the casts and performed ANOVA analysis on these data.

Results

Our morphological results indicated that vinclozolin has morphological effects similar to those of MPA, feminizing males (hypospadias) and masculinizing females (longer urethras). Because these results reflected our MPA results, we investigated the effects of in utero vinclozolin exposure on the mRNA expression levels of androgen, estrogen α and β, and progesterone receptors. At the molecular level, vinclozolin down-regulated estrogen receptor α mRNA in females and up-regulated progesterone receptor mRNA. Vinclozolin-exposed males exhibited up-regulated estrogen receptor α and progesterone receptor mRNA, effects we have also seen with exposure to the synthetic estrogen, ethinyl estradiol.

Conclusion

The results suggest that vinclozolin virilizes females and directly or indirectly affects progesterone receptor expression. It also affects estrogen receptor expression in a sex-based manner. We found no in vivo effect of vinclozolin on androgen receptor expression. We propose that vinclozolin, which has been designated an anti-androgen, may also exert its effects by involving additional steroid-signaling pathways.
Selected science: an industry campaign to undermine an OSHA hexavalent chromium standard
Authors: Michaels David , Monforton Celeste , Lurie Peter
Published: February 2006

While exposure to hexavalent chromium (Cr(VI)) has been associated with increased lung cancer risk for more than 50 years, the chemical is not currently regulated by the U.S. Occupational Safety and Health Administration (OSHA) on the basis of its carcinogenicity. The agency was petitioned in 1993 and sued in 1997 and 2002 to lower the workplace Cr(VI) exposure limit, resulting in a court order to issue a final standard by February 2006. Faced with the threat of stronger regulation, the chromium industry initiated an effort to challenge the scientific evidence supporting a more protective standard. This effort included the use of "product defense" consultants to conduct post hoc analyses of a publicly-funded study to challenge results viewed unfavorably by the industry.

The industry also commissioned a study of the mortality experience of workers at four low-exposure chromium plants, but did not make the results available to OSHA in a timely manner, despite multiple agency requests for precisely these sorts of data. The commissioned study found a statistically significant elevation in lung cancer risk among Cr(VI)-exposed workers at levels far below the current standard. This finding changed when the multi-plant cohort was divided into two statistically underpowered components and then published separately. The findings of the first paper published have been used by the chromium industry to attempt to slow OSHA's standard setting process. The second paper was withheld from OSHA until it was accepted for publication in a scientific journal, after the rulemaking record had closed.

Studies funded by private sponsors that seek to influence public regulatory proceedings should be subject to the same access and reporting provisions as those applied to publicly funded science. Parties in regulatory proceedings should be required to disclose whether the studies were performed by researchers who had the right to present their findings without the sponsor's consent or influence, and to certify that all relevant data have been submitted to the public record, whether published or not.
Throwing the dice for the diagnosis of vaginal complaints?
Authors: Schwiertz Andreas , Taras David , Rusch Kerstin , Rusch Volker
Published: February 2006

Backround

Vaginitis is among the most common conditions women are seeking medical care for. Although these infections can easily be treated, the relapse rate is high. This may be due to inadequate use of the diagnostic potential.

Methods

We evaluated the misjudgement rate of the aetiology of vaginal complaints. A total of 220 vaginal samples from women with a vaginal complaint were obtained and analysed for numbers of total lactobacilli, H2O2-producing lactobacilli, total aerobic cell counts and total anaerobic cell counts including bifidobacteria, Bacteroides spp., Prevotella spp. Additionally, the presence of Atopobium vaginae, Gardnerella vaginalis, Candida spp. and Trichomonas vaginalis was evaluated by DNA-hybridisation using the PCR and Affirm VPIII Microbial Identification Test, respectively.

Results

The participating physicians diagnosed Bacterial vaginosis (BV) as origin of discomfort in 80 cases, candidiasis in 109 cases and mixed infections in 8 cases. However, a present BV, defined as lack of H2O2-lactobacilli, presence of marker organisms, such as G. vaginalis, Bacteroides spp. or Atopobium vaginae, and an elevated pH were identified in only 45 cases of the women examined. Candida spp. were detected in 46 cases. Interestingly, an elevated pH corresponded solely to the presence of Atopobium vaginae, which was detected in 11 cases.

Conclusion

Errors in the diagnosis of BV and candida vulvovaginitis (CV) were high. Interestingly, the cases of misjudgement of CV (77%) were more numerous than that of BV (61%). The use of Amsel criteria or microscopy did not reduce the number of misinterpretations. The study reveals that the misdiagnosis of vaginal complaints is rather high.
The cyclin D1 proto-oncogene is sequestered in the cytoplasm of mammalian cancer cell lines
Authors: Alao John P , Gamble Simon C , Stavropoulou Alexandra V , Pomeranz Karen M , Lam Eric W-F , Coombes R Charles , Vigushin David M
Published: February 2006

Background

The cyclin D1 proto-oncogene is an important regulator of G1 to S-phase transition and an important cofactor for several transcription factors in numerous cell types. Studies on neonatal cardiomyocytes and postmitotic neurons indicate that the activity of cyclin D1 may be regulated through its cytoplasmic sequestration. We have demonstrated previously, that TSA induces the ubiquitin-dependent degradation of cyclin D1 in MCF-7 breast cancer cells. Additional studies were initiated in order to further investigate the effect of TSA on cyclin D1 regulation using sub-cellular fractionation techniques.

Results

Our studies revealed cyclin D1 to be localized predominantly within the cytoplasmic fraction of all cell lines tested. These observations were confirmed by confocal microscopy. GSK3β was found to be localized within both the nucleus and cytoplasm throughout the cell cycle. Inhibition of GSK3β or CRM1-dependent nuclear export resulted in only modest nuclear accumulation, suggesting that the cytoplasmic localization of cyclin D1 results from the inhibition of its nuclear import.

Conclusion

We have shown by several different experimental approaches, that cyclin D1 is in fact a predominantly cytoplasmic protein in mammalian cancer cell lines. Recent studies have shown that the cytoplasmic sequestration of cyclin D1 prevents apoptosis in neuronal cells. Our results suggest that cytoplasmic sequestration may additionally serve to regulate cyclin D1 activity in mammalian cancer cells.
Histone deacetylase inhibitor, Trichostatin A induces ubiquitin-dependent cyclin D1 degradation in MCF-7 breast cancer cells
Authors: Alao John P , Stavropoulou Alexandra V , Lam Eric W-F , Charles Coombes R , Vigushin David M
Published: February 2006

Background

Cyclin D1 is an important regulator of G1-S phase cell cycle transition and has been shown to be important for breast cancer development. GSK3β phosphorylates cyclin D1 on Thr-286, resulting in enhanced ubiquitylation, nuclear export and degradation of the cyclin in the cytoplasm. Recent findings suggest that the development of small-molecule cyclin D1 ablative agents is of clinical relevance. We have previously shown that the histone deacetylase inhibitor trichostatin A (TSA) induces the rapid ubiquitin-dependent degradation of cyclin D1 in MCF-7 breast cancer cells prior to repression of cyclin D1 gene (CCND1) transcription. TSA treatment also resulted in accumulation of polyubiquitylated GFP-cyclin D1 species and reduced levels of the recombinant protein within the nucleus.

Results

Here we provide further evidence for TSA-induced ubiquitin-dependent degradation of cyclin D1 and demonstrate that GSK3β-mediated nuclear export facilitates this activity. Our observations suggest that TSA treatment results in enhanced cyclin D1 degradation via the GSK3β/CRM1-dependent nuclear export/26S proteasomal degradation pathway in MCF-7 cells.

Conclusion

We have demonstrated that rapid TSA-induced cyclin D1 degradation in MCF-7 cells requires GSK3β-mediated Thr-286 phosphorylation and the ubiquitin-dependent 26S proteasome pathway. Drug induced cyclin D1 repression contributes to the inhibition of breast cancer cell proliferation and can sensitize cells to CDK and Akt inhibitors. In addition, anti-cyclin D1 therapy may be highly specific for treating human breast cancer. The development of potent and effective cyclin D1 ablative agents is therefore of clinical relevance. Our findings suggest that HDAC inhibitors may have therapeutic potential as small-molecule cyclin D1 ablative agents.
Protective effect of the DNA vaccine encoding the major house dust mite allergens on allergic inflammation in the murine model of house dust mite allergy
Authors: Kim Nacksung , Kwon Soon Seog , Lee Jaechun , Kim Sohyung , Yoo Tai June
Published: February 2006

Background

Vaccination with naked DNA encoding antigen induces cellular and humoral immunity characterized by the activation of specific Th1 cells.

Objective

To evaluate the effects of vaccination with mixed naked DNA plasmids encodingDer p1,Der p2,Der p3,Der f1,Der f2, andDer f3, the major house dust mite allergens on the allergic inflammation to the whole house dust mites (HDM) crude extract.

Methods

Three hundred micrograms of these gene mixtures were injected into muscle of BALB/c mice. Control mice were injected with the pcDNA 3.1 blank vector. After 3 weeks, the mice were actively sensitized and inhaled with the whole house dust mite extract intranasally.

Results

The vaccinated mice showed a significantly decreased synthesis of total and HDM-specific IgE compared with controls. Analysis of the cytokine profile of lymphocytes after challenge with HDM crude extract revealed that mRNA expression of interferon-γ was higher in the vaccinated mice than in the controls. Reduced infiltration of inflammatory cells and the prominent infiltration of CD8+ T cells were observed in histology of lung tissue from the vaccinated mice.

Conclusion

Vaccination with DNA encoding the major house dust mite allergens provides a promising approach for treating allergic responses to whole house dust mite allergens.
Sterile syringe access and disposal among injection drug users newly enrolled in methadone maintenance treatment: a cross-sectional survey
Authors: McNeely Jennifer , Arnsten Julia H , Gourevitch Marc N
Published: February 2006

Background

We sought to assess injection practices, means of acquiring and disposing of syringes, and utilization and knowledge of harm reduction resources among injection drug users (IDUs) entering methadone maintenance treatment (MMT).

Methods

Interviews with 100 consecutive patients, including 35 IDUs, entering a MMT program in the Bronx, NY.

Results

Utilization of unsafe syringe sources was reported by 69% of IDUs in our sample. Most (80%) IDUs reused syringes, and syringe sharing was also common. Fewer than half knew that non-prescription pharmacy purchase of syringes was possible. The most common means of disposing of injecting equipment were the trash (63%) and syringe exchange programs (49%).

Conclusions

These findings indicate that drug users entering treatment under-utilize sanctioned venues to obtain sterile syringes or safely dispose of used injection equipment. Programs providing services to drug users should adopt a proactive stance to address the safety and health issues faced by injectors.
Using individual growth model to analyze the change in quality of life from adolescence to adulthood
Authors: Chen Henian , Cohen Patricia
Published: February 2006

Background

The individual growth model is a relatively new statistical technique now widely used to examine the unique trajectories of individuals and groups in repeated measures data. This technique is increasingly used to analyze the changes over time in quality of life (QOL) data. This study examines the change from adolescence to adulthood in physical health as an aspect of QOL as an illustration of the use of this analytic method.

Methods

Employing data from the Children in the Community (CIC) study, a prospective longitudinal investigation, physical health was assessed at mean ages 16, 22, and 33 in 752 persons born between 1965 and 1975.

Results

The analyses using individual growth models show a linear decline in average physical health from age 10 to age 40. Males reported better physical health and declined less per year on average. Time-varying psychiatric disorders accounted for 8.6% of the explained variation in mean physical health, and 6.7% of the explained variation in linear change in physical health. Those with such a disorder reported lower mean physical health and a more rapid decline with age than those without a current psychiatric disorder. The use of SAS PROC MIXED, including syntax and interpretation of output are provided. Applications of these models including statistical assumptions, centering issues and cohort effects are discussed.

Conclusion

This paper highlights the usefulness of the individual growth model in modeling longitudinal change in QOL variables.
Better quality of life with neuropsychological improvement on HAART
Authors: Parsons Thomas D , Braaten Alyssa J , Hall Colin D , Robertson Kevin R
Published: February 2006

Background

Successful highly active antiretroviral therapy (HAART) regimens have resulted in substantial improvements in the systemic health of HIV infected persons and increased survival times. Despite increased systemic health, the prevalence of minor HIV-associated cognitive impairment appears to be rising with increased longevity, and it remains to be seen what functional outcomes will result from these improvements. Cognitive impairment can dramatically impact functional ability and day-to-day productivity. We assessed the relationship of quality of life (QOL) and neuropsychological functioning with successful HAART treatment.

Methods

In a prospective longitudinal study, subjects were evaluated before instituting HAART (naïve) or before changing HAART regimens because current therapy failed to maintain suppression of plasma viral load (treatment failure). Subjects underwent detailed neuropsychological and neurological examinations, as well as psychological evaluation sensitive to possible confounds. Re-evaluation was performed six months after institution of the new HAART regimen and/or if plasma viral load indicated treatment failure. At each evaluation, subjects underwent ultrasensitive HIV RNA quantitative evaluation in both plasma and cerebrospinal fluid.

Results

HAART successes performed better than failures on measures exploring speed of mental processing (p < .02). HAART failure was significantly associated with increased self-reports of physical health complaints (p < .01) and substance abuse (p < .01). An interesting trend emerged, in which HAART failures endorsed greater levels of psychological and cognitive complaints (p = .06). Analysis between neuropsychological measures and QOL scores revealed significant correlation between QOL Total and processing speed (p < .05), as well as flexibility (p < .05).

Conclusion

Our study investigated the relationship between HIV-associated neurocognitive impairment and quality of life. HAART failures experienced slower psychomotor processing, and had increased self-reports of physical health complaints and substance abuse. Contrariwise, HAART successes experienced improved mental processing, demonstrating the impact of successful treatment on functioning. With increasing life expectancy for those who are HIV seropositive, it is important to measure cognitive functioning in relation to the actual QOL these individuals report. The study results have implications for the optimal management of HIV-infected persons. Specific support or intervention may be beneficial for those who have failed HAART in order to decrease substance abuse and increase overall physical health.
Normocalcemic parathyroid carcinoma: an unusual clinical presentation
Authors: Messerer Corrie L , Bugis Samuel P , Baliski Chris , Wiseman Sam M
Published: February 2006

Background

Parathyroid carcinoma is a rare cause of primary hyperparathyroidism and may be associated with significant disease related morbidity and mortality. Preoperative diagnosis remains a challenge, which may jeopardize appropriate and successful patient treatment.

Case presentation

We report a case of parathyroid carcinoma diagnosed in a 60-year-old woman that presented with a tender nodule located at the left lower thyroid pole and had been present for several years. Ultrasound examination revealed a 2.7 × 1.6 × 2.7 cm mass within the lower left lobe of the thyroid with cystic and solid areas. Lab measurement of the intact PTH level revealed it to be three times the upper limit of normal and the serum calcium level was within normal limits. A left thyroid lobectomy and isthmusectomy was carried out. Histopathological evaluation was diagnostic for a parathyroid carcinoma. At greater than two years of follow-up, the patient has had no evidence of disease recurrence and her serum PTH and calcium levels have remained within normal.

Conclusion

Parathyroid carcinoma is a rare endocrine tumor which must be considered in the differential diagnosis of a nodular thyroid mass. En bloc resection remains the treatment of choice for this malignancy. Disease prognosis is influenced by the extent of the initial resection, the presence of metastases, and adequate long-term follow-up.
Undifferentiated embryonal sarcoma of the liver mimicking acute appendicitis. Case report and review of the literature
Authors: Sakellaridis Timothy , Panagiotou Ioannis , Georgantas Themistoclis , Micros George , Rontogianni Dimitra , Antiochos Christos
Published: February 2006

Background

Undifferentiated embryonal sarcoma (UES) of liver is a rare malignant neoplasm, which affects mostly the pediatric population accounting for 13% of pediatric hepatic malignancies, a few cases has been reported in adults.

Case presentation

We report a case of undifferentiated embryonal sarcoma of the liver in a 20-year-old Caucasian male. The patient was referred to us for further investigation after a laparotomy in a district hospital for spontaneous abdominal hemorrhage, which was due to a liver mass. After a through evaluation with computed tomography scan and magnetic resonance imaging of the liver and taking into consideration the previous history of the patient, it was decided to surgically explore the patient. Resection of I–IV and VIII hepatic lobe. Patient developed disseminated intravascular coagulation one day after the surgery and died the next day.

Conclusion

It is a rare, highly malignant hepatic neoplasm, affecting almost exclusively the pediatric population. The prognosis is poor but recent evidence has shown that long-term survival is possible after complete surgical resection with or without postoperative chemotherapy.
Measuring health inequalities in Albania: a focus on the distribution of general practitioners
Authors: Theodorakis Pavlos N , Mantzavinis Georgios D , Rrumbullaku Llukan , Lionis Christos , Trell Erik
Published: February 2006

Background

The health workforce has a dynamically changing nature and the regular documentation of the distribution of health professionals is a persistent policy concern. The aim of the present study was to examine available human medical resources in primary care and identify possible inequalities regarding the distribution of general practitioners in Albania between 2000 and 2004.

Methods

With census data, we investigated the degree of inequality by calculating relative inequality indices. We plotted the Lorenz curves and calculated the Gini, Atkinson and Robin Hood indices and decile ratios, both before and after adjusting for mortality and consultation rates.

Results

The Gini index for the distribution of general practitioners in 2000 was 0.154. After adjusting for mortality it was 0.126, while after adjusting for consultation rates it was 0.288. The Robin Hood index for 2000 was 11.2%, which corresponds to 173 general practitioners who should be relocated in order to achieve equality. The corresponding figure after adjusting for mortality was 9.2% (142 general practitioners), while after adjusting for consultation rates the number was 20.6% (315). These figures changed to 6.3% (100), 6.3% (115) and 19.8% (315) in 2004.

Conclusion

There was a declining trend in the inequality of distribution of general practitioners in Albania between 2000 and 2004. The trend in inequality was apparent irrespective of the relative inequality indicator used. The level of inequality varied depending on the adjustment method used. Reallocation strategies for general practitioners in Albania could be the key in alleviating the inequalities in primary care workforce distribution.
Developing a prioritisation framework in an English Primary Care Trust
Authors: Wilson Edward CF , Rees John , Fordham Richard J
Published: February 2006

Background

In the English NHS, Primary Care Trusts (PCTs) are required to commission health services, to maximise the well-being of the population, subject to the available budget. There are numerous techniques employed to make decisions, some more rational and transparent than others. A weighted benefit score can be used to rank options but this does not take into account value for money from investments.

Methods

We developed a weighted benefit score framework for use in an English PCT which ranked options in order of 'cost-value' or 'cost per point of benefit'. Our method differs from existing techniques by explicitly combining cost and a composite weighted benefit score into the cost-value ratio.

Results

The technique proved readily workable, and was able to accommodate a wide variety of data and competing criteria. Participants felt able to assign scores to proposed services, and generate a ranked list, which provides a solid starting point for the PCT Board to discuss and make funding decisions. Limitations included potential for criteria to be neither exhaustive nor mutually exclusive and the lack of an interval property in the benefit score limiting the usefulness of a cost-value ratio.

Conclusion

A technical approach to decision making is insufficient for making prioritisation decisions, however our technique provides a very valuable, structured and informed starting point for PCT decision making.
The relationship between prevalence and duration of weight loss strategies and weight loss among overweight managed care organization members enrolled in a weight loss trial
Authors: Linde Jennifer A , Erickson Darin J , Jeffery Robert W , Pronk Nicolaas P , Boyle Raymond G
Published: February 2006

Background

Many adults in the United States report engaging in weight loss behaviors. The current study examined weight loss strategies among managed care organization members, to determine the prevalence and impact of weight loss behaviors in this population. We hypothesized that greater engagement in weight loss strategies would be associated with greater weight loss success.

Methods

Data were taken from Weigh-to-Be (WTB), a two-year weight loss trial (N = 1801, 72% female, mean age = 50.7 years, mean weight = 95.9 kg, mean BMI = 34.2 kg/m2). Every six months, participants completed a questionnaire assessing frequency and duration of weight loss strategies (calorie reduction, fat reduction, increased fruit/vegetable intake, increased exercise, elimination of sweets, consumption of less food). General linear models and structural equation methods were used to examine associations between weight loss strategy use and weight change over time.

Results

Weight loss strategy prevalence rates ranged from 68% to 76% over two years. For all dietary strategies, any use of the strategy between baseline and 24 months was associated with weight loss at 24 months; those who did not engage in the strategy showed weight gains during that period. Results of general linear models and structural equation models indicated that increased use of weight loss strategies was significantly associated with greater 24-month weight loss.

Conclusion

The prevalence of weight loss strategies in this obese adult managed care population was quite high, and use of these strategies was associated in dose-response fashion with better weight loss. Future interventions may benefit from emphasis on persistence of similar strategies to achieve more successful outcomes.
Virus-mediated autoimmunity in Multiple Sclerosis
Authors: Grigoriadis Nikolaos , Hadjigeorgiou Georgios M
Published: February 2006

Epidemiological data suggest the notion that in Multiple Sclerosis (MS) is an acquired autoimmune disease and the cause may be an environmental factor(s), probably infectious, in genetically susceptible individuals. Several cases of viral induced demyelinatimg encephalomyelitis in human beings and in experimental models as well as the presence of IgG oligoclonal bands in the cerebrospinal fluid indicate that the infectious factor may be viral. However, the absence of a specific virus identification in MS central nervous system may hardly support this notion. On the other hand, the partial response of patients with MS to immunosuppressive and immunomodulatory therapy support the evidence of an autoimmune etiology for MS. However, the autoimmune hypothesis shares the same criticism with the infectious one in that no autoantigen(s) specific to and causative for MS has ever been identified. Nevertheless, the absence of identifiable infectious agent, especially viral does not rule out its presence at a certain time – point and the concomitant long term triggering of an autoimmune cascade of events thereafter. Several concepts have emerged in an attempt to explain the autoimmune mechanisms and ongoing neurodegeneration in MS on the basis of the infectious – viral hypothesis.
Endothelial cell activation and neovascularization are prominent in dermatomyositis
Authors: Nagaraju Kanneboyina , Rider Lisa G , Fan Chenguang , Chen Yi-Wen , Mitsak Megan , Rawat Rashmi , Patterson Kathleen , Grundtman Cecilia , Miller Frederick W , Plotz Paul H , Hoffman Eric , Lundberg Ingrid E
Published: February 2006

Background

While vascular and immune abnormalities are common in juvenile and adult dermatomyositis (DM), the molecular changes that contribute to these abnormalities are not clear. Therefore, we investigated pathways that facilitate new blood vessel formation and dendritic cell migration in dermatomyositis.

Methods

Muscle biopsies from subjects with DM (9 children and 6 adults) and non-myositis controls (6 children and 7 adults) were investigated by immunohistochemistry using antibodies that recognize existing (anti-CD146) and newly formed blood vessels (anti-αVβ3) and mature dendritic cells (anti-DC-LAMP). Blood vessel quantification was performed by digitalized image analysis. Additional muscle biopsies from subjects with adult DM and non-myositis controls were used for global gene expression profiling experiments.

Results

A significant increase in neovascularization was found in muscle biopsies of DM patients; neovascularization (αVβ3 positive capillaries and vessels per muscle fiber) was much higher in juvenile than in adult DM patients (control vs juvenile DM: Mean ± SE: 0.06 ± 0.01 vs 0.6 ± 0.05; p < 0.0001 and control vs adult DM: Mean ± SE: 0.60 ± 0.1 vs 0.75 ± 0.1; p = 0.051). Gene expression analysis demonstrated that genes that participate not only in angiogenesis but also in leukocyte trafficking and the complement cascade were highly up regulated in DM muscle in comparison to age matched controls. DC-LAMP positive dendritic cells were highly enriched at perivascular inflammatory sites in juvenile and adult DM patients along with molecules that facilitate dendritic cell transmigration and reverse transmigration (CD142 and CD31).

Conclusion

These results suggest active neovascularization and endothelial cell activation in both juvenile and adult DM. It is likely that close association of monocytes with endothelial cells initiate rapid dendritic cell maturation and an autoimmune response in DM.
CD40 deficiency mitigates Alzheimer's disease pathology in transgenic mouse models
Authors: Laporte Vincent , Ait-Ghezala Ghania , Volmar Claude-Henry , Mullan Michael
Published: February 2006

We have previously shown that transgenic mice carrying a mutant human APP but deficient in CD40L, display a decrease in astrocytosis and microgliosis associated with a lower amount of deposited Aβ. Furthermore, an anti-CD40L treatment causes a diminution of Aβ pathology in the brain and an improved performance in several cognitive tasks in the double transgenic PSAPP mouse model. Although these data suggest a potential role for CD40L in Alzheimer's disease pathology in transgenic mice they do not cast light on whether this effect is due to inhibition of signaling via CD40 or whether it is due to the mitigation of some other unknown role of CD40L. In the present report we have generated APP and PSAPP mouse models with a disrupted CD40 gene and compared the pathological features (such as amyloid burden, astrocytosis and microgliosis that are typical of Alzheimer's disease-like pathology in these transgenic mouse strains) with appropriate controls. We find that all these features are reduced in mouse models deficient for CD40 compared with their littermates where CD40 is present. These data suggest that CD40 signaling is required to allow the full repertoire of AD-like pathology in these mice and that inhibition of the CD40 signaling pathway is a potential therapeutic strategy in Alzheimer's disease.
A model for generating circadian rhythm by coupling ultradian oscillators
Authors: Paetkau Verner , Edwards Roderick , Illner Reinhard
Published: February 2006

Background

Organisms ranging from humans to cyanobacteria undergo circadian rhythm, that is, variations in behavior that cycle over a period about 24 hours in length. A fundamental property of circadian rhythm is that it is free-running, and continues with a period close to 24 hours in the absence of light cycles or other external cues. Regulatory networks involving feedback inhibition and feedforward stimulation of mRNA transcription and translation are thought to be critical for many circadian mechanisms, and genes coding for essential components of circadian rhythm have been identified in several organisms. However, it is not clear how such components are organized to generate a circadian oscillation.

Results

We propose a model in which two independent transcriptional-translational oscillators with periods much shorter than 24 hours are coupled to drive a forced oscillator that has a circadian period, using mechanisms and parameters of conventional molecular biology. Furthermore, the resulting circadian oscillator can be entrained by an external light-dark cycle through known mechanisms. We rationalize the mathematical basis for the observed behavior of the model, and show that the behavior is not dependent on the details of the component ultradian oscillators but occurs even if quite generalized basic oscillators are used.

Conclusion

We conclude that coupled, independent, transcriptional-translational oscillators with relatively short periods can be the basis for circadian oscillators. The resulting circadian oscillator can be entrained by 24-hour light-dark cycles, and the model suggests a mechanism for its evolution.
HSV-Mediated Expression of Interleukin-4 in Dorsal Root Ganglion Neurons Reduces Neuropathic Pain
Authors: Hao Shuanglin , Mata Marina , Glorioso Joseph C , Fink David J
Published: February 2006

Background

To examine the role of inflammatory mediators in neuropathic pain, we used a replication-defective genomic herpes simplex virus (HSV)-based vector containing the coding sequence for the anti-inflammatory peptide interleukin (IL)-4 under the transcriptional control of the HSV ICP4 immediate early promoter, vector S4IL4, to express IL-4 in dorsal root ganglion (DRG) neurons in vivo.

Results

Subcutaneous inoculation of S4IL4 in the foot transduced lumbar DRG to produce IL-4. Transgene-mediated expression of IL-4 did not alter thermal latency or tactile threshold in normal animals, but inoculation of S4IL4 1 week after spinal nerve ligation (SNL) reduced mechanical allodynia and reversed thermal hyperalgesia resulting from SNL. Inoculation of S4IL4 1 week before SNL delayed the development of thermal hyperalgesia and tactile allodynia, but did not prevent the ultimate development of these manifestations of neuropathic pain. S4IL4 inoculation suppressed non-noxious-induced expression of c-Fos immunoreactivity in dorsal horn of spinal cord and reversed the upregulation of spinal IL-1β, PGE2, and phosphorylated-p38 MAP kinase, characteristic of neuropathic pain.

Conclusion

HSV-mediated expression of IL-4 effectively reduces the behavioral manifestations of neuropathic pain, and reverses some of the biochemical and histologic correlates of neuropathic pain at the spinal level.
Genetic Reduction of Chronic Muscle Pain in Mice Lacking Calcium/Calmodulin-Stimulated Adenylyl Cyclases
Authors: Vadakkan Kunjumon I , Wang Hansen , Ko Shanelle W , Zastepa Evelyn , Petrovic Michele J , Sluka Kathleen A , Zhuo Min
Published: February 2006

Background

The Ca2+/calmodulin-stimulated adenylyl cyclase (AC) isoforms AC1 and AC8, couple NMDA receptor activation to cAMP signaling pathways in neurons and are important for development, learning and memory, drug addiction and persistent pain. AC1 and AC8 in the anterior cingulate cortex (ACC) and the spinal cord were previously shown to be important in subcutaneous inflammatory pain. Muscle pain is different from cutaneous pain in its characteristics as well as conducting fibers. Therefore, we conducted the present work to test the role of AC1 and AC8 in both acute persistent and chronic muscle pain.

Results

Using an acute persistent inflammatory muscle pain model, we found that the behavioral nociceptive responses of both the late phase of acute muscle pain and the chronic muscle inflammatory pain were significantly reduced in AC1 knockout (KO) and AC1&8 double knockout (DKO) mice. Activation of other adenylyl cyclases in these KO mice by microinjection of forskolin into the ACC or spinal cord, but not into the peripheral tissue, rescued the behavioral nociceptive responses. Additionally, intra-peritoneal injection of an AC1 inhibitor significantly reduced behavioral responses in both acute persistent and chronic muscle pain.

Conclusion

The results of the present study demonstrate that neuronal Ca2+/calmodulin-stimulated adenylyl cyclases in the ACC and spinal cord are important for both late acute persistent and chronic inflammatory muscle pain.
Depression of Presynaptic Excitation by the Activation of Vanilloid Receptor 1 in the Rat Spinal Dorsal Horn Revealed by Optical Imaging
Authors: Kusudo Kei , Ikeda Hiroshi , Murase Kazuyuki
Published: February 2006

In this study, we show that capsaicin (CAP) depresses primary afferent fiber terminal excitability by acting on vanilloid receptor 1 (TRPV1 channels) of primary afferent fibers in adenosine 5′-triphosphate (ATP)- and temperature-dependent manner using two optical imaging methods. First, transverse slices of spinal cord were stained with a voltage-sensitive dye and the net excitation in the spinal dorsal horn was recorded. Prolonged treatment (>20 min) with the TRPV1 channel agonist, CAP, resulted in a long-lasting inhibition of the net excitation evoked by single-pulse stimulation of C fiber-activating strength. A shorter application of CAP inhibited the excitation in a concentration-dependent manner and the inhibition was reversed within several minutes. This inhibition was Ca++-dependent, was antagonized by the TRPV1 channel antagonist, capsazepine (CPZ), and the P2X and P2Y antagonist, suramin, and was facilitated by the P2Y agonist, uridine 5′-triphosphate (UTP). The inhibition of excitation was unaffected by bicuculline and strychnine, antagonists of GABAA and glycine receptors, respectively. Raising the perfusate temperature to 39°C from 27°C inhibited the excitation (−3%/°C). This depressant effect was antagonized by CPZ and suramin, but not by the P2X antagonist, 2′, 3′-O-(2,4,6-trinitrophenyl) adenosine 5′-triphosphate (TNP-ATP). Second, in order to record the presynaptic excitation exclusively, we stained the primary afferent fibers anterogradely from the dorsal root. CAP application and a temperature increase from 27°C to 33°C depressed the presynaptic excitation, and CPZ antagonized these effects. Thus, this study showed that presynaptic excitability is modulated by CAP, temperature, and ATP under physiological conditions, and explains the reported central actions of CAP. These results may have clinical importance, especially for the control of pain.
Mathematical modeling of tumor therapy with oncolytic viruses: Regimes with complete tumor elimination within the framework of deterministic models
Authors: Novozhilov Artem S , Berezovskaya Faina S , Koonin Eugene V , Karev Georgy P
Published: February 2006

Background

Oncolytic viruses that specifically target tumor cells are promising anti-cancer therapeutic agents. The interaction between an oncolytic virus and tumor cells is amenable to mathematical modeling using adaptations of techniques employed previously for modeling other types of virus-cell interaction.

Results

A complete parametric analysis of dynamic regimes of a conceptual model of anti-tumor virus therapy is presented. The role and limitations of mass-action kinetics are discussed. A functional response, which is a function of the ratio of uninfected to infected tumor cells, is proposed to describe the spread of the virus infection in the tumor. One of the main mathematical features of ratio-dependent models is that the origin is a complicated equilibrium point whose characteristics determine the main properties of the model. It is shown that, in a certain area of parameter values, the trajectories of the model form a family of homoclinics to the origin (so-called elliptic sector). Biologically, this means that both infected and uninfected tumor cells can be eliminated with time, and complete recovery is possible as a result of the virus therapy within the framework of deterministic models.

Conclusion

Our model, in contrast to the previously published models of oncolytic virus-tumor interaction, exhibits all possible outcomes of oncolytic virus infection, i.e., no effect on the tumor, stabilization or reduction of the tumor load, and complete elimination of the tumor. The parameter values that result in tumor elimination, which is, obviously, the desired outcome, are compatible with some of the available experimental data.

Reviewers

This article was reviewed by Mikhail Blagosklonny, David Krakauer, Erik Van Nimwegen, and Ned Wingreen.
Aluminosis – Detection of an almost forgotten disease with HRCT
Authors: Kraus Thomas , Schaller Karl Heinz , Angerer Jürgen , Hilgers Ralf-Dieter , Letzel Stephan
Published: February 2006

The aim of this study was to investigate whether it is possible to detect high-resolution computed tomography (HRCT) findings in aluminium powder workers, which are consistent with early stages of aluminosis.

62 male workers from 8 departments of two plants producing aluminium (Al) powder were investigated using a standardized questionnaire, physical examination, lung function analysis, biological monitoring of Al in plasma and urine, chest X-ray, HRCT and immunological tests.

Chronic bronchitis was observed in 15 (24.2%) of the workers, and four workers (6.5%) reported shortness of breath during exercise. HRCT findings in 15 workers (24.2%) were characterized by ill-defined centrilobular nodular opacities. Workers with ill-defined centrilobular nodular opacities had a lower vital capacity than workers who had no such HRCT-findings (90.9 % pred. vs. 101.8 % pred., p = 0.01). Biological monitoring in plasma and urine revealed higher internal exposure to Al in affected workers (33.5 μg/l plasma to 15.4 μg/l plasma, p = 0.01) and (340.5 μg/g creat. to 135.1 μg/g creat., p = 0.007). Years of exposure and concentration of aluminum in urine and plasma appear to be the best predictors for HRCT findings. Age and decreased vital capacity show borderline significance.

We conclude that aluminosis is still relevant in occupational medicine. With HRCT it is possible to detect early stages of aluminosis and biological monitoring can be used to define workers at high risk.
Biological and biomechanical evaluation of interface reaction at conical screw-type implants
Authors: Büchter Andre , Joos Ulrich , Wiesmann Hans-Peter , Seper László , Meyer Ulrich
Published: February 2006

Background

Initial stability of the implant is, in effect, one of the fundamental criteria for obtaining long-term osseointegration. Achieving implant stability depends on the implant-bone relation, the surgical technique and on the microscopic and macroscopic morphology of the implant used. A newly designed parabolic screw-type dental implant system was tested in vivo for early stages of interface reaction at the implant surface.

Methods

A total of 40 implants were placed into the cranial and caudal part of the tibia in eight male Göttinger minipigs. Resonance frequency measurements (RFM) were made on each implant at the time of fixture placement, 7 days and 28 days thereafter in all animals. Block biopsies were harvested 7 and 28 days (four animals each) following surgery. Biomechanical testing, removable torque tests (RTV), resonance frequency analysis; histological and histomorphometric analysis as well as ultrastructural investigations (scanning electron microscopy (SEM)) were performed.

Results

Implant stability in respect to the measured RTV and RFM-levels were found to be high after 7 days of implants osseointegration and remained at this level during the experimented course. Additionally, RFM level demonstrated no alteration towards baseline levels during the osseointegration. No significant increase or decrease in the mean RFM (6029 Hz; 6256 Hz and 5885 Hz after 0-, 7- and 28 days) were observed. The removal torque values show after 7 and 28 days no significant difference. SEM analysis demonstrated a direct bone to implant contact over the whole implant surface. The bone-to-implant contact ratio increased from 35.8 ± 7.2% to 46.3 ± 17.7% over time (p = 0,146).

Conclusion

The results of this study indicate primary stability of implants which osseointegrated with an intimate bone contact over the whole length of the implant.