bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic and Predictive Roles of High-Degree Microsatellite Instability in Colon Cancer: A National Cancer Institute–National Surgical Adjuvant Breast and Bowel Project Collaborative Study
Authors: Kim George P. , Colangelo Linda H. , Wieand H. Samuel , Paik Soonmyung , Kirsch Ilan R. , Wolmark Norman , Allegra Carmen J.
Published: January 2007

Purpose

The role of high-degree microsatellite instability (MSI-H) as a marker to predict benefit from adjuvant chemotherapy remains unclear.

Patients and Methods

To help define its impact, we conducted an analysis of National Surgical Adjuvant Breast and Bowel Project (NSABP) patients who were randomly assigned to a surgery-alone group (untreated cohort) and patients assigned to an adjuvant fluorouracil (FU) -treated group (treated cohort). MSI-H and other potential markers were assessed (TGF-BRII, p53, thymidylate synthase, and Ki67).

Results

In all, 98 (18.1%) of 542 patients exhibited MSI-H, and there was a strong inverse relationship between MSI-H and mutant p53 status (P < .001). The prognostic analyses showed increased recurrence-free survival (RFS) for MSI-H patients versus MSS/MSI-L patients (P = .10), but showed no difference in overall survival (OS; P = .67). There was a potential interaction between MSI-H and mutant p53 in terms of improved RFS (P = .03). In the predictive marker analysis, we observed no interaction between MSI status and treatment for either RFS (P = .68) or OS (P = .62). Hazard ratios (HR) for RFS for MSI-H versus MSS/MSI-L patients were 0.77 (95% CI, 0.40 to 1.48) in the untreated-patients group and 0.60 (95% CI, 0.30 to 1.19) in the treated-patients group. HRs for OS were 0.82 (95% CI, 0.44 to 1.51) and 1.02 (95% CI, 0.56 to 1.85) for the respective groups. There was a trend toward improved RFS in patients with MSI-H and mutant p53.

Conclusion

These results do not support the use of MSI-H as a predictive marker of chemotherapy benefit.
Partially Matched, Nonmyeloablative Allogeneic Transplantation: Clinical Outcomes and Immune Reconstitution
Authors: Rizzieri David A. , Koh Liang Piu , Long Gwynn D. , Gasparetto Cristina , Sullivan Keith M. , Horwitz Mitchell , Chute John , Smith Clayton , Gong Jerald Z. , Lagoo Anand , Niedzwiecki Donna , Dowell Jeannette M. , Waters-Pick Barbara , Liu CongXiao , Marshall Dawn , Vredenburgh James J. , Gockerman Jon , Decastro Carlos , Moore Joseph , Chao Nelson J.
Published: January 2007

Purpose

Allogeneic transplantation is typically limited to younger patients having a matched donor. To allow a donor to be found for nearly all patients, we have used a nonmyeloablative conditioning regimen in conjunction with stem cells from a related donor with one fully mismatched HLA haplotype.

Patients and Methods

Fludarabine, cyclophosphamide, and alemtuzumab were used as the preparatory regimen. Additional graft-versus-host disease (GVHD) prophylaxis included mycophenolate with or without cyclosporine. Patients with persistence of disease had a donor lymphocyte boost planned. Toxicities, engraftment, response, survival, and immune recovery are reported.

Results

Forty-nine patients with hematologic malignancies or marrow failure and no other available donors were enrolled. Ninety-four percent of patients had successful engraftment, and 8% had secondary graft failure. The treatment-related mortality rate was 10.2%, and 8% of patients had severe GVHD. Encouraging evidence of quantitative lymphocyte recovery through expansion of transplanted T cells was noted by 3 to 6 months. Seventy-five percent of patients attained a complete remission, and 1-year survival rate was 31% (95% CI, 18% to 44%). A standard-risk group of 19 patients with aplasia or in remission at transplantation demonstrated a 63% 1-year survival rate (95% CI, 38% to 80%) and 2.9-year median overall survival time (95% CI, 6.2 to 48 months).

Conclusion

Nonmyeloablative therapy using haploidentical family member donors is feasible because the main obstacles of GVHD and graft rejection are manageable, allowing readily available stem-cell donors to be found for nearly all patients. Further qualitative and quantitative improvement in immune recovery is needed to address the high rate of relapse and risk of severe infections.
Phase II Clinical Trial of Chemotherapy-Naïve Patients ≥ 70 Years of Age Treated With Erlotinib for Advanced Non–Small-Cell Lung Cancer
Authors: Jackman David M. , Yeap Beow Y. , Lindeman Neal I. , Fidias Panos , Rabin Michael S. , Temel Jennifer , Skarin Arthur T. , Meyerson Matthew , Holmes Alison J. , Borras Ana M. , Freidlin Boris , Ostler Patricia A. , Lucca Joan , Lynch Thomas J. , Johnson Bruce E. , Jänne Pasi A.
Published: January 2007

Purpose

This is a phase II, multicenter, open-label study of chemotherapy-naïve patients with non–small-cell lung cancer (NSCLC) and age ≥ 70 years who were treated with erlotinib and evaluated to determine the median, 1-year, and 2-year survival. The secondary end points include radiographic response rate, time to progression (TTP), toxicity, and symptom improvement.

Patients and Methods

Eligible patients with NSCLC were treated with erlotinib 150 mg/d until disease progression or significant toxicity. Tumor response was assessed every 8 weeks by computed tomography scan using Response Evaluation Criteria in Solid Tumors. Tumor samples were analyzed for the presence of somatic mutations in EGFR and KRAS.

Results

Eighty eligible patients initiated erlotinib therapy between March 2003 and May 2005. There were eight partial responses (10%), and an additional 33 patients (41%) had stable disease for 2 months or longer. The median TTP was 3.5 months (95% CI, 2.0 to 5.5 months). The median survival time was 10.9 months (95% CI, 7.8 to 14.6 months). The 1- and 2- year survival rates were 46% and 19%, respectively. The most common toxicities were acneiform rash (79%) and diarrhea (69%). Four patients developed interstitial lung disease of grade 3 or higher, with one treatment-related death. EGFR mutations were detected in nine of 43 patients studied. The presence of an EGFR mutation was strongly correlated with disease control, prolonged TTP, and survival.

Conclusion

Erlotinib monotherapy is active and relatively well tolerated in chemotherapy-naïve elderly patients with advanced NSCLC. Erlotinib merits consideration for further investigation as a first-line therapeutic option in elderly patients.
Dynamic Histone Acetylation/Deacetylation with Progesterone Receptor-Mediated Transcription
Authors: Aoyagi Sayura , Archer Trevor K.
Published: January 2007

Histone acetylation is a highly dynamic posttranslational modification that plays an important role in gene expression. Previous work showed that promoter histone deacetylation is accompanied by progesterone receptor (PR)-mediated activation of the mouse mammary tumor virus (MMTV) promoter. We investigated the role of this deacetylation and found that this histone deacetylation is not a singular event. In fact, histone acetylation at the MMTV promoter is highly dynamic, with an initial increase in acetylation followed by an eventual net deacetylation of histone H4. The timing of increase in acetylation of H4 coincides with the time at which PR, RNA polymerase II, and histone acetyltransferases cAMP response element-binding protein (CREB)-binding protein and p300 are recruited to the MMTV promoter. The timing in which histone H4 deacetylation occurs (after PR and RNA polymerase II recruitment) and the limited effect that trichostatin A and small interfering RNA knockdown of histone deacetylase (HDAC)3 have on MMTV transcription suggests that this deacetylation activity is not required for the initiation of PR-mediated transcription. Interestingly, two HDACs, HDAC1 and HDAC3, are already present at the MMTV before transcription activation. HDAC association at the MMTV promoter fluctuates during the hormone treatment. In particular, HDAC3 is temporarily undetected at the MMTV promoter within minutes after hormone treatment when the histone H4 acetylation increases but returns to the promoter near the time when histone acetylation levels start to decline. These results demonstrate the dynamic nature of coactivator/corepressor-promoter association and histone modifications such as acetylation during a transcription activation event.
Reciprocal regulation of Rac1 and Rho1 inDrosophilacirculating immune surveillance cells
Authors: Williams Michael J. , Habayeb Mazen S. , Hultmark Dan
Published: January 2007

In many cell types it is evident that the small GTPases Rac and Rho regulate each other's activities. What is unclear is exactly how this regulation occurs. To further elucidate this interaction we examined the activities of Rac1 and Rho1 in Drosophila cellular immune surveillance cells. In larvae the cellular immune response involves circulating cells (hemocytes) that can be recruited from a hematopoietic organ located behind the brain, as well as a sessile population found just underneath the larval cuticle. We demonstrate for the first time that Rho-kinase activation requires both Rho1 and the Drosophila c-Jun N-terminal kinase (Basket). We also show that Rac1, via Basket, regulates Rho1 activity, possibly by inhibiting RhoGAPp190. In the reciprocal pathway, co-expression of dominant negative Rho-kinase and constitutive active Rho1 induces a Rac1-like phenotype. This induction requires the formin Diaphanous. Co-expression of dominant negative Rho-kinase and constitutive active Rho1 also induces filopodia formation, with Diaphanous enriched at the tips. The Rac1-like phenotypes, and filopodia formation, could be blocked by co-expression of dominant negative Rac1. Finally, though dominant negative Rac1 is able to block filopodia formation in the overexpression experiments, only Rac2 is necessary for filopodia formed by hemocytes after parasitization.
Wnt/β-catenin mediates radiation resistance of Sca1+ progenitors in an immortalized mammary gland cell line
Authors: Chen Mercy S. , Woodward Wendy A. , Behbod Fariba , Peddibhotla Sirisha , Alfaro Maria P. , Buchholz Thomas A. , Rosen Jeffrey M.
Published: January 2007

The COMMA-Dβ-geo cell line has been shown to contain a permanent subpopulation of progenitor cells that are enriched in outgrowth potential. Using the COMMA-Dβ-geo cell line as a model, we sought to study the radioresistance of mammary progenitor cells. Using the putative progenitor cell marker stem cell antigen 1 (Sca1), we were able to isolate a discrete subpopulation of Sca1+ multipotent cells from the immortalized COMMA-Dβ-geo murine mammary cell line. At a clinically relevant dose, the Sca1+ cells were resistant to radiation (2 Gy). Sca1+ cells contained fewer γ-H2AX+ DNA damage foci following irradiation, displayed higher levels of endogenous β-catenin, and selectively upregulated survivin after radiation. Expression of active β-catenin enhanced self-renewal preferentially in the Sca1+ cells, whereas suppressing β-catenin with a dominant negative, β-engrailed, decreased self-renewal of the Sca1+ cells. Understanding the radioresistance of progenitor cells may be an important factor in improving the treatment of cancer. The COMMA-Dβ-geo cell line may provide a useful model to study the signaling pathways that control mammary progenitor cell regulation.
Filamin links cell shape and cytoskeletal structure to Rho regulation by controlling accumulation of p190RhoGAP in lipid rafts
Authors: Mammoto Akiko , Huang Sui , Ingber Donald E.
Published: January 2007

Cytoskeleton-dependent changes in the activity of the small GTPase Rho mediate the effects of cell shape on cell function; however, little is known about how cell spreading and related distortion of the cytoskeleton regulate Rho activity. Here we show that rearrangements of the actin cytoskeleton associated with early phases of cell spreading in human microvascular endothelial (HMVE) cells suppress Rho activity by promoting accumulation of p190RhoGAP in lipid rafts where it exerts its Rho inhibitory activity. p190RhoGAP is excluded from lipid rafts and Rho activity increases when cell rounding is induced or the actin cytoskeleton is disrupted, and p190RhoGAP knockdown using siRNA prevents Rho inactivation by cell spreading. Importantly, cell rounding fails to prevent accumulation of p190RhoGAP in lipid rafts and to increase Rho activity in cells that lack the cytoskeletal protein filamin. Moreover, filamin is degraded in spread cells and cells that express a calpain-resistant form of filamin exhibit high Rho activity even when spread. Filamin may therefore represent the missing link that connects cytoskeleton-dependent changes of cell shape to Rho inactivation during the earliest phases of cell spreading by virtue of its ability to promote accumulation of p190RhoGAP in lipid rafts.
Tegaserod for Treating Chronic Constipation in Elderly Patients
Authors: Baun Ronald F , Levy Hedva Barenholtz
Published: January 2007

Objective:

To evaluate data that address the safety and efficacy of tegaserod for the management of chronic constipation (CC) in elderly patients.

Data Sources:

Primary literature was identified through MEDLINE (1966–January 2007) and EMBASE (2002–January 2007) using the search terms tegaserod, elderly, and constipation. Additional information was requested from the pharmaceutical manufacturer.

Study Selection and Data Extraction:

Clinical trials evaluating the efficacy and safety of tegaserod for treating CC were considered for inclusion. Emphasis was placed on data relevant to use of tegaserod in the elderly and on CC.

Data Synthesis:

Two efficacy trials evaluated tegaserod for treating constipation. They enrolled a total of 331 elderly patients, comprising approximately 13% of study patients. Tegaserod was effective for improving constipation in the overall study populations; no significant adverse events were noted. However, both studies lacked a subgroup analysis in the elderly. Diarrhea occurred more commonly with higher doses of tegaserod and may be a concern in older adults. A 13 month safety trial found tegaserod to be well tolerated for treatment of constipation, with similar adverse events seen as in the 12 week efficacy studies. Specific data were not provided for elderly patients.

Conclusions:

Tegaserod should not replace current therapies for treatment of CC in the elderly. The drug has been studied in a small number of older adults; thus, data are inconclusive about its use in this population. Older adults have a higher risk of diarrhea with tegaserod. Cautious use is warranted until further studies specifically address the elderly population.
Parapharyngeal Abscess in a Patient Receiving Etanercept
Authors: Borrás-Blasco Joaquín , Nuñez-Cornejo Claudia , Gracia-Perez Antonio , Rosique-Robles J Dolores , Casterá MD Elvira , Viosca Enrique , Abad F Javier
Published: January 2007

Objective:

To report a case of parapharyngeal abscess associated with Streptococcus viridans in a patient with rheumatoid arthritis receiving treatment with etanercept.

Case Summary:

A 40-year-old man diagnosed with rheumatoid arthritis had received treatment with nonsteroidal antiinflammatory drugs, methotrexate, and deflazacort. Six months prior to admission, the patient had a Disease Activity Score of 3.4; clinicians decided to start treatment with etanercept. Chest X-rays were normal and the tuberculin skin test was negative. Treatment with etanercept plus methotrexate was started. Three months later, methotrexate was discontinued. Six months after etanercept therapy was started, the patient presented to our emergency department with a swelling of his neck, odynophagia, otalgia, and trismus. The clinical course was consistent with parapharyngeal abscess. Etanercept treatment was suspended. The parapharyngeal abscess was drained and intravenous methylprednisolone, amoxicillin/clavulanic acid, and clindamycin were administered. The parapharyngeal abscess secretion culture was positive for S. viridans and Bacteroides spp. The patient's condition improved with antibiotic therapy; he was discharged 5 days after admission.

Discussion:

Tumor necrosis factor-α plays an essential role in the immune-mediated response to infection. In our patient, the most possible cause of parapharyngeal abscess was considered to be etanercept because of the temporal relationship between exposure to the drug and onset of symptoms. Etanercept was the only drug administered before the abscess developed. Based on the Naranjo probability scale, an association between etanercept and the adverse reaction could be considered possible.

Conclusions:

Patients initiated on etanercept therapy should be closely monitored for the development of tuberculosis and other infections. During treatment, all febrile or novel illnesses should be evaluated promptly. If clinical evaluation leads to the suspicion of tuberculosis and other infections associated with etanercept, it should be discontinued immediately.
Sequestosome 1: Mutation Frequencies, Haplotypes, and Phenotypes in Familial Paget's Disease of Bone
Authors: Morissette Jean , Laurin Nancy , Brown Jacques P
Published: January 2007

Mutations of the SQSTM1/p62 gene are commonly observed in PDB. Screening an updated sample from Quebec and using previously published data from other populations, we compared frequency estimates for SQSTM1/p62 mutations and haplotype distribution. The P392L mutation was the most prevalent, embedded in two different haplotypes, possibly shared by other populations. We also examined the phenotype and penetrance of P392L.

Introduction: There is accumulating evidence that supports a contribution of genetic factors in the etiology of Paget's disease of bone (PDB), and several genetic loci have been suggested for the disorder. The sequestosome1/p62 (SQSTM1/p62) gene was the first gene identified to have a role in PDB, with 14 mutations reported to date.

Material and Methods: To evaluate the importance of the SQSTM1/p62 mutations in PDB, we recruited, sequenced, and genotyped a total of 123 carriers from 20 families in addition to 214 unrelated PDB patients. We compared the frequency of SQSTM1/p62 mutations in familial and unrelated cases among different populations. Finally, we examined the phenotypic expression and penetrance of the P392L mutation in the Quebecois families.

Results and Conclusions: The 14 mutations reported in SQSTM1/p62 all affect the ubiquitin-associated domain of the protein. The P392L mutation is the most commonly observed mutation in PDB patients and was consistently found in unrelated and familial PDB cases in the populations tested. Analysis of adjacent polymorphisms suggests that P392L is associated with two different haplotypes in the Quebecois patients, similar to what has been observed in European populations. In Quebec, both haplotypes had similar frequencies in unrelated P392L carriers, whereas one haplotype was predominant in the other populations studied. These data suggest that these two haplotypes, possibly introduced by European founders in the Quebecois population, were equally distributed in the succeeding generations. Finally, the P392L mutation is transmitted as an autosomal dominant trait in the Quebecois families, with a high but incomplete penetrance peaking after age 60. The large phenotypic variability and similarity between unrelated and familial cases, respectively, remain unexplained and require further research.
Fibrous Dysplasia as a Stem Cell Disease
Authors: Riminucci Mara , Saggio Isabella , Gehron Robey Pamela , Bianco Paolo
Published: January 2007

At a time when significant attention is devoted worldwide to stem cells as a potential tool for curing incurable diseases, fibrous dysplasia of bone (FD) provides a paradigm for stem cell diseases. Consideration of the time and mechanism of the causative mutations and of nature of the pluripotent cells that mutate in early embryonic development indicates that, as a disease of the entire organism, FD can be seen as a disease of pluripotent embryonic cells. As a disease of bone as an organ, in turn, FD can be seen as a disease of postnatal skeletal stem cells, which give rise to dysfunctional osteoblasts. Recognizing FD as a stem cell disease provides a novel conceptual angle and a way to generate appropriate models of the disease, which will continue to provide further insight into its natural history and pathogenesis. In addition, skeletal stem cells may represent a tool for innovative treatments. These can be conceived as directed to alter the in vivo behavior of mutated stem cells, to replace mutated cells through local transplantation, or to correct the genetic defect in the stem cells themselves. In vitro and in vivo models are currently being generated that will permit exploration of these avenues in depth.
Cysteine at Position 217 in the Intracellular Loop 1 Plays a Critical Role in Human PTH Receptor Type 1 Membrane Translocation and Function
Authors: Thomas Beena E , Wittelsberger Angela , Woznica Iwona , Hsieh Mo-Ying , Monaghan Paul , Lee Byung-Kwon , Rosenblatt Michael
Published: January 2007

PTHR1 mutants lacking endogenous cysteines in transmembrane and intracellular domains were generated. Mutant receptors were tested for their biological activities and mRNA and cell surface expression levels. C217 in intracellular loop 1 was determined to play a critical role in cell surface translocation and function of the receptor.

Introduction: Elucidating the role of different domains of PTH receptor 1 (PTHR1) is essential for understanding the mechanism of ligand–receptor interactions. Here we present a study directed at determining the importance of cysteine residues present in the intracellular and transmembrane (TM) domains of the receptor.

Materials and Methods: Mutant receptors were generated by site-directed mutagenesis. Biological activities were characterized by adenylyl cyclase and competition binding assays. RT-PCR, ELISA, and immunofluorescence microscopy were carried out to determine receptor mRNA and protein expression levels.

Results: Mutations C460L and C462L in TM7, C568L in the C-terminal intracellular domain of the receptor, and removal of C397 in intracellular loop (ICL)3 by insertion of cleavage sites for Factor Xa did not affect binding affinity of PTH or agonist-induced adenylyl cyclase activity, although maximal responses (ICmax and ECmax) were decreased. However, mutations C217L in ICL1 or both C217L and C568L simultaneously resulted in a decrease in binding and loss of adenylyl cyclase activity. RT-PCR results showed that the observed changes in binding and activity were not caused by changes in mRNA expression. Next, we determined cell surface and total expression of the wildtype and mutant receptors by ELISA. We found that mutations of C460/C462 to L moderately decreased transfer of receptors to the cell surface. However, mutation of C217 to L in the ICL1 drastically reduced cell surface expression. Immunofluorescence and confocal microscopy studies confirmed reduced cell surface expression of receptors containing the C217L mutation. Similar results were obtained when replacing C217 and C460/C462 of the receptor with A instead of L.

Conclusions: Our studies indicate that the cysteine at position 217 in ICL1 plays a critical role in translocation to the cell surface and biological function of PTHR1.
Fragile External Phenotype of Modern Human Proximal Femur in Comparison with Medieval Bone
Authors: Sievänen Harri , Józsa László , Järvinen Markku , Järvinen Tero A , Kannus Pekka , Järvinen Teppo L
Published: January 2007

Proximal femur macroanatomy of 118 medieval and 67 contemporary adults, 84 contemporary elderly, and 48 contemporary hip fracture cases was evaluated. Within ∼1000 years, the femoral neck axis has become longer, and its cross-section has become proportionally smaller and more oval in shape. These changes in the present external phenotype alone account for ∼50% higher fall-induced stress compared with the medieval situation.

Introduction: Bones, as whole skeletal structures, adapt to mechanical stresses they customarily experience. Because the present, mechanized lifestyle apparently deprives our skeletons of vigorous, habitual physical exertion, we studied whether the proximal femur phenotype has evolved vulnerable to fragility fractures by time.

Materials and Methods: Proximal femur macroanatomy of 118 medieval and 67 contemporary adults, 84 contemporary elderly, and 48 contemporary hip fracture cases was evaluated. Using direct measurements of external bone dimensions and geometric properties, we estimated the fall-induced stress as an index of hip fragility.

Results: Within ∼1000 years, the femoral axis length has become substantially longer (analysis of covariance, body height adjusted, p < 0.001), whereas the neck circumference has not increased. The macroanatomy was found similar between the contemporary adult and elderly groups. In hip fracture cases, however, the femoral axis length was further lengthened (p < 0.001), but the circumference was somewhat smaller (p = 0.001). Consequently, the estimated fall-induced stress can be ∼1.5-fold today compared with the medieval times (p < 0.001), and the secular trend seemed to be worse in women (sex-time interaction, p = 0.001).

Conclusions: The modern, relatively slender phenotype of the proximal femur alone seems to increase the fall-induced stress considerably, and when this phenotype coincides the osteoporotic, internally deteriorated femoral neck structure, fracture risk is imminent. This mechanically compromised external phenotype underscores the importance of timely strengthening of the skeleton and its regular maintenance throughout life.
Networks of Parvalbumin-Positive Interneurons in the Basolateral Amygdala
Authors: Woodruff Alan R. , Sah Pankaj
Published: January 2007

The amygdala is a temporal lobe structure that is required for processing emotional information. Polymodal sensory information enters the amygdala at the level of the basolateral amygdala (BLA) and undergoes local processing, after which the behavioral and autonomic responses that accompany emotions are initiated. Two main neuron types are present in the BLA, pyramidal-like principal neurons that use glutamate as their transmitter, and local circuit interneurons that use GABA as their transmitter. Although the properties of principal neurons are known in some detail, very little is known about the properties of BLA interneurons or the local circuits in which they are involved. Using mice in which EGFP (enhanced green fluorescent protein) is expressed under the control of the parvalbumin promoter, we characterized the properties of parvalbumin-positive interneurons in the BLA. By making recordings from interneuron–interneuron and interneuron–principal neuron pairs, we analyzed the intrinsic circuitry of the BLA. We show that parvalbumin-positive interneurons can be divided into four subtypes as defined by their firing properties. Interneurons are electrically coupled in subtype-specific networks and exhibit subtype-specific heterogeneities in their synaptic dynamics and patterns of connectivity. We propose that these properties allow networks of parvalbumin-expressing neurons to perform an array of information-processing tasks within the BLA.
Roles of Subthreshold Calcium Current and Sodium Current in Spontaneous Firing of Mouse Midbrain Dopamine Neurons
Authors: Puopolo Michelino , Raviola Elio , Bean Bruce P.
Published: January 2007

We used a preparation of acutely dissociated neurons to quantify the ionic currents driving the spontaneous firing of substantia nigra pars compacta neurons, isolated from transgenic mice in which the tyrosine hydroxylase promoter drives expression of human placental alkaline phosphatase (PLAP) on the outer surface of the cell membrane. Dissociated neurons identified by fluorescent antibodies to PLAP showed firing properties similar to those of dopaminergic neurons in brain slice, including rhythmic spontaneous firing of broad action potentials and, in some cells, rhythmic oscillatory activity in the presence of tetrodotoxin (TTX). Spontaneous activity in TTX had broader, smaller spikes than normal pacemaking and was stopped by removal of external calcium. Normal pacemaking was also consistently silenced by replacement of external calcium by cobalt and was slowed by more specific calcium channel blockers. Nimodipine produced a slowing of pacemaking frequency. Pacemaking was also slowed by the P/Q-channel blocker ω-Aga-IVA, but the N-type channel blocker ω-conotoxin GVIA had no effect. In voltage-clamp experiments, using records of pacemaking as command voltage, cobalt-sensitive current and TTX-sensitive current were both sizeable at subthreshold voltages between spikes. Cobalt-sensitive current was consistently larger than TTX-sensitive current at interspike voltages from −70 to −50 mV, with TTX-sensitive current larger at voltages positive to −45 mV. These results support previous evidence for a major role of voltage-dependent calcium channels in driving pacemaking of midbrain dopamine neurons and suggest that multiple calcium channel types contribute to this function. The results also show a significant contribution of subthreshold TTX-sensitive sodium current.
Fibroblast Growth Factor (FGF)-2 and FGF Receptor 3 Are Required for the Development of the Substantia Nigra, and FGF-2 Plays a Crucial Role for the Rescue of Dopaminergic Neurons after 6-Hydroxydopamine Lesion
Authors: Timmer Marco , Cesnulevicius Konstantin , Winkler Christian , Kolb Julia , Lipokatic-Takacs Esther , Jungnickel Julia , Grothe Claudia
Published: January 2007

Basic fibroblast growth factor (FGF-2) is involved in the development and maintenance of the nervous system. Exogenous administration of FGF-2 increased dopaminergic (DA) graft survival in different animal models of Parkinson's disease. To study the physiological function of the endogenous FGF-2 system, we analyzed the nigrostriatal system of mice lacking FGF-2, mice overexpressing FGF-2, and FGF-receptor-3 (FGFR3)-deficient mice both after development and after 6-hydroxydopamine lesion. FGFR3-deficient mice (+/−) displayed a reduced number of DA neurons compared with the respective wild type. Whereas absence of FGF-2 led to significantly increased numbers of DA neurons, enhanced amount of the growth factor in mice overexpressing FGF-2 resulted in less tyrosine hydroxylase expression and a reduced DA cell density. The volumes of the substantia nigra were enlarged in bothFGF-2−/−and in FGF-2 transgenic mice, suggesting an important role of FGF-2 for the establishment of the proper number of DA neurons and a normal sized substantia nigra during development. In a second set of experiments, the putative relevance of endogenous FGF-2 after neurotoxin application was investigated regarding the number of rescued DA neurons after partial 6-OHDA lesion. Interestingly, the results after lesion were directly opposed to the results after development: significantly less DA neurons survived inFGF-2−/−mice compared with wild-type mice. Together, the results indicate that FGFR3 is crucially involved in regulating the number of DA neurons. The lack of FGF-2 seems to be (over)compensated during development, but, after lesion, compensation mechanisms fail. The transgenic mice showed that endogenous FGF-2 protects DA neurons from 6-OHDA neurotoxicity.
Aspectos moleculares da sensibilidade aos glicocorticóides
Authors: Faria Cláudia D.C. , Longui Carlos Alberto
Published: January 2007

Os glicocorticóides exercem um papel importante na regulação fisiológica e na adaptação a situações de stress, sendo a maioria dos efeitos destes hormônios mediada pela interação com os receptores glicocorticóides. A sensibilidade ao glicocorticóide depende da densidade celular de receptores expressos, bem como da eficiência da transdução do sinal mediada pelo complexo hormônio-receptor. Os estados de resistência ou de hipersensibilidade ao glicocorticóide, observados, respectivamente, nas doenças inflamatórias auto-imunes e na síndrome metabólica, podem representar a variabilidade dos fatores que influenciam a cascata de sinalização do glicocorticóide. O reconhecimento destes fatores contribui para uma melhor compreensão tanto do fenótipo clínico e da evolução destas doenças quanto da resposta terapêutica com glicocorticóide. A compreensão destes mecanismos fisiopatológicos também pode contribuir para a escolha de intervenções terapêuticas. Neste artigo de revisão, descrevemos os múltiplos fatores envolvidos nesta cascata de sinalização, os quais são capazes de influenciar a sensibilidade ao glicocorticóide.
Efeitos fisiológicos do treinamento físico em pacientes portadores de diabetes tipo 1
Authors: De Angelis Kátia , Pureza Demilto Y. da , Flores Lucinar J.F. , Rodrigues Bruno , Melo Karla F.S. , Schaan Beatriz D. , Irigoyen Maria C.
Published: January 2007

Insulinoterapia, atividade física regular e planejamento alimentar, em conjunto, consistem na abordagem mais completa no tratamento de portadores de diabetes mellitus tipo 1 (DM1). Estudos clínicos e experimentais têm evidenciado os benefícios do treinamento físico em indivíduos com DM1, tais como melhora na sensibilidade à insulina, redução das doses de insulina e atenuação das disfunções autonômicas e cardiovasculares. Essa revisão aborda as adaptações fisiológicas ao treinamento físico no indivíduo com DM1 e discute as recomendações e prescrição de atividade física para esta população.
O Polimorfismo no códon 98 do gene de galectina-3 não está associado a tumores benignos e malignos de tiróide
Authors: Martins Luciane , Leoni Suzana Garcia , Friguglietti Celso U.M. , Ward Laura Sterian , Kulcsar Marco Aurélio V. , Kimura Edna Teruko
Published: January 2007

Galectina-3 é uma proteína multifuncional altamente expressa em câncer de tiróide. O gene de galectina-3 (LGALS3) apresenta vários candidatos a SNPs anotados, no entanto a relação entre estes SNPs e variações fenotípicas específicas relevantes à saúde não foi avaliada. Neste estudo, investigamos SNPs do LGALS3 e uma possível associação destes com a tumorigênese tiroidiana. A presença de SNPs do LGALS3 em linhagens de carcinoma de tiróide (WRO, NPA, TPC-1, ARO), tecidos tiroidianos de 55 pacientes com diagnóstico de bócio multinodular ou carcinoma papilífero e linfócitos do sangue periférico de 45 indivíduos saudáveis foi avaliada por seqüenciamento e SSCP. A análise da seqüência codificadora do LGALS3 mostrou que o sítio T98P apresenta uma grande variação genotípica, visto que observamos os padrões homozigoto (AA ou CC) e heterozigoto (AC). Em linhagens de carcinoma de tiróide, o genótipo da NPA no sítio T98P do LGALS3 é CC, enquanto TPC-1, WRO e ARO são AC. As freqüências genotípicas do T98P do LGALS3 observadas em bócio multinodular (AC= 67%, AA= 23%, CC= 10%) e carcinoma papilífero (AC= 68%, AA= 20%, CC= 12%) foram semelhante à freqüência observada na população controle (AC= 60%, AA= 24%, CC= 16%). Em conclusão, não observamos associação entre o genótipo T98P do LGALS3 e o fenótipo de tumor benigno ou maligno de tiróide.
Tratamento clínico com drogas antitireoidianas ou dose terapêutica de iodo-131 no controle do hipertireoidismo na doença de graves: avaliação dos custos e benefícios
Authors: Cruz Júnior Antônio Fiel , Takahashi Míriam Hideco , Albino Cláudio Cordeiro
Published: January 2007

Com o objetivo de avaliar os custos e a efetividade das 2 formas de tratamento mais utilizadas em nosso meio para a Doença de Graves, iodo radioativo e tratamento clínico prolongado, analisamos pacientes submetidos a essas terapias na região de Maringá, PR. Foram estudados 23 pacientes, 7 homens e 16 mulheres, com idade média de 35,4 anos, submetidos ao tratamento clínico, e 34 pacientes, 5 homens e 29 mulheres, com idade média de 39,4 anos, submetidos à dose terapêutica com iodeto de sódio (iodo-131). Após 2 anos de tratamento clínico com tiamazol (Tapazol®), 21 pacientes atingiram o eutireoidismo e dois permaneceram hipertireóideos. No grupo da dose terapêutica com iodeto de sódio (iodo-131), 21 pacientes evoluíram para o hipotireoidismo, enquanto que 13 atingiram o eutireoidismo. Para o cálculo do custo de cada modalidade de tratamento, analisamos o número de consultas necessárias durante o seguimento, exames complementares solicitados e medicações utilizadas, como tiamazol e/ou tiroxina. O grupo submetido ao tratamento clínico necessitou de maior número de consultas e exames, sendo que o custo médio foi de R$ 1.345,81 neste período de dois anos, enquanto que no grupo com iodeto de sódio (iodo-131) o valor médio foi de R$ 622,94. Assim, os custos da dose terapêutica com iodeto de sódio (iodo-131) foram 53,7% menores do que o tratamento clínico com drogas antitireoidianas. Este trabalho demonstra que o tratamento com dose terapêutica com iodeto de sódio (iodo-131) apresenta um menor custo, sendo bastante efetivo no controle do hipertireoidismo na doença de Graves.
Preliminary evaluation of the endovascular treatment of intracranial aneurysms with detachable coils in vigil patients
Authors: Fonseca José Roberto Falco , Abdala Nitamar , Nalli Dárcio Roberto , Idagawa Marcos Hideki , Alves Jr João de Deus da Costa , Marques Márcio Chaves Pedro , Carrete Jr. Henrique , Nogueira Roberto Gomes , Szjenfeld Jacob
Published: January 2007

Endovascular treatment of intracranial aneurysms with coil embolization became the most important therapeutic option with better morbidity and mortality rates and quality of life. Following immobility, patients are treated with general anaesthesia. OBJECTIVE: To test viability of endovascular treatment on wake patients. METHOD: Considering clinical symptoms, psychological characteristics and aneurysmal morphology, four patients with five intracranial aneurysms were selected. RESULTS: Four among five cases were completed with this technique. Patient 1 was partially treated after 75 minutes presenting vesical stress. Patient 2 presented subarachnoid hemorrhage after aneurysmal re-rupture, and the procedure was completed under general anaesthesia. The other three patients presented no intercurrences during the treatment. CONCLUSION: Endovascular treatment on wake patients with intracranial aneurysm can be an alternative to a selected group of patients.
Percutaneous radiofrequency rhizotomy and neurovascular decompression of the trigeminal nerve for the treatment of facial pain
Authors: Teixeira Manoel J. , Siqueira Silvia R.D.T. , Almeida Gilberto M.
Published: January 2007

OBJECTIVE: To determine the outcomes of 354 radiofrequency rhizotomies and 21 neurovascular decompressions performed as treatment for 367 facial pain patients (290 idiopathic trigeminal neuralgia, 52 symptomatic trigeminal neuralgia, 16 atypical facial pain, 9 post-herpetic neuralgia). METHOD: Clinical findings and surgery success rate were considered for evaluation. A scale of success rate was determined to classify patients, which considered pain relief and functional/sensorial deficits. RESULTS: Radiofrequency rhizotomy was performed in 273 patients with idiopathic trigeminal neuralgia and in all other patients, except for trigeminal neuropathy; neurovascular decompression was performed in 18 idiopathic trigeminal neuralgia patients; 100% idiopathic trigeminal neuralgia, 96.2% symptomatic trigeminal neuralgia, 37.5% atypical facial pain and 88.9% post-herpetic neuralgia had pain relief. CONCLUSION: Both techniques for idiopathic trigeminal neuralgia are usefull. Radiofrequency rhizotomy was also efficient to treat symptomatic facial pain, and post-herpetic facial pain, but is not a good technique for atypical facial pain.
Manejo da infecção após cirurgia de fixação interna da coluna lombar
Authors: Falavigna Asdrubal , Righesso Neto Orlando , Fonseca Gabriela Poglia , Nervo Monique
Published: January 2007

A incidência de infecções profundas em cirurgias de coluna lombar situa-se na faixa de 0,7% e 11,6%, sendo uma das causas de morbidade na fase aguda deste procedimento. O objetivo deste estudo foi avaliar o tratamento da infecção após cirurgia de fixação interna de coluna lombar. Foram analisados 260 pacientes que se submeteram à cirurgia de fixação posterior da coluna lombar com instrumentação e enxertia de osso ilíaco no período de janeiro de 1997 a janeiro de 2005. A infecção pós-operatória ocorreu em oito (3%) casos. A idade média dos pacientes foi 56 anos, com maior prevalência do sexo masculino (5 casos). Staphylococcus aureus foi isolado em 85% dos pacientes (6 casos). O tratamento instituído foi a lavagem externa e a antibioticoterapia intravenosa, seguida pela via oral. O tempo médio de hospitalização dos pacientes foi 35,8 dias. Com o tratamento preconizado foi possível erradicar a infecção sem a necessidade da retirada do sistema de fixação interna em todos os casos.
Comparação de dipirona intravenosa com metoclopramida intravenosa no tratamento de crise aguda de enxaqueca: ensaio clínico randomizado
Authors: Fernandes Filho Sérgio Murilo Maciel , Costa Márcio Santos , Fernandes Mariana Torres , Foerster Miriam Vils
Published: January 2007

INTRODUÇÃO: A enxaqueca é uma das doenças mais comuns da prática clínica. OBJETIVO: Comparar o efeito analgésico da dipirona com a metoclopramida no alívio da dor. MÉTODO: Conduzimos um estudo piloto randomizado comparando dipirona intravenosa com metoclopramida intravenosa em 27 pacientes apresentando crise de enxaqueca. O objetivo primário foi comparar a redução da intensidade da dor até 2 horas, assim como efeitos colaterais. RESULTADOS: Os grupos tinham faixas etárias semelhantes, mas diferença entre os sexos. Nos homens a metoclopramida reduziu a dor em 80,0% contra 55,0% da dipirona (p=0,052). Já nas mulheres houve uma redução de 65,0% com a metoclopramida e 71,2% com a dipirona (p=0,748). Esses resultados podem ter sido influenciados pelo reduzido número de pacientes no estudo. Não foram encontrados efeitos colaterais significativos. CONCLUSÃO: Não houve diferença quanto à redução da dor nem quanto ao surgimento de efeitos colaterais quando comparados dipirona com metoclopramida.
Correlação entre os achados clínicos da deglutição e os achados da tomografia computadorizada de crânio em pacientes com acidente vascular cerebral isquêmico na fase aguda da doença
Authors: Barros Anna Flávia Ferraz , Fábio Soraia Ramos Cabette , Furkim Ana Maria
Published: January 2007

O acidente vascular cerebral (AVC) é uma das principais causas de lesões permanentes em adultos, podendo provocar seqüelas motoras globais, alterações de fala, linguagem e deglutição. Durante a fase aguda, a detecção do risco de aspiração é fundamental para prevenir complicações pulmonares e permitir apropriadas intervenções terapêuticas, possibilitando alimentação por via oral precoce e segura. Na literatura, as correlações entre o distúrbio da deglutição e a localização da lesão em pacientes com AVC são inespecíficas. Desta forma, o objetivo do presente estudo foi determinar se existe correlação entre a localização das lesão vascular encefálica e a dificuldade de deglutição em pacientes com AVC isquêmico (AVCI). Foram incluídos 27 pacientes com AVCI que foram submetidos à avaliação clínica da deglutição no leito. Os resultados foram confrontados com resultados obtidos pela tomografia computadorizada do crânio, relacionados à localização das lesões. Na avaliação clínica, 48% dos pacientes apresentaram disfagia orofaríngea e 52% deglutição funcional. Em 84% dos pacientes disfágicos foram observadas alterações no território carotídeo, sendo 76% na artéria cerebral média (ACM). Nos pacientes com deglutição funcional 57% apresentaram alterações em ACM e 22% em artéria cerebral posterior. O hemisfério esquerdo foi afetado em 50% dos pacientes com deglutição funcional e em 46% dos disfágicos. Em conclusão, a localização hemisférica não está associada com a presença ou não de disfagia, porém a maioria dos pacientes disfágicos apresentou alterações no território carotídeo, notadamente na ACM.
Lissencephaly, abnormal genitalia and refractory epilepsy: case report of XLAG syndrome
Authors: Spinosa Mônica Jaques , Liberalesso Paulo Breno Noronha , Vieira Simone Carreiro , Olmos Alaídes Susana Fojo , Löhr Júnior Alfredo
Published: January 2007

INTRODUCTION: X-linked lissencephaly with ambiguous genitalia (XLAG) is a recently described genetic disorder caused by mutation in the aristaless-related homeobox (ARX) gene (Xp22.13). Patients present with lissencephaly, agenesis of the corpus callosum, refractory epilepsy of neonatal onset, acquired microcephaly and male genotype with ambiguous genitalia. CASE REPORT: Second child born to healthy nonconsanguineous parents, presented with seizures within the first hour of life that remained refractory to phenobarbital, phenytoin and midazolam. Examination identified microcephaly, axial hypotonia, pyramidal signs and ambiguous genitalia. EEG showed disorganized background activity and seizures starting at the right midtemporal, central and occipital regions. MRI showed diffuse pachygyria, moderate thickening of the cortex, enlarged ventricles, agenesis of the corpus callosum and septum pellucidum. Karyotype showed a 46,XY genotype. Additional findings were hypercalciuria, vesicoureteral reflux, patent ductus arteriosus and chronic diarrhea.
Botulinum-A toxin in the treatment of painful post-stroke nocturnal paroxysmal dystonia triggered by periodic limb movements of sleep: case report
Authors: Kowacs Pedro A. , Teive Hélio A. Ghizoni , Piovesan Elcio J. , Zavala Jorge A. , Werneck Lineu C.
Published: January 2007

INTRODUCTION: Sleep disorders presenting involuntary movements may be very annoying to patients, apart from their negative influence on sleep. OBJECTIVE: To report the use of botulinum type-A toxin (BoNT-A) to manage the case of a patient whose sleep was severely disrupted by episodes of dystonic posturing of the right lower limb triggered by periodic limb movements of sleep (PLMS). METHOD: A 79-year-old woman with mild post-stroke right hemiparesis presented with recurrent painful episodes of dystonia of the right lower limb, which disrupted her sleep. The dystonic episodes could also be voluntarily triggered by extension of the right hallux. Polysomnography confirmed that the dystonic episodes were triggered by PLMS. Twenty units of BoNT-A (20U/500U vial) were injected into her right extensor hallucis longus. RESULTS: Shortly after BoNT-A was injected, the dystonic symptoms abated, and the patient achieved better sleep efficiency. CONCLUSION: The PLMS-related involuntary extension of the hallux was probably triggering the nocturnal post-stroke lower limb dystonic paroxysms. BoNT-A injection into the right extensor hallucis longus was effective in managing this condition and thus resolved the associated disruption of sleep.
Guillain-Barré syndrome after brachial plexus trauma: case report
Authors: Freitas Marcos R.G. de , Nascimento Osvaldo J.M. , Harouche Maria Beatriz B.P. , Vasconcelos Adolfo , Darroz Jr Heloy , Escada Tânia Maria
Published: January 2007

The Guilllain-Barré syndrome (GBS) is an acute predominantly demyelinating polyneuropathy. In many cases GBS is preceding by infection, immunization, surgery or trauma. Although there are a few reports of GBS after head trauma, there is no report of this syndrome after brachial plexus injury. We report on a 51 years-old man who presented GBS fifteen days after a brachial plexus trauma. The polineuropathy resolved completely in a few weeks. We believe that GBS was triggered by the trauma that evoked an immune mediated disorder producing inflammation and demyelination of the peripheral nerves.