bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional Coupling Between Motor and Sensory Nerves Through Contraction of Sphincters in the Pudendal Area of the Female Cat
Authors: Lagunes-Córdoba Roberto , Hernández Pablo Rogelio , Raya José Guadalupe , Muñoz-Martínez E. J.
Published: October 2009

The question of whether skin receptors might help in the perception of muscle contraction and body movement has not been settled. The present study gives direct evidence of skin receptor firing in close coincidence with the contraction of the vaginal and anal sphincters. The distal stump of the sectioned motor pudendal nerve was stimulated. Single shocks induced a wavelike increase in the lumen pressure of the distal vagina and the anal canal, as well as constriction of the vaginal introitus and the anus. The constriction pulls on and moves the surrounding skin, which was initially detected visually. In the present experiments, a thin strain gauge that pressed on the skin surface detected its displacement. Single shocks to the motor nerve induced a wave of skin movement with maximal amplitude at 5 mm from the anus and propagated with decrement beyond 35 mm. The peripheral terminals of the sensory pudendal nerve and the posterior femoral nerve supply the skin that moves. Sensory axons from both nerves fired in response to both tactile stimulation and the skin movement produced by the constriction of the orifices (motor–sensory coupling). In cats with all nerves intact, a single shock to the sensory nerves induced reflex waves of skin movement and lumen pressure (sensory–motor coupling). Both couplings provide evidence for a feedforward action that might help to maintain the female posture during mating and to the perception of muscle contraction.
Terminal differentiation of goat mammary tissue during pregnancy requires the expression of genes involved in immune functions
Authors: Faucon F. , Rebours E. , Bevilacqua C. , Helbling J.-C. , Aubert J. , Makhzami S. , Dhorne-Pollet S. , Robin S. , Martin P.
Published: October 2009

Terminal differentiation of mammary tissue into a functional epithelium that synthesizes and secretes milk occurs during pregnancy. The molecular mechanisms underlying this complex process are poorly understood, especially in ruminants. To obtain an overview of the ruminant mammary gland's final differentiation process, we conducted time-course gene expression analysis of five physiological stages: four during pregnancy (P46, P70, P90, and P110) and one after 40 days of lactation (L40). An appropriate loop experimental design was used to follow gene expression profiles. Using three nulliparous (pregnancy) or primiparous (lactation) goats per stage, we performed a comparison starting from nine dye-swaps and using a 22K bovine oligoarray. Statistical analysis revealed that the expression of 1,696 genes varied significantly at least once in the study. These genes fell into 19 clusters based on their expression profiles. Identification of biological functions with Ingenuity Pathway Analysis software revealed several similarities, in keeping with physiological stages described in mice. As in mice, expression of milk protein genes began at midpregnancy, and genes regulating lipid biosynthesis were induced at the onset of lactation. During the first half of pregnancy, the molecular signature of goat mammary tissue was characterized by the expression of genes associated with tissue remodeling and differentiation, while the second half was mainly characterized by the presence of messengers encoding genes involved in cell proliferation. A large number of immune-related genes were also induced, supporting recent speculation that mammary tissue has an original immune function, and the recruitment of migrating hematopoietic cells possibly involved in the branching morphogenesis of the mammary gland. These data hint that the induction of differentiation occurs early in pregnancy, very likely before P46. This period is therefore crucial for obtaining a healthy and productive mammary gland.
Structural Changes in Macroinvertebrate Communities Associated with Reduction in the Management of Coastal Saltpans
Authors: Tavares P. C. , Alves D. , Shapouri M.
Published: October 2009

Saltpans with different management levels were studied for macroinvertebrate community and abiotic variables like water depth, water conductivity, and organic matter in sediments. Significant variation was observed between saltpans, between ponds within saltpans, and between periods within ponds for abundance, and also between saltpans for biomass. Environmental variables varied significantly between saltpans and between ponds. Significant positive correlations occurred between depth and total abundance, between depth and Corixidae abundance, and also between organic matter in sediments and diversity. Significant negative correlations were observed between depth and diversity and between organic matter in sediments and total abundance. Multidimensional Scaling and Canonical Correspondence Analysis confirmed results of analysis of variance and correlations. Invertebrate communities were numerically dominant as also revealed by ABC method. Abandoned saltpan ponds show the largest changes in water depth, with communities dominated by some opportunist species, varying within short temporal scales, which is typical from highly disturbed systems.
Physiological Function of Mycobacterial mtFabD, an Essential Malonyl-CoA:AcpM Transacylase of Type 2 Fatty Acid Synthase FASII, in Yeastmct1ΔCells
Authors: Gurvitz Aner
Published: October 2009

Mycobacterium tuberculosismtFabD is an essential malonyl-CoA:AcpM transacylase and is important for vital protein-protein interactions within type 2 fatty acid synthase FASII. mtFabD contacts KasA, KasB, FabH, InhA, and possibly also HadAB, HadBC, and FabG1/MabA. Disruption of mtFabD's interactions during FASII has been proposed for drug development. Here, the gene for a mitochondrially targeted mtFabD was ectopically expressed inSaccharomyces cerevisiae mct1Δmutant cells lacking the corresponding mitochondrial malonyl-CoA transferase Mct1p, allowing the mutants to recover their abilities to respire on glycerol and synthesize lipoic acid. Hence, mtFabD could physiologically function in an environment lacking holo-AcpM or other native interaction partners.
p27Kip1 Stabilization Is Essential for the Maintenance of Cell Cycle Arrest in Response to DNA Damage
Authors: Cuadrado Myriam , Gutierrez-Martinez Paula , Swat Aneta , Nebreda Angel R. , Fernandez-Capetillo Oscar
Published: October 2009

One of the current models of cancer proposes that oncogenes activate a DNA damage response (DDR), which would limit the growth of the tumor in its earliest stages. In this context, and in contrast to studies focused on the acute responses to a one-time genotoxic insult, understanding how cells respond to a persistent source of DNA damage might become critical for future studies in the field. We here report the discovery of a novel damage-responsive pathway, which involves p27Kip1 and retinoblastoma tumor suppressors and is only implemented after a persistent exposure to clastogens. In agreement with its late activation, we show that this pathway is critical for the maintenance, but not the initiation, of the cell cycle arrest triggered by DNA damage. Interestingly, this late response is independent of the canonical ataxia telangiectasia mutated–dependent and ataxia telangiectasia mutated and Rad3-related–dependent DDR but downstream of p38 mitogen-activated protein kinase. Our results might help to reconcile the oncogene-induced DNA damage model with the clinical evidence that points to non-DDR members as the most important tumor suppressors in human cancer. [Cancer Res 2009;69(22):8726–32]
Constitutive Activation of the DNA Damage Signaling Pathway in Acute Myeloid Leukemia with Complex Karyotype: Potential Importance for Checkpoint Targeting Therapy
Authors: Cavelier Cindy , Didier Christine , Prade Naïs , Mansat-De Mas Véronique , Manenti Stéphane , Recher Christian , Demur Cécile , Ducommun Bernard
Published: October 2009

Genomic instability in solid tumors participates in the oncogenetic process and is associated with the activation of the DNA damage response pathway. Here, we report the activation of the constitutive DNA damage and checkpoint pathway associated with complex karyotypes in samples from patients with acute myeloid leukemia (AML). We show that antagonizing CHK1 kinase with a small inhibitory compound or by RNA interference strongly reduces the clonogenic properties of high–DNA damage level AML samples, particularly those with complex karyotypes. Moreover, we observe a beneficial effect of CHK1 inhibition in high–DNA damage level AML samples treated with 1-β-d-arabinofuranosylcytosine. In contrast, CHK1 inhibition has no effect on the clonogenic properties of normal hematopoietic progenitors. All together, our results indicate that CHK1 inhibition may represent an attractive therapeutic opportunity in AML with complex karyotype. [Cancer Res 2009;69(22):8652–61]
Three-Dimensional Imaging and Quantification of Both Solitary Cells and Metastases in Whole Mouse Liver by Magnetic Resonance Imaging
Authors: Townson Jason L. , Ramadan Soha S. , Simedrea Carmen , Rutt Brian K. , MacDonald Ian C. , Foster Paula J. , Chambers Ann F.
Published: October 2009

The metastatic cell population, ranging from solitary cells to actively growing metastases, is heterogeneous and unlikely to respond uniformly to treatment. However, quantification of the entire experimental metastatic cell population in whole organs is complicated by requirements of an imaging modality with the large field of view and high spatial resolution necessary to detect both single cells and metastases in the same organ. Thus, it is difficult to assess differential responses of these distinct metastatic populations to therapy. Here, we develop a magnetic resonance imaging (MRI) technique capable of quantifying the full population of metastatic cells in a secondary organ. B16F1 mouse melanoma cells were labeled with micron-sized iron oxide particles (MPIO) and injected into mouse liver via the mesenteric vein. Livers were removed immediately or at day 9 or 11, following doxorubicin or vehicle control treatment, and imaged using a 3T clinical magnetic resonance scanner and custom-built gradient coil. Both metastases (>200 μm) and MPIO-labeled single cells were detected and quantified from MR images as areas of hyperintensity or hypointensity (signal voids), respectively. We found that 1mg/kg doxorubicin treatment inhibited metastasis growth (n = 11 per group; P = 0.02, t test) but did not decrease the solitary metastatic cell population in the same livers (P > 0.05). Thus, the technique presented here is capable of quickly quantifying the majority of the metastatic cell population, including both growing metastases and solitary cells, in whole liver by MRI and can identify differential responses of growing metastases and solitary cells to therapy. [Cancer Res 2009;69(21):8326–31]
p53 Pre- and Post-Binding Event Theories Revisited: Stresses Reveal Specific and Dynamic p53-Binding Patterns on the p21 Gene Promoter
Authors: Millau Jean-François , Bastien Nathalie , Bouchard Éric F. , Drouin Régen
Published: October 2009

p53 is a master transcription factor that prevents neoplasia and genomic instability. It is an important target for anticancer drug design. Understanding the molecular mechanisms behind its transcriptional activities in normal cells is a prerequisite to further understand the deregulation effected by mutant p53 in cancerous cells. Currently, how p53 coordinates transcription programs in response to stress remains unclear. One theory proposes that stresses induce pre-binding events that direct p53 to bind to specific response elements, whereas a second posits that, in response to stress, p53 binds most response elements and post-binding events then regulate transcription initiation. It is critical to establish the relevance of both theories and investigate whether stresses induce specific p53-binding patterns correlated with effector gene induction. Using unique in cellulo genomic footprinting experiments, we studied p53 binding to the five response elements of p21 in response to stresses and monitored p21 mRNA variant transcription. We show clear footprints of p53 bound to response elements in living cells and reveal that the binding of p53 to response elements is transient, subject to dynamic changes during stress responses, and influenced by response element pentamer orientations. We show further that stresses lead to specific p53-binding patterns correlated with particular p21 mRNA variant transcription profiles and that p53 binding is necessary but not sufficient to induce p21 transcription. Our results indicate that pre- and post-binding events act together to regulate adapted stress responses; this paves the way to the unification of pre- and post-binding event theories. [Cancer Res 2009;69(21):8463–71]
Oncogenic KRAS and BRAF Differentially Regulate Hypoxia-Inducible Factor-1α and -2α in Colon Cancer
Authors: Kikuchi Hirotoshi , Pino Maria S. , Zeng Min , Shirasawa Senji , Chung Daniel C.
Published: October 2009

KRAS and BRAF mutations are frequently observed in human colon cancers. These mutations occur in a mutually exclusive manner, and each is associated with distinctive biological features. We showed previously that K-ras can interact with hypoxia to activate multiple signaling pathways. Many hypoxic responses are mediated by hypoxia-inducible factor (HIF)-1α and HIF-2α, and we sought to define the roles of mutant KRAS and BRAF in the induction of HIF-1α and HIF-2α in colon cancer cells. Ectopic expression of mutant K-ras in Caco2 cells enhanced the hypoxic induction of only HIF-1α, whereas mutant BRAF enhanced both HIF-1α and HIF-2α. Knockout or knockdown of mutant KRAS in DLD-1 and HCT116 cells impaired the hypoxic induction of only HIF-1α. HIF-1α mRNA levels were comparable in cells with and without a KRAS mutation. However, the rate of HIF-1α protein synthesis was higher in cells with a KRAS mutation, and this was suppressed by the phosphoinositide 3-kinase inhibitor LY294002. In contrast, knockdown of mutant BRAF in HT29 cells suppressed both HIF-1α and HIF-2α. Although BRAF regulated mRNA levels of both HIF-1α and HIF-2α, knockdown of BRAF or treatment with the MEK inhibitor PD98059 impaired the translation of only HIF-2α. Our data reveal that oncogenic KRAS and BRAF mutations differentially regulate the hypoxic induction of HIF-1α and HIF-2α in colon cancer, and this may potentially contribute to the phenotypic differences of KRAS and BRAF mutations in colon tumors. [Cancer Res 2009;69(21):8499–506]
Identification of Compounds Selectively Killing Multidrug-Resistant Cancer Cells
Authors: Türk Dóra , Hall Matthew D. , Chu Benjamin F. , Ludwig Joseph A. , Fales Henry M. , Gottesman Michael M. , Szakács Gergely
Published: October 2009

There is a great need for the development of novel chemotherapeutic agents that overcome the emergence of multidrug resistance (MDR) in cancer. We catalogued the National Cancer Institute's DTP drug repository in search of compounds showing increased toxicity in MDR cells. By comparing the sensitivity of parental cell lines with MDR derivatives, we identified 22 compounds possessing MDR-selective activity. Analysis of structural congeners led to the identification of 15 additional drugs showing increased toxicity in Pgp-expressing cells. Analysis of MDR-selective compounds led to the formulation of structure activity relationships and pharmacophore models. This data mining coupled with experimental data points to a possible mechanism of action linked to metal chelation. Taken together, the discovery of the MDR-selective compound set shows the robustness of the developing field of MDR-targeting therapy as a new strategy for resolving Pgp-mediated MDR. [Cancer Res 2009;69(21):8293–301]
The Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase 1/2 Inhibitor AZD6244 (ARRY-142886) Enhances the Radiation Responsiveness of Lung and Colorectal Tumor Xenografts
Authors: Shannon Aoife M. , Telfer Brian A. , Smith Paul D. , Babur Muhammed , Logie Armelle , Wilkinson Robert W. , Debray Camille , Stratford Ian J. , Williams Kaye J. , Wedge Stephen R.
Published: October 2009

Purpose: Novel molecularly targeted agents, given in combination with radiotherapy, have the potential to increase tumor response rates and the survival of patients with lung cancer. AZD6244 is a potent and selective inhibitor of mitogen-activated protein kinase (MAPK) kinase 1/2 (MEK1/2), a critical enzyme within the MAPK/extracellular signal-regulated kinase (ERK) signaling pathway that regulates the proliferation and survival of tumor cells.

Experimental Design: This study examined the potential benefit of combining AZD6244 with fractionated radiotherapy using human lung and colon carcinoma xenograft models.

Results: AZD6244 reduced ERK phosphorylation in Calu-6 lung cancer cells in vitro. Administration of AZD6244 for 10 days (25 mg/kg twice daily p.o.) inhibited the tumor growth of Calu-6 xenografts, with regrowth occurring on cessation of drug treatment. When fractionated tumor-localized radiotherapy (5 × 2 Gy) was combined with AZD6244 treatment, the tumor growth delay was enhanced significantly when compared with either modality alone, and this effect was also seen in a colon tumor model. We examined the effect of inhibiting MEK1/2 on the molecular responses to hypoxia, a potential interaction that could contribute to radioresponsiveness. AZD6244 reduced hypoxia-inducible factor–specific transactivation in vivo, shown using Calu-6 dual clone cells that stably express a Firefly luciferase gene under the control of a hypoxia-driven promoter. Furthermore, hypoxia-inducible factor-1α, GLUT-1, and vascular endothelial growth factor levels were reduced by AZD6244, and there was a significant decrease in vascular perfusion in the tumors given combination treatment when compared with the other treatment groups.

Conclusions: These data provide support for the clinical development of AZD6244 in combination with radiotherapy and indicate a potential role for AZD6244 in inhibiting the tumor hypoxia response. (Clin Cancer Res 2009;15(21):6619–29)
Circulating Mesothelin Protein and Cellular Antimesothelin Immunity in Patients with Pancreatic Cancer
Authors: Johnston Fabian Mc. , Tan Marcus C.B. , Tan Benjamin R. , Porembka Matthew R. , Brunt Elizabeth M. , Linehan David C. , Simon Peter O. , Plambeck-Suess Stacey , Eberlein Timothy J. , Hellstrom Karl Erik , Hellstrom Ingegerd , Hawkins William G. , Goedegebuure Peter
Published: October 2009

Purpose: Mesothelin is a glycoprotein expressed on normal mesothelial cells and is overexpressed in several histologic types of tumors including pancreatic adenocarcinomas. A soluble form of mesothelin has been detected in patients with ovarian cancer and malignant mesothelioma, and has prognostic value. Mesothelin has also been considered as a target for immune-based therapies. We conducted a study on the potential clinical utility of mesothelin as a biomarker for pancreatic disease and therapeutic target pancreatic cancer.

Experimental Design: Tumor cell–bound and soluble mesothelin in patients was evaluated by immunohistochemistry and ELISA, respectively. The in vitro cellular immune response to mesothelin was evaluated by INFγ ELISA and intracellular cytokine staining for IFNγ in CD4+ and CD8+ T cells. The level of circulating antibodies to mesothelin was measured by ELISA.

Results: All tumor tissue from patients with pancreatic adenocarcinoma expressed mesothelin (n = 10). Circulating mesothelin protein was detected in patients with pancreatic adenocarcinoma (73 of 74 patients) and benign pancreatic disease (5 of 5) but not in healthy individuals. Mesothelin-specific CD4+ and CD8+ T cells were generated from peripheral blood lymphocytes of patients with pancreatic cancer in 50% of patients compared with only 20% of healthy individuals. Antibodies reactive to mesothelin were detected in <3% of either patients or healthy individuals.

Conclusions: Circulating mesothelin is a useful biomarker for pancreatic disease. Furthermore, mesothelin-specific T cells can be induced in patients with pancreatic cancer. This suggests that mesothelin is a potential target for immune-based intervention strategies in pancreatic cancer. (Clin Cancer Res 2009;15(21):6511–8)
Repeated Treatment with Subtoxic Doses of TRAIL Induces Resistance to Apoptosis through Its Death Receptors in MDA-MB-231 Breast Cancer Cells
Authors: Yoshida Tatsushi , Zhang Yaqin , Rivera Rosado Leslie A. , Zhang Baolin
Published: October 2009

Recombinant human tumor necrosis factor–related apoptosis–inducing ligand (rhTRAIL) is being evaluated clinically in treating various malignancies. Previous studies have shown that repeated application of high doses of rhTRAIL results in a subpopulation of parental cells that is unresponsive to the death ligand. However, it is not clear whether TRAIL-sensitive cancer cells could acquire resistance to TRAIL treatment. Here, we found that MDA-MB-231 breast cancer cells, which are highly sensitive to TRAIL-induced apoptosis, became resistant to TRAIL killing after a prolonged exposure to subtoxic doses of rhTRAIL. The resulting TRAIL-resistant cells were cross-resistant to antibodies against its death receptors (DR4 and DR5); however, they retained sensitivity to several clinically relevant chemotherapies. Surface expression of DR4 and DR5 was significantly reduced in the selected cells, resulting in failure in death-inducing signaling complex formation and caspase activation. In addition, real-time PCR analysis revealed an upregulation in multiple apoptosis-regulator genes, including c-FLIP, Stat5a, and Stat5b. Inhibition of Janus-activated kinase, an upstream activator of signal transducer and activator of transcription 5 (Stat5), or knockdown of Stat5 itself partially restored cellular sensitivity to TRAIL-induced apoptosis, suggesting that Stat5 signaling is also involved in the development of TRAIL resistance. Furthermore, we showed that acquired TRAIL resistance was effectively eliminated by combination with etoposide, doxorubicin, or paclitaxel. These results suggest that tumor cells could acquire resistance to TRAIL therapy especially when they are repeatedly exposed to low levels of the death ligand, highlighting the necessity of combination with therapies that target the resistance mechanisms. (Mol Cancer Res 2009;7(11):1835–44)
Simultaneous Ring Voice-over-Internet Phone System Enables Rapid Physician Elicitation of Explicit Informed Consent in Prehospital Stroke Treatment Trials
Authors: Sanossian Nerses , Starkman Sidney , Liebeskind David S. , Ali Latisha K. , Restrepo Lucas , Hamilton Scott , Conwit Robin , Saver Jeffrey L.
Published: October 2009

Background: Cellular phone conversations between on-scene patients or their legally authorized representatives (LARs) and off-scene enrolling physician-investigators require immediate and reliable connection systems to obtain explicit informed research consent in prehospital treatment trials. Methods: The NIH Field Administration of Stroke Therapy – Magnesium (FAST-MAG) Trial implemented a voice-over-internet protocol (VOIP) simultaneous ring system (multiple investigator cell phones called simultaneously and first responder connected to call) to enable physician-investigators to elicit consent immediately from competent patients or LARs encountered by 228 ambulances enrolling patients in a multicenter prehospital stroke trial. For 1 month, the number, origin, duration, and yield of enrolling line calls were monitored prospectively. Results: Six investigators were connected to 106 enrolling line calls, with no identified unanswered calls. Thirty-five percent of new patient calls yielded an enrollment. The most common reasons for non-enrollment were last known well >2 h (n = 7) and uncon sentable patient without LAR available (n = 7). No non-enrollments were directly attributable to the VOIP system. In enrollments, consent was provided by the patient in 67% and a LAR in 33%. The duration of enrollment calls (mean ± SD: 8.4 ± 2.5 min, range 6–14) was longer than non-enrollment calls (5.5 ± 3.5, range 2–13; p < 0.001). The median interval from last known well to study agent start was 46 min, and 70% were enrolled within 60 min of onset. Conclusions: The simultaneous ring system was reliable and effective, permitting enrollment of a substantial number of patients within the first hour after stroke onset. VOIP cellular networks with simultaneous ring are a preferred means of facilitating consent in prehospital treatment trials.
Relationship between High-Sensitivity C-Reactive Protein and Clinical Functional Outcome after Acute Ischemic Stroke in a Korean Population
Authors: Song In-Uk , Kim Joong-Seok , Kim Yeong-In , Lee Kwang-Soo , Jeong Du-Shin , Chung Sung-Woo
Published: October 2009

Background: High-sensitivity C-reactive protein (hs-CRP) has been shown to be a powerful predictor of coronary ischemic events. However, the prognosis of functional disability in patients with cerebrovascular disease has not been well established. Therefore, we performed this study to determine the prognostic significance of hs-CRP levels in patients with functional disability after acute ischemic stroke. Methods: A total of 417 Korean patients with ischemic stroke were examined within 24 h after symptom onset. hs-CRP measurements were obtained on admission and on the seventhhospital day. The correlations between the concentration of hs-CRP and functional disability duration 12 months after stroke onset were analyzed. Results: The present study showed that hs-CRP levels on admission and on the seventh hospital day were significantly correlated with the modified Rankin Scale (mRS) score 12 months after stroke onset. These results also demonstrated that mRS scores are more closely associated with hs-CRP levels on the seventh hospital day than hs-CRP levels on admission. Conclusion: This study demonstrated that elevated hs-CRP levels on the seventh hospital day, rather than within 24 h after stroke onset, could strongly predict the prognosis of functional disability. These results supported that hs-CRP is a useful marker of ischemic stroke in the Korean population.
Safety and Efficacy of IV-TPA for Ischaemic Stroke in Clinical Practice – A Bayesian Analysis
Authors: O’Rourke Killian E.T. , Walsh Cathal D. , Kelly Peter J.
Published: October 2009

Background: Observational studies of new treatments in routine practice are clinically important but may be limited by bias. We used a Bayesian approach to interpret and sequentially combine phase 4 studies of IV-TPA within 3 h for acute ischaemic stroke to quantify the cumulative evidence for the efficacy and safety of this therapy in clinical practice. Methods: Prior probability distributions for favourable outcome (modified Rankin Score, mRS, 0–1), symptomatic intracerebral haemorrhage, and mortality 3 months after IV-TPA were derived from the NINDS trial. Phase 4 studies from observational case series and from regulator-mandated large registries were included. A cumulative analysis was performed to quantify the increase in the total evidence base over time, unadjusted and adjusted for potential bias. Results: The cumulative analysis indicated that IV-TPA <3 h was associated with 3-month favourable outcome in 37.1% (95% credible interval, CrI, 36.1–38.0%, n = 9,578) compared to 26% (95% confidence interval, CI, 19.6–32.9%, n = 165) in placebo-treated patients in NINDS, symptomatic intracranial haemorrhage in 6.6% (95% CrI 5.9–7.4%, n = 10, 834) compared to 6.4% (95% CI 4.0–9.4%) in the NINDS IV-TPA group, and 3-month mortality in 13.6% (95% CrI 12.6–14.8%, n = 9, 901) compared to 20.5% (95% CI 16.0–25.0%, n = 312) in the NINDS placebo group. Conclusion: A Bayesian approach provides further confirmatory evidence of the efficacy and safety of IV-TPA for treatment of acute ischaemic stroke within 3 h in diverse clinical practice settings, after adjusting for potential observational bias.
Gender-Based Differences in Drug Prescription: Relation to Adverse Drug Reactions
Authors: Zopf Y. , Rabe C. , Neubert A. , Janson C. , Brune K. , Hahn E.G. , Dormann H.
Published: October 2009

Background/Aim: The female gender appears to suffer from more adverse drug reactions (ADRs) than the male gender. So far, there has been no epidemiologic study analyzing gender-based differences in drug prescribing and its ADR risks. The aim of the present study was to establish a drug risk stratification adjusted to age, number of prescriptions and drug classes with respect to gender differences based on intensive data acquisition methods. Method: A prospective multicenter study was conducted in several departments in Germany and Israel (pediatrics, medicine and geriatrics) enclosing 2,371 inpatients. Results: A total of 25,532 drug prescriptions during hospitalization were evaluated. At least 1 ADR was found in 774 patients (32.6%). Drugs for the cardiovascular system, nervous system, alimentary tract and musculoskeletal system were prescribed most often in females. The following drug classes led significantly more often to ADRs in women as compared to men: alimentary tract (OR 0.5; p = 0.0002), cardiovascular system (OR 0.72; p = 0.0140), musculoskeletal system (OR 0.31; p = 0.0004) and nervous system (OR 0.62; p = 0.0023). After adjustment to age, total number of prescriptions and drug class, only anti-infectives (antibacterials) and musculoskeletal system (anti-inflammatory) drugs stand out as causing more ADRs in women. Conclusion: Antibacterials and anti-inflammatory agents cause more ADRs in females as compared to males.
Use of Coagulant Spray Glue (Glubran 2®) for Aerostatic Purposes in Pulmonary Parenchyma Resections in Pigs: A Preliminary Study
Authors: Davoli F. , Sellitri F. , Brandolini J. , Dolci G. , Castagnoli A. , Bedetti B. , Stella F.
Published: October 2009

Background: The aim of our study was to test the aerostatic validity of a cyan-acrylic glue (Glubran 2®), applied by means of a spray catheter, on an experimental pig model. Materials and Methods: 15 young pigs were divided into three study groups of 5 based on surgical techniques: (1) atypical pulmonary resection with mechanical suturing and reinforcement with continuous suturing; (2) resection of the pulmonary parenchyma with a cold scalpel, followed by local application of Glubran 2; (3) atypical pulmonary resection with mechanical suturing followed by application of Glubran 2. Results: The mean aerostasis time was calculated at 3.5 ± 1.26 s. The histopathological analysis did not show any particular differences when comparing the effects of the treatments carried out with Glubran 2 spray glue and the standard treatments. No statistically significant differences were recorded in the short- and medium-term survival of pigs treated with Glubran 2 compared with the respective control groups. Conclusions: The application of Glubran 2 spray on wounds caused by pulmonary resections in pigs proved to have a rapid and effective influence for the purposes of aerostasis without significant differences in air losses and survivals.
Fenticonazole Cream Once Daily in Dermatomycosis, a Double-Blind Controlled Trial versus Bifonazole
Authors: Jung E.G. , Bisco A. , Azzollini E. , Sartani A. , Ruffmann R.
Published: October 2009

A randomized, double-blind clinical trial was undertaken in 41 patients with dermatomycosis to compare topical 2% fenticonazole cream (group A: 21 patients) with topical 1% bifonazole cream (group B: 20 patients). Treatment was performed as a once daily application. Mycological and clinical parameters were assessed before treatment and after 7, 14, 21 and 28 days. At the control visits the clinical investigator also expressed an overall judgement on the patient’s state of disease. This parameter was based on a combined clinical and mycological assessment by the physician; laboratory screening investigations were undertaken before and at the end of treatments. All patients were checked for their state of disease 3–4 weeks after the end of treatment. All assessment criteria showed fenticonazole to be at least as efficacious as bifonazole. Several trends in favor of fenticonazole were also found: fenticonazole achieved superior results in the overall clinical evaluation, and after 3 weeks of treatment 15 patients out of 21 on fenticonazole were cured in mycological and clinical terms, whereas treatment with bifonazole resulted in complete healing of only 7 patients out of 20. This difference is statistically significant (p = 0.021) and indicates a more rapid therapeutic activity of fenticonazole. At the posttreatment rechecks no recurrent disease was registered, irrespective of whether patients had received fenticonazole or bifonazole. Laboratory screening investigations revealed no evidence of significant treatment-related changes or abnormalities in both treatments. No adverse events were noted for either treatment.
Further Characterization of the Keratinocyte Somatomedin-C/Insulin-like Growth Factor I (SM-C/IGF-I) Receptor and the Biological Responsiveness of Cultured Keratinocytes to SM-C/IGF-I
Authors: Nickoloff Brian J. , Misra Pratima , Morhenn Vera B. , Hintz Raymond L. , Rosenfeld Ron G.
Published: October 2009

Somatomedin-C/insulin-like growth factor I (SM-C/IGF-I) binds to both cultured keratinocytes trypsinized to single-cell suspensions and fresh epidermal sheets derived from 1 M NaBr-treated 6-mm punch biopsies. A gradual increase of 1–4% in specific binding of SM-C/IGF-I to fresh epidermal sheets was observed during a 5-hour incubation period at 15°C. The human keratinocyte SM-C/IGF-I receptor was isolated by polyacrylamide gel electrophoresis after cross-linking with iodinated SM-C/IGF-I and migrated at 135,000 daltons under reducing conditions. Both a partially purified preparation of SM-C/IGF-I, as well as recombinant DNA-derived thr-59-SM-C/IGF-I (25–100 ng/ml), stimulated keratinocyte replication in a serum-free system, with an approximately equivalent effect as insulin (10 μg/ml). Since fibroblasts produce SM-C/IGF-I, our data suggest that some dermal-epidermal interactions in diseases such as psoriasis may be mediated, in part, by SM-C/IGF-I.
Macular Amelanotic Melanoma in situ
Authors: Pichler Evelyn , Fritsch Peter
Published: October 2009

This report aims at directing the attention to the rare entity of amelanotic melanoma in situ, as exemplified in a patient who had an amelanotic lentigo maligna 10 years ago and a recurrent lesion of identical clinical and histological (except for pagetoid tumor cells in the epidermis) appearance 4 years ago. Amelanotic melanomas in situ appear as inconspicuous reddish macules, which can hardly be diagnosed or even suspected on clinical grounds.
Cholinergic Urticaria, Passive Transfer Experiments from Human to Monkey
Authors: Murphy G.M. , Greaves M.W. , Zollman P.E. , Winkelmann R.K.
Published: October 2009

Passive transfer experiments in cholinergic urticaria were carried out from 16 patients to a Macaca cymnologous monkey. Intravenous Evans blue dye was used to demonstrate vascular permeability. The animal was challenged after 24 h first by heating the serum-injected dorsal skin to 45 °C and secondly by super injection of acetylcholine into serum-injected sites, and a control site. Local heat proved insufficient to evoke a response. Seven of 16 serum-injected sites showed positive reaction to acetylcholine, control injection of acetylcholine did not. These experiments suggest the presence of a serum factor in cholinergic urticaria which, with acetylcholine, causes increased vascular permeability.
Malignant Acanthosis nigricans Associated with Non-Hodgkin’s Lymphoma
Authors: Janier M. , Blanchet-Bardon C. , Bonvalet D. , Lenoble M. , Boiget F. , Civatte J.
Published: October 2009

Two cases of malignant acanthosis nigricans associated with non-Hodgkin’s lymphoma are presented. A 61-year-old negro male with a diffuse large cell non-Hodgkin’s lymphoma presented extensive acanthosis nigricans, pachydermatoglyphy and florid cutaneous papillomatosis. No viral particles were observed by electron microscopic studies of the wart-like lesions. Acanthosis nigricans disappeared under chemotherapy. The second case was a 21-year-old Caucasian male with non T non B diffuse large cell non-Hodgkin’s lymphoma. Very few cases of acanthosis nigricans associated with non-Hodgkin’s lymphoma have been reported in the literature, since to our knowledge these two are only the fourth and fifth. Pachydermatoglyphy and florid cutaneous papillomatosis are markers of malignant acanthosis nigricans.
Familial Becker’s Nevus
Authors: Panizzon R. , Schnyder U.W.
Published: October 2009

The authors describe 4 patients with Becker’s nevus (BN) in two families. Another 4 patients of the german literature are also presented. Together with the first two published cases of BN, familial BN is now known in 10 patients. All three clinical types of BN could be noticed.
Eosinophilic Cellulitis (Wells’ Syndrome): Ultrastructural Study of a Case with Circulating Immune Complexes
Authors: Ferrier M.C. , Janin-Mercier A. , Souteyrand P. , Bourges M. , Hermier C.
Published: October 2009

A 42-year-old woman was observed during 3 bouts of eosinophilic cellulitis over a 6-year-period. Skin biopsies were taken at each relapse and processed for histological, immunofluorescent and ultrastructural studies. Histologically the eosinophilic infiltrate extended to the deep dermis and the subcutaneous fat. High levels of circulating immune complexes, and complement and IgG deposits around the vessels were detected for as long as the cutaneous lesions lasted. Under the electron microscope eosinophils were numerous, half of them degranulated and some granules had a double cristal core. No injury to the vessel walls was observed. The 3 recurrences occurred respectively after lincomycin, nesdonal, acetyl salicylic acid and pholcodin ingestion and responded to sulfone and steroid therapy.
Protection of Photosensitized Rats against Long Ultraviolet Radiation by Topical Application of Compounds with Structures Similar to That of Dihydroxyacetone
Authors: Follett Kenneth A. , Johnson John A. , Fusard Ramon M.
Published: October 2009

Dihydroxyacetone (DHA), a browning agent, protects photosensitive rats and humans against long ultraviolet radiation (UVA, 320–400 nm) and visible (blue) light. The photoprotective efficacy of DHA and structurally similar compounds was assessed as prevention of edema in the paws of psoralen-sensitized rats, after exposure to blacklight fluorescent lamps. Methylglyoxal produced a yellow-brown color and provided nearly the same protection as DHA, whereas monohydroxyacetone did not color the skin and afforded little or no protection. Glyceraldehyde provided a moderate amount of protection, which was enhanced by prior exposure of the agent to alkaline pH. A solution of 5-hydroxymethylfurfuraldehyde was yellow and provided minimal protection by staining the skin rather than browning it. We conclude that the ability to produce a brown color in skin is a useful criterion for screening compounds for photoprotective efficacy against UVA radiation.
Clinically Specific Type of Focal Palmoplantar Keratoderma with Sensorineural Deafness: An Entity
Authors: Blanchet-Bardon Claudine , Nazzaro Vincenzo , Puissant Antoine
Published: October 2009

A case of focal palmoplantar keratoderma with associated sensorineural deafness is reported. The palmoplantar keratoderma was sharply marginated by geometric borders, spared the plantar arch and was accompanied by marked hyperkeratosis of palmar flexural creases. This syndrome, consisting of a very particular type of palmoplantar keratoderma associated with sensorineural deafness, appears to be distinctive enough to be considered as a clinical entity.
Retinoids in Disorders of Keratinization: Their Use in Children
Authors: Ruiz-Maldonado Ramon , Tamayo Lourdes
Published: October 2009

During the last 10 years we treated 39 children with severe keratinization disorders with the aromatic retinoid etretinate. Six of these children were followed-up for 8–9 years. Mucocutaneous serum enzymatic and lipid side effects of etretinate were mild, transient and well tolerated. Osseous side effects were present after 4–6 years in all our 6 patients on prolonged retinoid therapy. Asymptomatic osseous neoformation and osseous reabsorp-tion in the absence of calcium, phosphate, and alkaline phosphatase serum alterations have been observed. The growth and development curves and the sexual development of our patients (with exception of a patient with Rud’s syndrome) have been normal. Osteoporosis and slender diaphysis were often present at initiation of therapy. On the basis of our findings and recent reports of the literature we suggest restricting retinoid therapy of keratinizing disorders in children to conditions severe enough to be physically, psychologically or socially incapacitating. In an attempt to reduce the risk of chronic toxicity and possibly to allow regression of initial bone alterations, intermittent therapy and combination therapy are recommended.
Isolation and Characterization of Omental Adipose Progenitor Cells in Children: A Potential Tool to Unravel the Pathogenesis of Metabolic Syndrome
Authors: Maiorana Arianna , Fierabracci Alessandra , Cianfarani Stefano
Published: October 2009

Background/Aim: Visceral adipose tissue plays a pivotal role in the pathogenesis of metabolic syndrome. Several investigations refer to the physiology of subcutaneous and visceral adipose tissue of adult obese subjects, focusing on the characterization of adipose-derived stem cells and their differentiation capacity. To date, no study has been carried out on visceral adipose tissue of children, the main limitation being the amount of fat tissue available. The aim of this investigation was to establish a method to successfully isolate adipose progenitor cells from very small specimens of omental fat obtained from children undergoing abdominal surgery. Methods: A previously described procedure employed to extract adipose progenitors from large amounts of lipoaspirate was modified. 0.5-cm3 specimens of omental fat were collected from 13 children and 2 newborns. Primary, secondary and higher passaged adipocytic progenitor cell cultures were established. Immunophenotyping of the generated lines was carried out by flow cytometry analysis. Differentiation experiments concerning the adipogenic phenotype were conducted. Results: A feasible method for isolating adipose progenitors from pediatric specimens of omental fat was established. Cells showed a fibroblast-like appearance consistent with that of mesenchymal stem cells obtained from bone marrow. The mesenchymal phenotype was confirmed by the surface antigenic profile of these cells. Cells also underwent adipogenic differentiation in vitro. Conclusion: The availability of progenitor primary cell lines from omental adipose tissue of children may allow future investigations aimed at unraveling whether fetal programming of adipogenesis is responsible for the pathogenesis of the metabolic syndrome that develops during adulthood in subjects, born with low birth weight, typically showing central fat redistribution.
Follicule to Follicule Heterogeneity of Sebum Excretion
Authors: Piérard G.E.
Published: October 2009

We have evaluated the normal variations in the sebum excretion rate from follicle to follicle on the forehead by using the noninvasive techniques of the Lipometre® and Sebutape®. For a given overall amount of sebum excreted to the surface of the skin during a limited period of time, both the number of active sebaceous follicles and the amount of lipids excreted by them may vary. Significant intraindividual and interindividual differences may be found for these parameters. Such a noninvasive approach to the biology of sebaceous glands represents a new tool allowing a precise evaluation of diseases of the sebum excretion and of their treatments.
Sweet’s Syndrome Associated with Yersinia enterocolitica Infection
Authors: Elsner P. , Hartmann A.A. , Lechner W.
Published: October 2009

Acute febrile neutrophilic dermatosis (Sweet’s syndrome) was diagnosed on the basis of typical clinical and histological features in a 45-year-old woman. Gastrointestinal symptoms had preceded the dermatosis, and an intestinal infection with Yersinia enterocolitica could be proven by culture and serology. This first report on an association between Yersinia infection and Sweet’s syndrome widens the spectrum of both infectious diseases possibly inducing acute febrile neutrophilic dermatosis and dermatological manifestations of yersiniosis.
Imidazoles and Benzoyl Peroxide: A Comparative Trial of Two Treatment Schedules
Authors: Van Neste D. , Tennstedt D. , Decroix J.
Published: October 2009

A double-blind, split-face, self-controlled pilot trial was designed for comparing the therapeutical effect of (a) combination of 2% miconazole nitrate and 5% benzoyl peroxide applied twice daily and (b) topical application of 1% isoconazole nitrate in the morning followed in the evening by 5% benzoyl peroxide. There were no clinically relevant differences between both treatment regimes. These results are interpreted in terms of bioavailability of the active substances.
Syndrome de Lyell sur Vectren®
Authors: Bourlond A. , Dubois D. , de Sélys R. , Frankart M.
Published: October 2009

While treated with isoxicam, a middle-aged lady developed first diffuse maculopapules and afterwards a syndrome of Lyell; similar observations of bimodal toxicodermatitis have been reported in the literature.
Etretinate Therapy in Generalized Pustular Psoriasis (Zumbusch Type)
Authors: Wolska H. , Jabłonska S. , Langner A. , Fraczykowska M.
Published: October 2009

Etretinate therapy in 18 cases of generalized pustular psoriasis of the Zumbusch type proved to be effective and the therapy of choice. Only in 4 patients was maintenance therapy needed; in most cases relapses occurred after various intervals and patients responded invariably to reintroduction of the drug. Side-effects were slight. In 3 patients triglyceride levels became elevated, but only in 1 case the drug had to be withdrawn. In most of the patients generalized pustular eruption was accompanied, in some relapses or in some areas, by plaques of common psoriasis.
An Assessment of the Novel Antihistamine BW 825C in the Treatment of Chronic Idiopathic Urticaria
Authors: Gibson J.R. , Harvey S.G. , Barth J.H. , Moss M.Y. , Burke C.A.
Published: October 2009

20 patients with a diagnosis of chronic idiopathic urticaria were entered into a double-blind placebo-controlled cross-over study. All patients completed the trial and during the assessment period they were treated with placebo, BW 825C (4 mg) and BW 825C (8 mg) according to a fully randomised and balanced treatment plan. Both doses of BW 825C were found to be highly effective and significantly better than placebo in controlling signs and symptoms of urticaria. Few adverse reactions were reported and in this small group of patients there was no significant difference from placebo in reports of drowsiness or any other side-effects.
Pseudo-Allergen-Free Diet in Chronic Urticaria
Authors: Verschave A. , Stevens E. , Degreef H.
Published: October 2009

An elimination diet for additives and tyramine was prescribed to 67 patients with chronic urticaria. 55% of them reacted favorably. Success of dietary treatment was associated with atopy and normal levels of biochemical markers of inflammation.
Cimetidine and Chlorpheniramine in the Treatment of Psoriasis
Authors: Merk H. , Goerz G. , Runne U. , Kurka M. , Schäfer J. , Brendel E.
Published: October 2009

We examined the efficacy of cimetidine and chlorpheniramine alone and in combination in the treatment of psoriasis under the conditions of a randomised controlled double-blind study. Analysis of data from 52 patients revealed that none of the treatment regimes showed a demonstrable beneficial effect on the course of the psoriasis.