bluuebunny/crossref_metadata_2025 huggingface dataset:
Tissue Levels of WR-1065, the Active Metabolite of Amifostine (Ethyol®), Are Equivalent following Intravenous or Subcutaneous Administration in Cynomolgus Monkeys
Authors: Bachy Christine M. , Fazenbaker Christine A. , Kifle Gizachew , McCarthy Michael P. , Cassatt David R.
Published: December 2004

Amifostine (Ethyol®) is a cytoprotective drug approved for the reduction of xerostomia in head and neck cancer when administered to patients receiving postoperative radiation therapy. Although amifostine is approved for intravenous infusion, the off-label subcutaneous route of administration has become more prevalent. Although human patient data indicate higher plasma bioavailability of the active metabolite (WR-1065) following intravenous compared to subcutaneous administration, there are no corresponding data showing human tissue levels of WR-1065 following either route of administration due to the difficulty in obtaining human specimens. In our study we compared plasma and tissue pharmacokinetics of WR-1065 in primates following both routes of administration. Monkeys received amifostine at a dose of 260 mg/m2 either intravenously or subcutaneously. Plasma samples were analyzed for total WR-1065 by reverse-phase high-pressure liquid chromatography (HPLC) and fluorescence detection up to 4 h after amifostine administration. Tissues were analyzed for free WR-1065 by reverse-phase HPLC and electrochemical detection 30 and 60 min after administration. Following intravenous administration, plasma WR-1065 levels peaked rapidly and showed a bi-exponential decline, while following subcutaneous administration WR-1065 levels rose slowly and declined exponentially. The relative plasma bioavailability of WR-1065 given subcutaneously was lower at 30 and 60 min. Interestingly, after 30 min, tissues showed equal or slightly greater concentrations of WR-1065 following subcutaneous administration. Levels following 60 min were comparable following both routes. The plasma bioavailability studies performed in primates confirm human plasma data. Expanding the study to evaluate primate tissue levels of WR-1065 revealed that despite lower plasma bioavailability following subcutaneous administration, tissue levels of the active metabolite were surprisingly greater than or equal to those measured in animals that received the drug intravenously. These studies strengthen the argument for subcutaneous administration of amifostine in radiation oncology.
Clinical Perspective on Desmoplastic Small Round-Cell Tumor
Authors: Gil Alberto , Gomez Portilla Alberto , Brun Erwin A. , Sugarbaker Paul H.
Published: December 2004

Rare diseases are often associated with uninformed medical decisions and poorly executed treatments because of inexperience of the physicians. Desmoplastic small round-cell tumor is a rare disease that is a form of peritoneal surface malignancy usually affecting young males, with a mean survival of 29 months. In order to begin to build a more knowledgeable clinical pathway all 7 patients treated at the Washington Hospital Center were studied and compared to patients described in the medical literature. Clinical and pathological data, tumor distribution, cytoreductive surgery, completeness of cytoreduction and survival were recorded and analyzed. The first most common symptoms were pain, increased abdominal girth and palpable abdominal mass in our patients and in the literature review. The overall survival did not improve with cytoreductive surgery plus intraperitoneal chemotherapy (mean survival 32 months); however, 2 long-term survivors who responded to systemic chemotherapy of 55 and 101 months were recorded. The latter may be the longest survivor reported in the literature. No consistent response to chemotherapy was observed in our patients or in any literature review. Complete surgical removal of this malignancy did not correlate with survival in our patients. The absence of improved survival of our aggressively treated patients as compared to the literature was thought to be a consequence of an advanced stage of the disease. A new comprehensive approach that uses complete clearing of cancer by surgery and perioperative systemic and perioperative intraperitoneal chemotherapy as early as is possible in the natural history of the disease emerged as goals for future management.
Expression Profiles of a Human Pancreatic Cancer Cell Line upon Induction of Apoptosis Search for Modulators in Cancer Therapy
Authors: Blasco F. , Peñuelas S. , Cascalló M. , Hernández J.L. , Alemany C. , Masa M. , Calbó J. , Soler M. , Nicolás M. , Pérez-Torras S. , Gómez A. , Tarrasón G. , Noé V. , Mazo A. , Ciudad C.J. , Piulats J.
Published: December 2004

We analyzed the differential gene expression in the pancreatic cancer cell line NP-18 upon induction of apoptosis caused by cyclin-dependent kinase inhibition triggered by either overexpression of the tumor suppressor gene p16INK4Ausing an adenoviral construction or incubation with the chemical inhibitors, roscovitine or olomoucine. Screening was performed using cDNA arrays from Clontech that allowed the determination of the expression of 1,176 genes specifically related with cancer. The analysis was carried out using the Atlas Image 2.01 (Clontech) and GeneSpring 4.2 (Silicon Genetics) softwares. Among the differentially expressed genes, we chose for further validation histone deacetylase 1 (HDAC1), von Hippel Lindau and decorin as upregulated genes, and Sp1, hypoxia-inducible factor-1 alpha and DNA primase as downregulated genes. The changes in the expression of these genes to mRNA were validated by quantitative RT-PCR and the final translation into protein by Western blot analysis. Inhibition of HDAC activity, Sp1 binding and DNA primase expression led to an increase in the level of apoptosis, both in parental cells and in doxorubicin-resistant cells. Therefore, these proteins could constitute possible targets to develop modulators in cancer chemotherapy that would increase or restore apoptosis.
Prognostic Significance of Stromelysin-3 and Tissue Inhibitor of Matrix Metalloproteinase-2 in Esophageal Cancer
Authors: Sharma Rinu , Chattopadhyay Tushar Kant , Mathur Meera , Ralhan Ranju
Published: December 2004

Objective: Stromelysins (matrix metalloproteinases: MMP-10 or ST-2 and MMP-11 or ST-3) and tissue inhibitors of matrix metalloproteinases (TIMP-1 and 2) have been shown to be associated with human tumor progression, invasion and metastasis. The aim of the present study was to determine the prognostic significance of these proteins in esophageal squamous cell carcinoma (ESCC). Methods: Immunohistochemical analysis was carried out in 65 surgically resected ESCCs and 49 distant histologically normal esophageal tissues and 16 cases of dysplasias. Statistical analyses were performed to determine the associations between the protein expression and clinicopathological parameters and survival of esophageal cancer patients. Results: Expression of ST-2, ST-3, TIMP-1 and TIMP-2 was observed in 43/65 (66%), 51/65 (78%), 43/65 (66%) and 47/65 (72%) ESCC cases, respectively. Univariate analysis showed that TIMP-2 expression was associated with tumor site (OR = 2.63, p = 0.017). TIMP-1+/TIMP-2+ phenotype was inversely correlated with nodal invasiveness of the tumor (OR = 0.4, p = 0.04). Interestingly, p53 expression was associated with increased levels of ST-3 (OR = 0.11, p = 0.02) and TIMP-1 (OR = 3.2, p = 0.007) suggesting possible involvement of p53 in the regulation of these proteins. An increased expression of ST-2, ST-3, TIMP-1 and TIMP-2 was observed in 11/16 (69%), 7/17 (44%), 11/16 (69%) and 8/16 (50%) dysplasias also suggesting that these alterations are early events in esophageal tumorigenesis. All the ESCC patients were followed up postesophagectomy for a maximum period of 59 months (mean disease-free survival = 12 months). Kaplan-Meier survival analysis showed that patients with ST-3-positive and TIMP-2-negative carcinoma had a significantly shorter disease-free survival (median disease-free survival time of 4 months) as compared to patients in the other groups (median disease-free survival time of 20 months; p = 0.0016). To our knowledge this is the first report showing that ST-3+/TIMP-2– phenotype remained of significant predictive value for disease-free survival (p = 0.0007) in multivariate analysis including a conventional clinicopathological factor, tumor stage (p = 0.051). Conclusion: Our results suggest that ST-3+/TIMP-2– phenotype is an adverse prognosticator in esophageal cancer patients.
Involvement of ERK1/2 and p38 MAP Kinase in Doxorubicin-Induced uPA Expression in Human RC-K8 Lymphoma and NCI-H69 Small Cell Lung Carcinoma Cells
Authors: Niiya Masami , Niiya Kenji , Shibakura Misako , Asaumi Noboru , Yoshida Chikamasa , Shinagawa Katsuji , Teshima Takanori , Ishimaru Fumihiko , Ikeda Kazuma , Tanimoto Mitsune
Published: December 2004

We previously demonstrated the doxorubicin-induced urokinase-type plasminogen activator (uPA) expression in human RC-K8 lymphoma cells and NCI-H69 small cell lung carcinoma cells in which reactive oxygen species might be involved. Western blotting analysis revealed phosphorylation/activation of mitogen-activated protein (MAP) kinases, such as extracellular signal-regulated kinase (ERK) 1/2, p38 MAP kinase and stress-activated protein kinase/c-jun N-terminal protein kinase (SAPK/JNK) in doxorubicin-treated RC-K8 and H69 cells, and, therefore, we attempted to identify the MAP kinases implicated in doxorubicin-induced uPA expression by the use of their specific inhibitors. U0126, SB202190 and JNKI-1, inhibitors for MAPK kinase, (MEK) 1/2, p38 MAP kinase and SAPK/JNK, respectively, specifically and clearly inhibited their corresponding kinases. U0126 and SB202190, but not JNKI-1, almost completely inhibited the doxorubicin-induced uPA expression in both RC-K8 and H69 cells. However, U0126 rather enhanced the doxorubicin-induced activation of caspase-3 and poly ADP-ribose polymerase (PARP), and U0126 itself activated caspase-3 and PARP. Interestingly, JNKI-1 inhibited the doxorubicin-induced activation of caspase-3 and PARP. Therefore, doxorubicin treatment activates the above three kinases, but different MAP kinase signaling is responsible in the doxorubicin-induced caspase activation and expression of uPA. Thus, we could possibly manipulate the direction of doxorubicin-induced MAP kinase activation and the effects of doxorubicin on the tumor cell biology by the use of MAP kinase inhibitors.
Analysis of Candidate Genes for Prostate Cancer
Authors: Burmester James K. , Suarez Brian K. , Lin Jennifer H. , Jin Carol H. , Miller Raymond D. , Zhang Kai-Qi , Salzman Sherry A. , Reding Douglas J. , Catalona William J.
Published: December 2004

Considerable evidence demonstrates that genetic factors are important in the development and aggressiveness of prostate cancer. To identify genetic variants that predispose to prostate cancer we tested candidate SNPs from genomic regions that show linkage to prostate cancer susceptibility and/or aggressiveness, as well as genes that show a significant difference in mRNA expression level between tumor and normal tissue. Cases had histologically verified prostate cancer. Controls were at least 65 years old, never registered a PSA above 2.5 ng/ml, always had digital rectal examinations that were not suspicious for cancer, and have no known family history of prostate cancer. Thirty-nine coding SNPs and nine non-coding SNPs were tested in up to 590 cases and 556 controls resulting in over 40,000 SNP genotypes. Significant differences in allele frequencies between cases and controls were observed for ID3 (inhibitor of DNA binding), p = 0.05, HPN (hepsin), p = 0.009, BCAS1 (breast carcinoma amplified sequence 1), p = 0.007, CAV2 (caveolin 2), p = 0.007, EMP3 (epithelial membrane protein 3), p < 0.0001, and MLH1 (mutL homolog 1), p < 0.0001. SNPs in three of these genes (BCAS1, EMP3 and MLH1) remained significant in an age-matched subsample.
A Note on Inference of Trait Associations with SNP Haplotypes and Other Attributes in Generalized Linear Models
Authors: Burkett Kelly , McNeney Brad , Graham Jinko
Published: December 2004

Recently, Lake et al. [Human Heredity 2003;55:56–65] have proposed an approach based on the EM algorithm for maximum-likelihood inference of trait associations with haplotypes and environmental cofactors in generalized linear models. In this short report, we describe an extension to accommodate missing SNP genotype information. We also discuss differences in the calculation of standard errors between their implementation and our own. Finally, we present results indicating that inference is robust to low levels of dependence between haplotypes and nongenetic factors, but that biased inference can result when there is moderate to strong dependence. Overall, the method is found to perform well in the models we considered.
On Computation of p-Values in Parametric Linkage Analysis
Authors: Kurbasic Azra , Hössjer Ola
Published: December 2004

Parametric linkage analysis is usually used to find chromosomal regions linked to a disease (phenotype) that is described with a specific genetic model. This is done by investigating the relations between the disease and genetic markers, that is, well-characterized loci of known position with a clear Mendelian mode of inheritance. Assume we have found an interesting region on a chromosome that we suspect is linked to the disease. Then we want to test the hypothesis of no linkage versus the alternative one of linkage. As a measure we use the maximal lod score Zmax. It is well known that the maximal lod score has asymptotically a (2 ln 10)–1 × (1/2 χ2(0) + 1/2 χ2(1)) distribution under the null hypothesis of no linkage when only one point (one marker) on the chromosome is studied. In this paper, we show, both by simulations and theoretical arguments, that the null hypothesis distribution of Zmax has no simple form when more than one marker is used (multipoint analysis). In fact, the distribution of Zmax depends on the number of families, their structure, the assumed genetic model, marker denseness, and marker informativity. This means that a constant critical limit of Zmax leads to tests associated with different significance levels. Because of the above-mentioned problems, from the statistical point of view the maximal lod score should be supplemented by a p-value when results are reported.
Linkage Analysis Using Single Nucleotide Polymorphisms
Authors: Browning Brian L. , Brashear Donna L. , Butler Andy A. , Cyr Devon D. , Harris Elizabeth C. , Nelsen Anita J. , Yarnall David P. , Ehm Margaret G. , Wagner Michael J.
Published: December 2004

We performed multipoint linkage analysis using 83 markers from the SNP Consortium (TSC) SNP linkage map in 3 regions covering 190 cM previously scanned with microsatellite markers and found to be linked to type 2 diabetes. Since the average linkage disequilibrium present in the TSC SNP marker clusters is relatively low, we assumed the intracluster genetic distances were a reasonable small nonzero distance (0.03 cM) and performed linkage analysis using GENEHUNTER PLUS and ASM linkage analysis software. We found that for the pedigree structures and missing data patterns in our samples the average information content in all three regions and the LOD score curves in two regions obtained from the TSC SNP markers were similar to results obtained from microsatellite marker maps with 10 cM average spacing. We also give an algorithm which extends the Lander-Green algorithm to permit multipoint linkage analysis of clusters of tightly linked markers with arbitrarily high levels of intracluster linkage disequilibrium.
The Pattern of Inflammation and a Potential New Clinical Meaning and Usefulness of C-Reactive Protein in End-Stage Renal Failure Patients
Authors: Tsirpanlis George
Published: December 2004

Inflammatory indexes are frequently elevated in end-stage renal failure (ESRF) patients. It seems that the pattern of inflammation is particular in this population. In the presence of a higher than normal microinflammatory background (CRP, C-reactive protein, values between 0.1 and 10–15 mg/l) that varies with time, waves of ‘true’ inflammation (CRP > 10–15 mg/l), mainly due to infections, are added periodically. To accurately assess the average microinflammation in these patients, multiple CRP measurements are required. As recent experimental studies showed that inflammation and particularly elevated CRP levels may be risk factors and not just a risk index for atherosclerosis, in this case, the characteristic inflammation pattern might be of importance in the evolution of this disease in ESRF patients. The causes of the inflammatory state in ESRF patients are multiple: renal insufficiency per se and its complications, coexisting diseases, established atherosclerosis, the consequences of renal replacement treatment, and frequent infections are potentially the main ones. The fluctuating inflammatory pattern is probably due to destabilization or changes in time of the above-mentioned parameters. Thus, the clinical meaning of the average microinflammation in these patients, as assessed by CRP measurements, seems to be that of an index indicative of the grade of their health aggravation by the multiple factors implicated in the inflammation formation. CRP is a sensitive, but not specific, risk index of the overall morbidity and mortality in these patients. The manipulation of the inflammation in ESRF patients should include follow-up and treatment of all the factors that contribute to this state and probably medications such as the statins. If inflammation and CRP in particular definitely prove to be risk factors for atherosclerosis, intensification of this treatment will be necessary.
Mentorship in Medical Research
Authors: Kjeldsen Keld , Bech Jan , Andersen Schmidt Thomas
Published: December 2004

Mentorship has been recognised as essential for success in medical research. We describe how to make contact with the medical research community and find a mentor. Moreover, we describe how to establish a working relationship with a proficient mentor and provide answers to some of the most important questions that the novice in medical research should always ask himself before committing himself to a supervisor: What is your bid – and what is your mentor’s quid pro quo in the relationship? How do you find a field of research? How do you evaluate a potential mentor? How can you make first contact with a mentor? And what about resources? It is important that the student’s expectations regarding the mentor’s input – and vice versa – are well defined at an early stage. We advocate finding a field of research that genuinely interests you and, most importantly, where you have a proven record of your industriousness. A mentor should be evaluated on the basis of his insight and knowledge as well as the time he can spare for supervision and productivity. PubMed and Science Citation Index checks may give useful information regarding a supervisor’s publication profile; but you should also take into account someone’s reputation as a supervisor. A mentor should provide the resources needed to get started. Try to obtain an appointment with a prospective mentor and go there prepared by having read relevant information. Start contemplating the research plan once both parties decide to give it a go. It will serve as a written agreement between student and mentor.
Parietal Lobe Epilepsy: Surgical Treatment and Outcome
Authors: Kim Chi Heon , Chung Chun-Kee , Lee Sang Kun , Lee Yoon Kyung , Chi Je G.
Published: December 2004

Objective: Parietal lobe epilepsy (PLE) is neither common nor easily diagnosed because of its variable clinical features. To elucidate its characteristics and surgical outcome, the authors reviewed their surgical experiences. Methods: Between September 1994 and August 2001, 38 patients with PLE received surgical treatment at the Seoul National University Hospital. All patients underwent resection, mainly involving the parietal lobe. Results: Preoperatively, over 60% of the cases were not considered to be PLE, even though PLE was the most common diagnosis (15/38, 39.8%). An invasive study was performed in 37 of the 38 patients. Awake operations under regional anesthesia were performed in 20 patients (52.6%). Seizure disappeared in 15 (Engel’s classification I, 39.5%), and rare seizure remained in 5 (Engel II, 13.2%). Thirteen patients showed a worthwhile improvement (Engel III, 34.2%), whereas 5 exhibited no worthwhile improvement (Engel IV, 13.2%). Pathologies were diverse, the most common being cortical dysplasia (94.3%). Conclusion: Since PLE is difficult to diagnose preoperatively, an invasive study covering the parietal lobe is mandatory, if PLE is suspected. Cortical dysplasia was the most common etiology, thus awake operation under regional anesthesia and intraoperative brain mapping is helpful during extensive resection in order to spare the eloquent cortex.
Aphasia and Thalamotomy: Important Issues
Authors: Bruce Beau B. , Foote Kelly D. , Rosenbek John , Sapienza Christine , Romrell Janet , Crucian Greg , Okun Michael S.
Published: December 2004

Patients may present with classical symptoms suggesting aphasia following thalamotomy (repetition, comprehension, fluency and naming abnormalities). They may also present with ‘freezing of speech’, and this symptom should not be considered as a speech disorder or a symptom of Parkinson’s disease progression, without careful testing to rule out language deficits, particularly dysfluency. There are important issues related to all language complications of thalamotomy, including (1) the time course of problems following surgery, (2) the impact of preexistingspeech problems, (3) the importance of the size and location of lesions, (4) the potential circuits important in the pathogenesis of a thalamic language disturbance and (5) whether laterality makes a difference (left- versus right-sided thalamic lesions). As more centers switch from thalamotomy to deep brain stimulation, the issues regarding aphasia will need to be addressed.
Deep Brain Stimulation for Parkinson’s Disease: Association between Stimulation Parameters and Cognitive Performance
Authors: Francel P. , Ryder K. , Wetmore J. , Stevens A. , Bharucha K. , Beatty W.W. , Scott J.
Published: December 2004

Chronic subthalamic nucleus stimulation produces inconsistent patterns of cognitive change in Parkinson’s disease patients. Individually tailored stimulation parameters may contribute to this variable pattern of change. Systematic variation of amplitude, pulse width, and rate of stimulation has been reported to produce unique changes in motor and limbic response. To evaluate the association between stimulation parameters and cognitive/behavioral response, neuropsychological performance and stimulation parameter data of 8 Parkinson’s disease patients were submitted to Pearson r correlation analysis. Results indicate that each stimulation parameter was significantly associated with a subset of measures. The current findings raise the possibility that adverse cognitive/behavioral responses may be treated through parameter modification while maintaining motor symptom efficacy.
Indigestible Components of Grape Seeds Modify Cecal Enzyme Activity in Rats
Authors: Goñi Isabel
Published: December 2004

Background: The effect of grape seed indigestible fraction (GSIF) on cecal enzyme activity was studied. Methods: β-Glucuronidase, β-glucosidase, azoreductase, nitroreductase and nitrate reductase were measured in the cecal content of adult Wistar rats fed with a fiber-free diet supplemented with 5% cellulose or 5% GSIF as the source of dietary fiber for 4 weeks. Results: The intake of GSIF did not affect body weight gain nor food intake. However, GSIF caused a significant increase in cecal content, cecal wall and fresh and dry stool weight. Bacterial enzyme activities were lower in the GSIF-fed group than in the cellulose-fed group, although the difference was also significant for nitroreductase and β-glucuronidase. Conclusion: Adaptation to a diet containing GSIF led to changes in microbial activity that involved a decrease in reductive and hydrolytic enzymatic activities implicated in the conversion of procarcinogens into carcinogens.
Benevolent Voices Are Not So Kind: The Functional Significance of Auditory Hallucinations
Authors: Favrod J. , Grasset F. , Spreng S. , Grossenbacher B. , Hodé Y.
Published: December 2004

Background: This study measures the impact of beliefs about auditory hallucinations on social functioning. Sampling and Methods: Twenty-nine subjects who met the ICD-10 criteria for schizophrenia or a schizo-affective disorder were included. Beliefs about voices and coping responses as measured by the Beliefs about Voices Questionnaire were compared with social functioning as assessed with the Life Skills Profile (LSP). Results: The belief that voices are benevolent was associated with poor communication. Engagement with voices was correlated with the non-turbulence and the compliance factors of the LSP. Patients who held the belief that their voices were benevolent functioned significantly more poorly on the communication factor of the LSP than patients who interpreted their voices as malevolent. Discussion: The results indicate that a positive relationship with voices may affect social functioning. However, the size of the sample is small and patients with benevolent voices are overrepresented. Nonetheless, these results have implications for the use of cognitive therapy for psychotic symptoms.
Monoclonal Antibody-Based ELISA to Quantify the Major Allergen of Cynodon dactylon (Bermuda Grass) Pollen, Cyn d 1
Authors: Duffort O. , Calabozo B. , González R. , Carpizo J.A. , Barber D. , Polo F.
Published: December 2004

Background: Pollen of Bermuda grass (Cynodon dactylon) is an important cause of pollinosis in many areas of the world. Most patients show sensitivity to the major allergen Cyn d 1, a glycoprotein composed of a number of isoforms with a molecular mass of 31–32 kDa. The aim of this work was to develop a monoclonal antibody (mAb)-based ELISA to quantify Cyn d 1, and to assess the correlation of the allergen content with the biological activity of C. dactylon pollen extracts. Methods:After fusion of myeloma cells with spleen cells from a BALB/c mouse immunized with C. dactylon pollen extract, Cyn d 1-specific mAbs secreting hybridomas were selected, and the antibodies characterized. One of them (4.4.1) was used as the capture antibody in an ELISA method for Cyn d 1 quantitation. An anti-Cyn d 1 rabbit serum was used as the second antibody. Cyn d 1 was purified by immunoaffinity chromatography with mAb 4.4.1, characterized, and used as the standard in the assay. Results: The identity, purity and isoallergen composition of affinity-purified Cyn d 1 was confirmed by N-terminal amino acid sequencing, SDS-PAGE, Western blot and 2D electrophoresis. The Cyn d 1 ELISA is highly specific and sensitive, with a detection limit of 0.24 ng/ml and a linear range of 1.1–9.2 ng/ml. An excellent correlation was found when the content of Cyn d 1, measured in 16 different extracts, was compared with the allergenic activity of the same extracts determined by RAST inhibition. Conclusions: The results prove the usefulness of the Cyn d 1 ELISA for the standardization of C. dactylon-allergen products on the basis of major allergen content.
T-Cell Receptor-Mediated Cross-Allergenicity
Authors: Burastero Samuele E. , Paolucci Clara , Breda Daniela , Longhi Renato , Silvestri Michela , Hammer Juergen , Protti Maria Pia , Rossi Giovanni A.
Published: December 2004

Background: Profilins are conserved and ubiquitous plant and animal proteins. We wanted to discover whether the T-cell response to conserved epitopes on birch and grass profilins could account for cross-allergenicity in subjects allergic to these two pollens. Methods: Thirty-one patients allergic to grass and birch were recruited for the study. Grass and birch reactive T lymphocytes were studied by measuring proliferation to birch and grass allergen, respectively, followed by Vβ T-cell receptor family-specific polymerase chain reaction and heteroduplex analysis. T-cell clones were derived from patients with cross-proliferating T cells. Results: In 25 of 31 subjects the T-cell response to grass was quite distinct from that to birch. In contrast, in 6 of 31 individuals grass T cells cross-proliferated to birch and this was reproduced in 4 patients by birch profilin. CD4 Th2 cell clones were derived which promiscuously recognized homologously conserved regions on birch and grass profilins. Conclusion: We conclude that a functionally relevant T-cell response to conserved regions of panallergens underlie cross-allergenicity in a subset of allergic patients. These results suggest that a reciprocal modulation of the response to one sensitizing allergen can occur following natural exposure to or immunotherapy with another allergen. These results have relevance in the management of patients with multiple allergies.
Staphylococcal Enterotoxin-B-Mediated Stimulation of Interleukin-13 Production as a Potential Aetiologic Factor in Eczema in Infants
Authors: Lehmann H.S. , Heaton T. , Mallon D. , Holt P.G.
Published: December 2004

Background: Staphylococcus aureus colonization has been found in 80–100% of lesional skin from patients with atopic eczema dermatitis syndrome (AEDS) and is thought to have a role in the pathogenesis of the disease. Furthermore, up to 65% of S. aureus from lesional skin has been shown to produce toxigenic superantigens. Methods: Using a cohort of 11 children under 2 years of age diagnosed with AEDS, we isolated peripheral blood mononuclear cells, cultured them with staphylococcal enterotoxin B (SEB) and phytohaemagglutinin, and assessed the cytokine response profiles. Plasma was also collected for immunoglobulin E analysis. In addition, skin and nasal swabs were taken and cultured to determine the presence of SEB-producing S. aureus by polymerase chain reaction (PCR) and reverse passive latex agglutination. Results: We found a significant increase in the production of the SEB-induced cytokines interleukin (IL)-5 and IL-13 in the patient group when compared with non-atopic, healthy controls. For IL-13, there was almost no overlap in the levels between the groups. However, there was no correlation between SEB-induced IL-13 and disease severity. This difference was not seen when heat-inactivated S. aureus was used to stimulate the cells. Conclusions: IL-13 is an important factor in AEDS development in early childhood, and prophylactic anti-staphylococcal treatment may provide protection from AEDS in atopic individuals.
Efficacy of Injection Immunotherapy with Ragweed and Birch Pollen in Elderly Patients
Authors: Asero Riccardo
Published: December 2004

Background: The role of specific immunotherapy (SIT) in elderly allergic patients is still debated. Objective: The aim of this study was to assess whether SIT is associated with a better control of symptoms and a better quality of life also in older allergic patients. Methods: The effect of injection SIT was assessed in 39 patients [age >54 years, median 59; 29 patients (74%) with asthma, otherwise healthy] monosensitized to birch (n = 20) and ragweed (n = 19). Thirty-three younger subjects [age <50 years, median 35; 26 patients (79%) with asthma, otherwise healthy] monosensitized to birch (n = 10) and ragweed (n = 23), and 37 subjects >54 years old (25 males/12 females; age 55–79 years, median 59 years) monosensitized to birch (n = 18) and ragweed (n = 19) who refused to undergo SIT were enrolled as positive and negative controls, respectively. All groups had a disease duration <10 years; the disease was inadequately controlled with standard drug therapies in all cases. SIT was carried out using the same extracts and was administered using a perennial schedule both in patients and controls. Seasonal therapies were the same in all groups and were not changed after SIT was started. After 1–5 years of SIT, patients and controls were asked to quantify symptom reduction on a visual analogue scale: reductions >50% were considered significant. Moreover, the use of cetirizine and/or salbutamol as an adjunct to standard therapies during the last pollen season was assessed as an objective measure of SIT outcome. Results: 37/39 (95%) patients versus 32/33 (97%) controls submitted to SIT reported a symptom reduction >50% after 1–5 years of SIT (nonsignificant). The median clinical efficacy of SIT was 80% in both groups (nonsignificant). 27/37 controls not submitted to SIT did not report any change in symptom severity at the follow-up visits, whereas 10/37 reported a more severe disease (4 subjects reported the appearance of seasonal asthma) (p < 0.001 vs. patients submitted to SIT). Patients used less frequently cetirizine (p < 0.001) and/or salbutamol (p < 0.05) than controls not submitted to SIT. Conclusion: Injection SIT can be considered an effective therapeutic option in otherwise healthy elderly patients with a short disease duration whose symptoms cannot be adequately controlled by drug therapies alone.
Differential Expression of L- and T-Type Calcium Channels between Longitudinal and Circular Muscles of the Rat Myometrium during Pregnancy
Authors: Ohkubo Tsuyako , Kawarabayashi Tatsuhiko , Inoue Yoshihito , Kitamura Kenji
Published: December 2004

The aim of this study was to evaluate the difference in the expression of mRNA of two types of calcium channels between longitudinal and circular muscle layer of rat myometrium during pregnancy. Changes in the expressions of the mRNA encoding L-type (α1C) and T-type (α1G, α1H, and α1I) calcium channels in longitudinal and circular smooth muscle cells of the rat myometrium were examined using a comparative kinetic RT/PCR method. During the course of pregnancy, α1C mRNA expression showed an N-shaped change in longitudinal muscle, but simply increased after mid-pregnancy in circular muscles. The mRNAs for α1G and α1H, but not that for α1I, were expressed in both longitudinal and circular smooth muscle. In longitudinal muscle, the change in α1H mRNA was similar to that in α1C mRNA during gestation, but the expression of α1G mRNA changed significantly only at term (day 22). In circular muscle, α1H mRNA expression was stable at any stage during pregnancy, but α1G mRNA significantly increased on day 15 and at term. No relationship was observed between voltage-dependent calcium-channel mRNA expressions and either proliferation or hypertrophy of circular muscle during pregnancy. These results show (a) that during pregnancy, the expression levels of L-type channels change dynamically, and it may contribute directly to the regulation of cell excitability, and (b) that the T-subtype that increases during pregnancy differs between longitudinal and circular muscle cells, although their functions remain unclear.
Pathological Validation of a CT-Based Scale for Subcortical Vascular Disease
Authors: Rossi Roberta , Joachim Catherine , Geroldi Cristina , Esiri Margaret M. , Smith A. David , Frisoni Giovanni B.
Published: December 2004

The validity of a computed tomography (CT)-based rating scale that separately rates leukoaraiosis, patchy lesions, and lacunes was tested using neuropathological findings collected on 87 subjects enrolled in the Oxford Project to Investigate Memory and Ageing. The CT-based score (range 0–64) was associated with both small vessel disease (p = 0.015) and microinfarcts (p = 0.002) on pathology. A sum score of subcortical cerebrovascular disease (CVD) on pathology was computed, 0 indicating absent/mild small vessel CVD and no microinfarcts, 1 moderate small vessel CVD or microinfarcts, and 2 and higher both conditions or severe small vessel CVD. Subjects with a sum score of 0 were decreasing with increasing severity of CT-based score (64, 46, and 25% in those with CT-based scores of 0, 1–38, and 39 and higher), while those with a sum score of 2 and higher were increasing (0, 14, and 44%; p = 0.002). A standardized assessment of subcortical CVD on CT films can be compounded into a unique score that is in good agreement with neuropathology. This supports the validity of the CT-based visual rating scale as a valid tool to detect subcortical vascular changes in elderly persons.
Changes in γ-Aminobutyric Acid Tone and Extracellular Serotonin in the Dorsal Raphe Nucleus Over the Rat Estrous Cycle
Authors: Felton Tracy M. , Auerbach Sidney B.
Published: December 2004

Gender differences in serotonin (5-HT) metabolism, synthesis, and release suggest that the gonadal steroids estrogen (E) and progesterone (P) influence 5-HT neurotransmission. Based on the effects of ovarian steroids in forebrain sites, this might involve changes in the strength of GABA afferent tone in the dorsal raphe nucleus (DRN). To test this hypothesis, the present study used in vivo microdialysis to measure basal extracellular 5-HT in the rat DRN across the estrous cycle and changes in 5-HT in response to the GABAA receptor antagonists bicuculline (50 µM) and picrotoxin (50 µM). During proestrus and estrus, baseline 5-HT levels were significantly higher compared to ovariectomized (OVX) rats. Mean baseline levels across experiments were 8.4 ± 1.3 pg/ 30 µl in proestrus, 5.2 ± 0.8 pg/30 µl in estrus, and 3.1 ± 0.5 pg/30 µl in the DRN of OVX rats. Bicuculline and picrotoxin produced significantly greater increases in 5-HT during proestrus compared to estrus. Moreover, in the DRN of OVX rats, bicuculline and picrotoxin produced negligible increases in 5-HT. These data provide evidence of decreased 5-HT efflux and GABA tone in the rat DRN associated with low circulating E and P.
The Clinical Syndrome Associated with Lumbar Spinal Stenosis
Authors: Goh Khean Jin , Khalifa Waël , Anslow Philip , Cadoux-Hudson Tom , Donaghy Michael
Published: December 2004

Lumbar spinal stenosis is well defined in patho-anatomical terms but its clinical features are heterogeneous. We carried out a comprehensive retrospective review of the clinical features, radiological changes and outcome of 75 patients with radiologically diagnosed lumbar spinal stenosis in order to define its clinical spectrum. The presenting complaints were of weakness, numbness/tingling, radicular pain and neurogenic claudication in almost equal proportions. The commonest symptom was numbness or tingling of the legs. Neurogenic claudication eventually occurred in only 61%. Ninety-three per cent showed abnormalities on neurological examination, but these were generally mild with reduced ankle jerks being commonest. Imaging of the lumbar spine showed that moderate to severe central spinal stenosis correlated with complaints of weakness and abnormal motor power on clinical examination. Patients were reviewed at a mean of 4 years after diagnosis and 65% had undergone surgical decompression; this was not a prospective comparison of different treatment modalities. Overall, a third of patients felt that their symptoms had improved while a quarter felt that they had worsened. More than half had satisfactory neurological function at the time of review. Thirty-nine per cent of those treated surgically, and 25% of those managed conservatively, reported improved symptoms. A poorer functional status at review correlated with complaints of motor weakness and associated comorbid disease. Degenerative lumbar stenosis is a clinically heterogeneous neurological disorder of the lower limbs in the elderly with variable longer-term outcome. A high index of suspicion is required and neuroimaging should be obtained to confirm the diagnosis.
Recovery of Pain Control by Intensive Reprogramming after Loss of Benefit from Motor Cortex Stimulation for Neuropathic Pain
Authors: Henderson Jaimie M. , Boongird Atthaporn , Rosenow Joshua M. , LaPresto Eric , Rezai Ali R.
Published: December 2004

Introduction: Motor cortex stimulation (MCS) may serve as an adjunct in managing neuropathic pain after other conservative and interventional methods have failed. However, the magnitude and duration of the benefit are highly variable, with a significant percentage of patients losing pain relief over time. We investigated whether intensive reprogramming could recapture the beneficial effects of MCS. Methods: Six patients who had previously undergone MCS implantation for neuropathic pain but had lost benefit were brought back for 1–5 days of intensive reprogramming. Four patients were evaluated as inpatients while the others were seen as outpatients during multiple visits over several days. Several hours a day were spent with each patient. Patients completed visual analog scale (VAS) ratings at intervals throughout the reprogramming period to judge effectiveness of stimulation. Pre- and postadjustment VAS were compared using a paired t test. Results: The patients’ average age was 50 years (range 26–71). The diagnoses were trigeminal neuropathic pain (2 patients), complex regional pain syndrome I (2), phantom limb pain (1) and poststroke pain (1). The mean duration of pain was 6 years. The MCS benefit had initially lasted for a mean of 7.16 months (range 2–18 months). After reprogramming, 5 of 6 patients experienced improvement in pain. Average VAS scores decreased from 7.44 to 2.28 (p < 0.001) in those patients who responded to reprogramming. The average stimulation parameters in these patients were 5 V amplitude (range 1.7–10), 313 µs pulse width (range 240–390) and frequency of 84 Hz (range 55–130). Three patients experienced seizures during reprogramming. The mean seizure threshold was 8.9 V. No patient experienced seizures at their therapeutic settings. Pain control has been maintained after discharge. Conclusion: Intensive reprogramming can recapture the benefit of MCS in patients who have lost pain control. The use of broad dipoles using two contacts rather than one contact of the 1 × 4 electrode array improved the ability to recapture beneficial stimulation. There is a significant risk of seizures during aggressive reprogramming.
Regulatory Effect of Sense Line Diet on Cholesterol and Body Weight in Mice Fed a High-Fat Diet
Authors: An Hyo-Jin , Chung Hwan-Suck , Kim Na-Hyung , Hong Seung-Heon , Park Eun-Jeong , Baek Seung-Hwa , Kim Hyung-Min
Published: December 2004

Background/Aims: Sense line diet (SLD) is a newly developed dietary functional food that is composed of a lot of herbs. The function of SLD is to help control weight. Although it is reported that each herb has effects on lipid metabolism and obesity, these effects are not the same as SLD. The aim of this study was therefore to investigate whether SLD combined with high fat (HF) diet can influence body weight and fat accumulation. Methods: An experiment was conducted with 40 C57BL/6J mice with an initial body weight of about 16 g. Body weight was recorded every week, plasma levels of triglyceride, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol were analyzed at the end of the study. Results: Weight increases in the 10 or 20% SLD group were significantly less than in the HF diet group (p < 0.05). Plasma triglyceride and LDL cholesterol levels were decreased by 52.1 and 34.2% in the 10% SLD group and 15.4 and 15.4% in the 20% SLD group, respectively, compared to the high-fat diet group. HDL cholesterol level was increased by 7.8% in the 10% SLD and by 54.9% in the 20% SLD group. Conclusions: Our findings indicate that SLD may be beneficial in the regulation of high-fat-diet-induced blood circulatory disorders as well as overweight.
Aortic Stiffness Is an Independent Predictor of Left Ventricular Function in Patients with Coronary Heart Disease
Authors: Sakuragi Satoru , Iwasaki Jun , Tokunaga Naoto , Hiramatsu Shigeki , Ohe Toru
Published: December 2004

Although aortic stiffness plays an important role in patients with coronary artery disease (CAD), the influence of aortic stiffness on left ventricular systolic function has not yet been fully evaluated. In the present study, we measured brachial-ankle pulse wave velocity (baPWV), which is a new index of aortic stiffness, in patients with CAD (CAD group, n = 170, 67 ± 9 years old) and without CAD (non-CAD group, n = 81, 63 ± 8 years old), and evaluated the relationship between baPWV and left ventricular systolic function in patients with CAD. baPWV in the CAD group was significantly higher than that in the non-CAD group (1,794 ± 350 vs. 1,469 ± 292 cm/s, p < 0.05), although both systolic and diastolic blood pressure were comparable between the two groups. In the CAD group, the baPWV was higher in patients with three-vessel disease than that in patients with one-vessel disease (1,885 ± 542 vs. 1,720 ± 373 cm/s, p < 0.05). In the CAD group, multivariate analysis demonstrated that baPWV and pulse pressure independently correlated with left ventricular ejection fraction (LVEF). In conclusion, in patients with CAD, baPWV, which is a simple marker of aortic stiffness, increases with CAD severity and correlates with left ventricular systolic function independent of CAD severity.
Postprandial Lipoprotein Changes in Patients Taking Antiretroviral Therapy for HIV Infection
Authors: Stein James H. , Merwood Michelle A. , Bellehumeur Jennifer B. , McBride Patrick E. , Wiebe Donald A. , Sosman James M.
Published: December 2004

Objective—

Dyslipidemia is common among patients receiving antiretroviral therapy for HIV infection. The purpose of this study was to determine whether postprandial lipemia contributes to the dyslipidemia observed in HIV-positive patients taking antiretroviral therapy.

Methods and Results—

A standardized fat load was administered to 65 subjects (group 1 35 HIV-positive subjects receiving protease inhibitors [PIs]; group 2 20 HIV-positive subjects not receiving PIs; group 3 10 HIV-negative controls). Serum triglycerides, retinyl palmitate, and lipoproteins were measured using enzymatic and nuclear magnetic resonance spectroscopic techniques. Compared with HIV-negative controls, peak postprandial retinyl palmitate and large very low-density lipoprotein (VLDL) levels occurred later in both HIV-positive groups, and a delayed decrease in serum triglycerides was observed. However, postprandial areas under the curve (AUCs) for triglycerides, retinyl palmitate, chylomicrons, and large VLDL were similar. Postprandial AUCs for intermediate-density lipoproteins (IDLs) and low-density lipoproteins (LDLs) were higher in group 1 than groups 2 and 3 (all
P
<0.035).

Conclusions—

Postprandial clearance of triglyceride-rich lipoproteins is delayed in HIV-positive individuals receiving antiretroviral therapy. Compared with HIV-positive individuals not on PIs, those taking PIs do not have increased postprandial triglyceride-rich lipoproteins but do have increased postprandial IDLs and LDLs.
Concurrent Treatment With Renin-Angiotensin System Blockers and Acetylsalicylic Acid Reduces Nuclear Factor κB Activation and C-Reactive Protein Expression in Human Carotid Artery Plaques
Authors: Sattler Katherine J.E. , Woodrum Julie E. , Galili Offer , Olson Monica , Samee Saquib , Meyer Fredric B. , Zhu Xiang-Yang , Lerman Lilach O. , Lerman Amir
Published: December 2004

Background and Purpose—

The local renin-angiotensin system (RAS) and cyclooxygenase-2 contribute to the activation of nuclear factor κB (NFκB) and C-reactive protein (CRP). We hypothesized that the combination of RAS blockers (RASb) and ASA reduces NFκB and CRP within atherosclerotic plaques.

Methods—

Patients undergoing carotid endarterectomy were divided into groups according to treatment (RASb–acetylsalicylic acid [ASA], ASA, RASb, and control). The expression of NFκB, CRP, and CD40L was analyzed through Western blots in the obtained plaques.

Results—

Plaques from patients treated with the combination of RASb and ASA showed lower expression of NFκB (25.4±9.8 densitometric units [DU]) than those of the control group (57.6±13.2 DU,
P
=0.03) as well as lower expression of CRP (20.9±9.6 DU) than those of the other treatment groups (ASA 86.1±13 DU, RASb 88.4±31 DU, controls 67.8±18.6,
P
=0.004). A negative expression of NFκB was associated with a reduced incidence of symptoms compared with a positive expression (5/33 [15.1%] versus 14/35 [40%],
P
=0.031).

Conclusions—

The combined treatment with RASb and ASA decreases the expression of inflammatory markers in atherosclerosis in humans. This study supports the role of the local RAS and cyclooxygenase-2 in the progression of atherosclerosis.