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1.
Nature ; 593(7858): 233-237, 2021 05.
Article in English | MEDLINE | ID: mdl-33981052

ABSTRACT

Atmospheric acidity is increasingly determined by carbon dioxide and organic acids1-3. Among the latter, formic acid facilitates the nucleation of cloud droplets4 and contributes to the acidity of clouds and rainwater1,5. At present, chemistry-climate models greatly underestimate the atmospheric burden of formic acid, because key processes related to its sources and sinks remain poorly understood2,6-9. Here we present atmospheric chamber experiments that show that formaldehyde is efficiently converted to gaseous formic acid via a multiphase pathway that involves its hydrated form, methanediol. In warm cloud droplets, methanediol undergoes fast outgassing but slow dehydration. Using a chemistry-climate model, we estimate that the gas-phase oxidation of methanediol produces up to four times more formic acid than all other known chemical sources combined. Our findings reconcile model predictions and measurements of formic acid abundance. The additional formic acid burden increases atmospheric acidity by reducing the pH of clouds and rainwater by up to 0.3. The diol mechanism presented here probably applies to other aldehydes and may help to explain the high atmospheric levels of other organic acids that affect aerosol growth and cloud evolution.

2.
Phys Chem Chem Phys ; 23(9): 5496-5515, 2021 Mar 11.
Article in English | MEDLINE | ID: mdl-33650589

ABSTRACT

The initial stages of the nitrate radical (NO3) initiated oxidation of isoprene, in particular the fate of the peroxy (RO2) and alkoxy (RO) radicals, are examined by an extensive set of quantum chemical and theoretical kinetic calculations. It is shown that the oxidation mechanism is highly complex, and bears similarities to its OH-initiated oxidation mechanism as studied intensively over the last decade. The nascent nitrated RO2 radicals can interconvert by successive O2 addition/elimination reactions, and potentially have access to a wide range of unimolecular reactions with rate coefficients as high as 35 s-1; the contribution of this chemistry could not be ascertained experimentally. The chemistry of the alkoxy radicals derived from these peroxy radicals is affected by the nitrate moiety, and can lead to the formation of nitrated epoxy peroxy radicals in competition with isomerisation and decomposition channels that terminate the organic radical chain by NO2 elimination. The theoretical predictions are implemented in the FZJ-NO3-isoprene mechanism for NO3-initiated atmospheric oxidation of isoprene. The model predictions are compared against peroxy radical (RO2) and methyl vinyl ketone (MVK) measurements in a set of experiments on the isoprene + NO3 reaction system performed in the SAPHIR environmental chamber (IsopNO3 campaign). It is shown that the formation of NO2 from the peroxy radicals can prevent a large fraction of the peroxy radicals from being measured by the laser-induced fluorescence (ROxLIF) technique that relies on a quantitative conversion of peroxy radicals to hydroxyl radicals. Accounting for the relative conversion efficiency of RO2 species in the experiments, the agreement between observations and the theory-based FZJ-NO3-isoprene model predictions improves significantly. In addition, MVK formation in the NO3-initiated oxidation was found to be suppressed by the epoxidation of the unsaturated RO radical intermediates, allowing the model-predicted MVK concentrations to be in good agreement with the measurements. The FZJ-NO3-isoprene mechanism is compared against the MCM v3.3.1 and Wennberg et al. (2018) mechanisms.

3.
Epidemiol Infect ; 147: e280, 2019 09 27.
Article in English | MEDLINE | ID: mdl-31558173

ABSTRACT

Enteric illness outbreaks are complex events, therefore, outbreak investigators use many different hypothesis generation methods depending on the situation. This scoping review was conducted to describe methods used to generate a hypothesis during enteric illness outbreak investigations. The search included five databases and grey literature for articles published between 1 January 2000 and 2 May 2015. Relevance screening and article characterisation were conducted by two independent reviewers using pretested forms. There were 903 outbreaks that described hypothesis generation methods and 33 papers which focused on the evaluation of hypothesis generation methods. Common hypothesis generation methods described are analytic studies (64.8%), descriptive epidemiology (33.7%), food or environmental sampling (32.8%) and facility inspections (27.9%). The least common methods included the use of a single interviewer (0.4%) and investigation of outliers (0.4%). Most studies reported using two or more methods to generate hypotheses (81.2%), with 29.2% of studies reporting using four or more. The use of multiple different hypothesis generation methods both within and between outbreaks highlights the complexity of enteric illness outbreak investigations. Future research should examine the effectiveness of each method and the contexts for which each is most effective in efficiently leading to source identification.


Subject(s)
Communicable Disease Control/methods , Disease Outbreaks , Epidemiologic Methods , Gastrointestinal Diseases/epidemiology , Humans
4.
Ann Oncol ; 29(4): 910-916, 2018 04 01.
Article in English | MEDLINE | ID: mdl-29415128

ABSTRACT

Backround: The primary aim of this study was to investigate information needs and treatment preferences of patients with ovarian cancer, focusing especially on physician-patient relationship and treatment. Patients and methods: A questionnaire was developed based on the experiences of the national German survey 'Expression II', and was provided to patients with ovarian cancer either at initial diagnosis or with recurrent disease via Internet (online-version) or as print-out-version. Results: From December 2009 to October 2012, a total of 1830 patients with ovarian cancer from eight European countries (Austria, Belgium, France, Germany, Italy, Poland, Romania, Spain) participated, 902 (49.3%) after initial diagnosis and 731 (39.9%) with recurrent ovarian cancer. The median age was 58 years (range 17-89). Nearly all patients (96.2%) had experienced upfront surgery followed by first-line chemotherapy (91.8%). The majority of patients were satisfied with the completeness and comprehensibility of the explanation about the diagnosis and treatment options. The three most important aspects, identified by patients to improve the treatment for ovarian cancer included: 'the therapy should not induce alopecia' (42%), 'there must be more done to counter fatigue' (34.5%) and 'the therapy should be more effective' (29.7%). Out of 659 (36%) patients, who were offered participation in a clinical trial, 476 (26%) were included. Conclusion: This study underlines the high need of patients with ovarian cancer for all details concerning treatment options irrespective of their cultural background, the stage of disease and the patient's age. Increased information requirements regarding potential side effects and treatment alternatives were recorded. Besides the need for more effective therapy, alopecia and fatigue are the most important side effects of concern to patients.


Subject(s)
Ovarian Neoplasms/psychology , Ovarian Neoplasms/therapy , Patients/psychology , Physician-Patient Relations , Adult , Aged , Europe , Female , Health Services Needs and Demand , Humans , Middle Aged , Surveys and Questionnaires
5.
Ann Oncol ; 28(suppl_8): viii36-viii39, 2017 Nov 01.
Article in English | MEDLINE | ID: mdl-29232473

ABSTRACT

Paclitaxel and carboplatin combination chemotherapy has remained the standard of care in the front-line therapy of advanced epithelial ovarian cancer during the last decade. Maintenance chemotherapy has not been proven to impact on overall survival. Acceptable alternatives include weekly paclitaxel plus 3-weekly carboplatin, the addition of bevacizumab to 3-weekly carboplatin and paclitaxel, and intraperitoneal chemotherapy. In particular, anti-angiogenic therapy has been identified as the most promising targeted therapy, and the addition of bevacizumab to first-line chemotherapy followed by a maintenance period of bevacizumab in monotherapy has shown to prolong progression-free survival. This was considered the proof of concept of the value of anti-angiogenic therapy in the front-line of ovarian cancer, and the results of two additional clinical trials with anti-angiogenic tyrosine kinase inhibitors have shown results in the same direction.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms, Glandular and Epithelial/drug therapy , Ovarian Neoplasms/drug therapy , Bevacizumab/administration & dosage , Carboplatin/administration & dosage , Carcinoma, Ovarian Epithelial , Female , Humans , Paclitaxel/administration & dosage , Randomized Controlled Trials as Topic
6.
Faraday Discuss ; 200: 331-351, 2017 08 24.
Article in English | MEDLINE | ID: mdl-28580998

ABSTRACT

Ambient measurements of PM1 aerosol chemical composition at Cabauw, the Netherlands, implicate higher ammonium concentrations than explained by the formation of inorganic ammonium salts. This additional particulate ammonium is called excess ammonium (eNH4). Height profiles over the Cabauw Experimental Site for Atmospheric Research (CESAR) tower, of combined ground based and airborne aerosol mass spectrometric (AMS) measurements on a Zeppelin airship show higher concentrations of eNH4 at higher altitudes compared to the ground. Through flights across the Netherlands, the Zeppelin based measurements furthermore substantiate eNH4 as a regional phenomenon in the planetary boundary layer. The excess ammonium correlates with mass spectral signatures of (di-)carboxylic acids, making a heterogeneous acid-base reaction the likely process of NH3 uptake. We show that this excess ammonium was neutralized by the organic fraction forming particulate organic ammonium salts. We discuss the significance of such organic ammonium salts for atmospheric aerosols and suggest that NH3 emission control will have benefits for particulate matter control beyond the reduction of inorganic ammonium salts.

7.
Br J Cancer ; 111(8): 1519-25, 2014 Oct 14.
Article in English | MEDLINE | ID: mdl-25225907

ABSTRACT

BACKGROUND: This is the first study investigating the safety and efficacy of the trifunctional antibody catumaxomab administered i.p. at the end of cytoreductive surgery and postoperatively prior to standard chemotherapy in patients with primary epithelial ovarian cancer (EOC). METHODS: Patients received i.p. catumaxomab 10 µg intraoperatively and 10, 20, 50 and 150 µg on days 7, 10, 13 and 16, respectively, postoperatively. After the study, patients received standard chemotherapy and were followed for 23 months. The primary endpoint was the rate of postoperative complications. RESULTS: Forty-one patients entered the study and were evaluable for safety and 34 were alive at 24 months. Complete tumour resection rate was 68%. Postoperative complications were observed in 51%, the most common anastomotic leakage (7%) and wound infections (5%). The most common catumaxomab-related adverse events were abdominal pain, nausea, vomiting and pyrexia. Thirty-nine percent discontinued catumaxomab therapy, and 98% received chemotherapy post study. Kaplan-Meier estimates of disease-free and overall survival after 24 months were 56% and 85%, respectively. CONCLUSIONS: Intra- and close postoperative catumaxomab seems feasible, but efficacy and safety were limited by postsurgical complications. In the future prospective trials are needed to investigate the best schedule of integration of catumaxomab into current treatment strategies for EOC.


Subject(s)
Antibodies, Bispecific/therapeutic use , Neoplasms, Glandular and Epithelial/drug therapy , Ovarian Neoplasms/drug therapy , Adult , Aged , Antibodies, Bispecific/administration & dosage , Carcinoma, Ovarian Epithelial , Female , Humans , Intraoperative Care , Middle Aged , Neoplasms, Glandular and Epithelial/surgery , Ovarian Neoplasms/surgery , Postoperative Care
8.
Neoplasma ; 59(6): 747-55, 2012.
Article in English | MEDLINE | ID: mdl-22862176

ABSTRACT

Because of its semi-solid character in dissemination and growth, advanced ovarian cancer with its hundreds of peritoneal tumor nodules and plaques appears to be an excellent in vivo model for studying the cancer stem cell hypothesis. The most important obstacle, however, is to adequately define and isolate these tumor-initiating cells endowed with the properties of anoikis-resistance and unlimited self-renewal. Until now, no universal single marker or marker constellation has been found to faithfully isolate (ovarian) cancer stem cells. As these multipotent cells are known to possess highly elaborated efflux systems for cytotoxic agents, these pump systems have been exploited to outline putative stem cells as a side-population (SP) via dye exclusion analysis. Furthermore, the cells in question have been isolated via flow cytometry on the basis of cell surface markers thought to be characteristic for stem cells.In the Vienna variant of the ovarian cancer cell line A2780 a proof-of-principle model with both a stable SP and a stable ALDH1A1+ cell population was established. Double staining clearly revealed that both cell fractions were not identical. Of note, A2780V cells were negative for expression of surface markers CD44 and CD117 (c-kit). When cultured on monolayers of healthy human mesothelial cells, green-fluorescence-protein (GFP)-transfected SP of A2780V exhibited spheroid-formation, whereas non-side-population (NSP) developed a spare monolayer growing over the healthy mesothelium. Furthermore, A2780V SP was found to be partially resistant to platinum. However, this resistance could not be explained by over-expression of the "excision repair cross-complementation group 1" (ERCC1) gene, which is essentially involved in the repair of platinated DNA damage. ERCC1 was, nonetheless, over-expressed in A2780V cells grown as spheres under stem cell-selective conditions as compared to adherent monolayers cultured under differentiating conditions. The same was true for the primary ovarian cancer cells B-57.In summary our investigations indicate that even in multi-passaged cancer cell lines hierarchic government of growth and differentiation is conserved and that the key cancer stem cell population may be composed of small overlapping cell fractions defined by various arbitrary markers.


Subject(s)
Neoplastic Stem Cells/physiology , Ovarian Neoplasms/pathology , Animals , Cell Separation , Coculture Techniques , DNA-Binding Proteins/genetics , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Endonucleases/genetics , Female , Humans , Ovarian Neoplasms/drug therapy
9.
Oncogene ; 30(38): 4038-49, 2011 Sep 22.
Article in English | MEDLINE | ID: mdl-21516127

ABSTRACT

Recently we showed an integral epidermal growth factor receptor (EGFR)-E2F3a signaling path, in which E2F3a was found to be essential in EGFR-mediated proliferation in ovarian cancer cells. The present work evaluates the clinical relevance of this novel axis and of E2F3a itself in a large set of 130 ovarian cancer specimens. For this purpose E2F3a and its counterpart, E2F3b, were measured by RT-PCR and activated EGFR was assessed by immunohistochemistry. When compared with healthy control tissue, both E2F3 isoforms were overexpressed in the cancers, but only E2F3a expression correlated with tumor stage (ρ=0.349, P=0.0001) and residual disease (ρ=0.254, P=0.004). Univariate survival analyses showed E2F3a and activated EGFR to be associated with poor PFS and OS. Furthermore, a strong, positive correlation between activated EGFR and E2F3a expression was shown (P=0.0001). We further identified two EGFR-independent mechanisms that regulate E2F3a expression, namely one, acting by promoter methylation of miR-34a, which by its physical interaction with E2F3a transcripts causes their degradation, and the second based on 6p22 gene locus amplification. MiRIDIAN-based knockdown and induction of miR-34a evidenced a direct regulatory link between miR-34a and E2F3a, and the tumor-suppressive character of miR-34a was documented by its association with improved survival. Although, 6p22 gene locus amplification was detected in a significant number of ovarian cancer specimens, 6p22 ploidy was not relevant in predicting survival. In Cox regression analysis, E2F3a, but not activated EGFR or miR-34a expression, retained independent prognostic significance (PFS: hazards ratio 3.785 (1.326-9.840), P=0.013; OS: hazards ratio 4.651 (1.189-15.572), P=0.013). These clinical findings highlight the relevance of E2F3a in the biology of ovarian cancer. Moreover, identification of EGFR-independent mechanisms in E2F3a control can be helpful in explaining the non-responsiveness of therapeutic EGFR targeting in ovarian cancer.


Subject(s)
E2F3 Transcription Factor/physiology , Ovarian Neoplasms/pathology , Aged , Chromosomes, Human, Pair 6 , DNA Methylation , E2F3 Transcription Factor/analysis , E2F3 Transcription Factor/genetics , ErbB Receptors/physiology , Female , Gene Amplification , Humans , MicroRNAs/genetics , Middle Aged , Ovarian Neoplasms/chemistry , Ovarian Neoplasms/genetics , Prognosis , Promoter Regions, Genetic
10.
Exp Clin Endocrinol Diabetes ; 118(5): 291-7, 2010 May.
Article in English | MEDLINE | ID: mdl-20198556

ABSTRACT

Progressive hirsutism can be a symptom of an androgen-producing tumor, especially in postmenopausal women. We report a case of a 58-year-old woman who complained of progressive hirsutism, nervousness, irritability, anxiousness and an increased libido. Examination showed an unusual redness of her head, décolleté, palms and soles of her feet. Basal laboratory tests revealed a profound elevation of testosterone levels (7.5 microg/l) and normal levels of androstendione, dehydroepiandrosterone-sulfate, 17alpha-hydroxy-progesterone and thyroid-stimulating hormone. Also remarkable was that her red blood count, hemoglobin and hematocrit values were elevated while erythropoietin was within normal limits. Functional laboratory tests ruled out heterozygous C21-hydroxylase deficiency and showed a moderate insulin resistance on the oral glucose tolerance test. Transvaginal ultrasound revealed a slightly hyperdensic area of 6 mm in the left ovary. Magnetic resonance imaging showed a contrast medium-accumulating area of 2 cm in the left ovary. Since the patient was initially reluctant to undergo surgery, a GnRH-analogue (triptoreline) was administered VIA intramuscular injection once per month for two months and testosterone levels were lowered to less than one third of the initial level (2 microg/l). Surgery was eventually performed with laparoscopic bilateral salpingoophorectomy, hysteroscopy and uterine curettage. The histologic examination revealed a Leydig cell tumor in the hilus and stroma of the left ovary. Postoperatively testosterone levels dropped dramatically and instantly into the normal range. Within months, the red blood count and hematocrit levels were within normal limits. The patient's face became more feminine, the redness of her face and hirsutism regressed. Her anxiousness and nervosity resolved and the insulin sensitivity improved. In this paper, polyglobulia, the metabolic and psychological changes due to hyperandrogenism are discussed, as well as the phenomenon that the tumor responded to a GnRH-analogue. Such a response implies that the tumor is either under gonadotropin control or that GnRH analogues have direct effects via receptors on tumorous Leydig cells.


Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Leydig Cell Tumor/drug therapy , Ovarian Neoplasms/drug therapy , Triptorelin Pamoate/therapeutic use , Female , Follicle Stimulating Hormone/blood , Humans , Leydig Cell Tumor/blood , Leydig Cell Tumor/diagnostic imaging , Leydig Cell Tumor/surgery , Luteinizing Hormone/blood , Luteolytic Agents/therapeutic use , Middle Aged , Ovarian Neoplasms/blood , Ovarian Neoplasms/diagnostic imaging , Ovarian Neoplasms/surgery , Postmenopause , Testosterone/blood , Ultrasonography
11.
Ultraschall Med ; 31(1): 63-7, 2010 Feb.
Article in English, German | MEDLINE | ID: mdl-20094979

ABSTRACT

PURPOSE: We assessed the value of contrast-enhanced US for differentiating between benign and malignant axillary lymph nodes in breast cancer. MATERIALS AND METHODS: A total of 120 axillary lymph nodes in 92 patients with breast cancer were studied. All patients underwent grayscale US examination, unenhanced and enhanced color and power Doppler US, and enhanced grayscale harmonic US examination. RESULTS: The mean size of the 120 axillary lymph nodes was 1.5 cm (range 0.5 - 3.4 cm). Of all 120 axillary lymph nodes studied, 80 (67 %) were malignant and 40 (33 %) were benign according to pathological examination. The total number of vessels in baseline US did not increase between benign and malignant lymph nodes (3.3 +/- 2.2 vs. 5.4 +/- 4.0; p > 0.05). The total number of peripheral vessels was 0.5 +/- 0.8 for benign lymph nodes vs. 2.0 +/- 1.7 for malignant lymph nodes (p > 0.05). Enhanced US studies showed enhancement in both benign and malignant lymph nodes after contrast administration with a significantly higher degree of enhancement in malignant lymph nodes (p < 0.01). The total number of vessels was significantly higher in malignant lymph nodes after contrast administration (17.3 +/- 8.0 vs. 8.2 +/- 5.1, p < 0.01). Malignant lymph nodes demonstrated longer contrast enhancement duration compared to benign lymph nodes. CONCLUSION: This preliminary data shows that contrast-enhanced US can differentiate between benign and malignant lymph nodes in breast cancer.


Subject(s)
Breast Neoplasms/diagnostic imaging , Image Enhancement/methods , Lymph Nodes/diagnostic imaging , Lymphatic Metastasis/diagnostic imaging , Ultrasonography, Doppler, Color/methods , Ultrasonography, Mammary/methods , Aged , Axilla/diagnostic imaging , Breast Neoplasms/blood supply , Breast Neoplasms/pathology , Contrast Media/administration & dosage , Female , Humans , Lymph Nodes/blood supply , Lymph Nodes/pathology , Lymphatic Metastasis/pathology , Middle Aged , Neovascularization, Pathologic/diagnostic imaging
12.
Oncogene ; 29(13): 1997-2004, 2010 Apr 01.
Article in English | MEDLINE | ID: mdl-20101229

ABSTRACT

Similar to p73, the tumor suppressor gene p53 is subject to alternative splicing. Besides p53DeltaE6 and p53beta, we identified p53zeta, p53delta and p53varepsilon, arising from alternative splicing of exon 6 and intron 9, respectively. p53 splice variants were present in 18 of 34 ovarian cancer cell lines (52.9%) and 134 of 245 primary ovarian cancers (54.7%). p53delta expression was associated with impaired response to primary platinum-based chemotherapy (P=0.032). Also, p53delta expression constituted an independent prognostic marker for recurrence-free and overall survival (hazard ratio 1.854, 95% confidence interval 1.121-3.065, P=0.016; and hazard ratio 1.937, 95% confidence interval 1.177-3.186, P=0.009, respectively). p53beta expression was associated with adverse clinicopathologic markers, that is, serous and poorly differentiated cancers (P=0.002 and P=0.008, respectively), and correlated with worse recurrence-free survival in patients exhibiting functionally active p53 (P=0.049). DeltaN'p73 constituted the main N-terminally truncated p73 isoform and was preferentially found in ovarian cancer cell lines showing functionally active p53, supporting our hypothesis that N-terminally truncated p73 isoforms can alleviate the selection pressure for p53 mutations by the inhibition of p53 protein function.


Subject(s)
Alternative Splicing , DNA-Binding Proteins/genetics , Nuclear Proteins/genetics , Ovarian Neoplasms/genetics , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Proteins/genetics , Female , Humans , Introns , Tumor Protein p73 , Tumor Suppressor Protein p53/metabolism
13.
Eur J Gynaecol Oncol ; 29(3): 272-5, 2008.
Article in English | MEDLINE | ID: mdl-18592794

ABSTRACT

BACKGROUND: A case of cervical cancer associated with irreducible procidentia successfully treated with external beam radiation and extracorporeal HDR-AL with concomitant chemotherapy followed by obliterative vaginal surgery is reported for the first time. CASE: A 73-year-old woman presented in frail condition suffering from a huge, irreducible uterovaginal procidentia combined with a squamous cell carcinoma of the cervix in FIGO Stage IIa. Successful treatment consisted of sequential application of combined radiotherapy with concurrent cisplatin chemotherapy followed by total vaginal hysterectomy and partial colpectomy with colpocleisis according to the Labhardt method. The five-year follow-up documents the excellent long-term results with regard to cervical cancer and pelvic floor stability. CONCLUSION: Especially in patients ineligible for extended surgery, radiochemotherapy followed by an obliterative surgical approach is feasible without aberrant wound healing and constitutes a suitable and efficient option for treating carcinomas of the cervix associated with irreducible genital prolapse.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Squamous Cell/therapy , Cisplatin/therapeutic use , Uterine Cervical Neoplasms/therapy , Uterine Prolapse/therapy , Aged , Antineoplastic Agents/administration & dosage , Carcinoma, Squamous Cell/pathology , Chemotherapy, Adjuvant , Cisplatin/administration & dosage , Female , Frail Elderly , Humans , Hysterectomy, Vaginal , Neoadjuvant Therapy , Radiotherapy, Adjuvant , Uterine Cervical Neoplasms/pathology , Uterine Prolapse/pathology
15.
Eur J Gynaecol Oncol ; 29(2): 168-70, 2008.
Article in English | MEDLINE | ID: mdl-18459555

ABSTRACT

OBJECTIVE: To report an uncommon case of a recurrent episode of primarily paraneoplastic dermatomyositis which was completely disconnected from the initially triggering malignancy and manifested as a silent pure multivisceral exacerbation. CASE: A 70-year-old woman presented with a pure multivisceral episode of dermatomyositis without characteristic musculo-cutaneous symptoms one year after successful treatment of fallopian tube carcinoma with complete resolvement of a concomittant paraneoplastic dermatomyositis. The uncommon manifestation of recurrent dermatomyositis involving the lungs, spleen and liver, both adrenal glands and abdominal lymph nodes, mimicked a highly disseminated recurrence of the fallopian tube cancer. Physicians participating in the interdisciplinary tumor board were misled to opt for reinductive chemotherapy. Only histologic diagnosis obtained from multiple biopsies uncovered the inflammatory nature of the disease and spared the patient unneeded chemotherapy. CONCLUSION: Asymptomatic multivisceral dermatomyositis may mimic metastatic spread of the initially underlying malignancy and may misdirect therapeutic strategies towards inadequate antineoplastic treatment.


Subject(s)
Carcinoma/complications , Dermatomyositis/physiopathology , Fallopian Tube Neoplasms/complications , Paraneoplastic Syndromes/physiopathology , Adrenal Cortex Hormones/therapeutic use , Aged , Cryptogenic Organizing Pneumonia/diagnostic imaging , Cryptogenic Organizing Pneumonia/etiology , Dermatomyositis/complications , Dermatomyositis/drug therapy , Female , Humans , Paraneoplastic Syndromes/drug therapy , Recurrence , Tomography, X-Ray Computed
16.
J Prosthet Dent ; 85(5): 516-8, 2001 May.
Article in English | MEDLINE | ID: mdl-11357081

ABSTRACT

The use of a metal housing-retained attachment for implant-supported overdentures: (1) facilitates easy removal and replacement of a matrix attachment during routine recall examinations, and (2) ensures correct alignment and retention to the implant-supported bar assembly. This article describes a laboratory technique for processing the bar assembly (without allowing acrylic resin to seep under it) with the master cast invested in the metal flask. The technique ensures a precise fit of retentive attachments at the delivery of the overdenture to the patient.


Subject(s)
Dental Prosthesis Retention/instrumentation , Dental Prosthesis, Implant-Supported , Denture, Overlay , Dental Abutments , Humans , Models, Dental , Technology, Dental
17.
J Biol Chem ; 276(25): 22100-6, 2001 Jun 22.
Article in English | MEDLINE | ID: mdl-11285265

ABSTRACT

In cochlea inner hair cells (IHCs), L-type Ca(2+) channels (LTCCs) formed by alpha1D subunits (D-LTCCs) possess biophysical and pharmacological properties distinct from those of alpha1C containing C-LTCCs. We investigated to which extent these differences are determined by alpha1D itself by analyzing the biophysical and pharmacological properties of cloned human alpha1D splice variants in tsA-201 cells. Variant alpha1D(8A,) containing exon 8A sequence in repeat I, yielded alpha1D protein and L-type currents, whereas no intact protein and currents were observed after expression with exon 8B. In whole cell patch-clamp recordings (charge carrier 15-20 mm Ba(2+)), alpha1D(8A) - mediated currents activated at more negative voltages (activation threshold, -45.7 versus -31.5 mV, p < 0.05) and more rapidly (tau(act) for maximal inward currents 0.8 versus 2.3 ms; p < 0.05) than currents mediated by rabbit alpha1C. Inactivation during depolarizing pulses was slower than for alpha1C (current inactivation after 5-s depolarizations by 90 versus 99%, p < 0.05) but faster than for LTCCs in IHCs. The sensitivity for the dihydropyridine (DHP) L-type channel blocker isradipine was 8.5-fold lower than for alpha1C. Radioligand binding experiments revealed that this was not due to a lower affinity for the DHP binding pocket, suggesting that differences in the voltage-dependence of DHP block account for decreased sensitivity of D-LTCCs. Our experiments show that alpha1D(8A) subunits can form slowly inactivating LTCCs activating at more negative voltages than alpha1C. These properties should allow D-LTCCs to control physiological processes, such as diastolic depolarization in sinoatrial node cells, neurotransmitter release in IHCs and neuronal excitability.


Subject(s)
Calcium Channels, L-Type/metabolism , Amino Acid Sequence , Calcium Channel Blockers/pharmacology , Calcium Channels, L-Type/genetics , Cell Line , Cloning, Molecular , DNA, Complementary , Humans , Isradipine/pharmacology , Molecular Sequence Data
18.
FEBS Lett ; 467(1): 65-9, 2000 Feb 04.
Article in English | MEDLINE | ID: mdl-10664458

ABSTRACT

Various beta subunit isoforms stabilize different gating properties of voltage-gated L-type Ca(2+) channels. We therefore investigated the expression of Ca(2+) channel beta subunit isoforms in different smooth muscle types on the protein level by immunoblotting and immunoprecipitation employing beta subunit-selective sequence-directed antibodies. From the four known beta subunit isoforms only beta2 and beta3 were detected in porcine uterus, bovine trachea and bovine aorta membranes. Multiple immunoreactive beta2 bands were detected in a tissue-selective manner indicating structural heterogeneity of beta2. Immunoprecipitation of (+)-[(3)H]isradipine-prelabeled channels revealed that beta2 and beta3 participate in Ca(2+) channel formation in uterus and trachea, and beta3 in aortic smooth muscle. We conclude that beta2 and beta3 subunits form L-type Ca(2+) channels in smooth muscle tissues. This subunit heterogeneity may be important to fine-tune channel function.


Subject(s)
Calcium Channels, L-Type/analysis , Calcium Channels, L-Type/chemistry , Muscle, Smooth/chemistry , Animals , Antibodies/immunology , Aorta , Blotting, Western , Calcium Channel Blockers/metabolism , Calcium Channels, L-Type/immunology , Calcium Channels, L-Type/metabolism , Cattle , Cell Membrane/metabolism , Cerebral Cortex/chemistry , Female , Isradipine/metabolism , Molecular Weight , Muscle, Smooth/immunology , Muscle, Smooth, Vascular/chemistry , Muscle, Smooth, Vascular/immunology , Myocardium/chemistry , Myometrium/chemistry , Myometrium/cytology , Myometrium/immunology , Organ Specificity , Precipitin Tests , Protein Isoforms/analysis , Protein Isoforms/chemistry , Protein Isoforms/immunology , Protein Isoforms/metabolism , Rabbits , Swine , Trachea/chemistry , Trachea/immunology
19.
Methods Mol Med ; 25: 255-304, 2000.
Article in English | MEDLINE | ID: mdl-21318851

ABSTRACT

The overall goal of gene therapy is to cure or stabilize a disease process that results from the production of a mutant protein (for example, the chloride channel protein important in cystic fibrosis) or overproduction of a normal protein (such as the products of certain oncogenes). We can achieve this goal by replacing the defective gene or by reducing the overexpression of the target gene using an antisense strategy, thus reducing the production of the diseasepromoting protein (1,2). For either method, it is critical to transfer DNA into target cells in a concentration high enough to be effective in modifying the disease. DNA must be delivered to the desired cell population in an intact state, whereby it can be efficiently transcribed and ultimately translated. The method of gene transfer must be highly efficient and nontoxic, and the delivery system must be relatively easy to prepare and administer (3). There is a great deal of optimism surrounding the development of gene therapy as an effective strategy for management of many different human diseases. The active agent used to procure gene therapy is likely to consist of oligonucleotides, ribozymes, or a DNA sequence that can be transcribed into a message capable of eliciting a therapeutic response. Unlike conventional small-molecule therapeutics however, gene therapy requires the use of a carrier system to deliver the active agent directly into the target cell population.

20.
Can J Anaesth ; 46(12): 1185-90, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10608216

ABSTRACT

PURPOSE: Efforts to harmonize the standards of the CSA and the ISO, as they relate to compressed medical gas supply and piping, prompted us to review ten years experience with oxygen concentrators (OCs) in Canada used as a primary hospital oxygen supply. The goals of this study were; 1) To document the number of Canadian OC Hospital sites, 2) to define what impact these units have had on medical practice and patient care, and 3) to explore trends in oxygen costing and utilization at the study sites. METHODS: Following a four part mail survey and telephone follow up, site surveys were conducted for all hospitals utilizing an OC. Installation and service records, operating costs, amortization detail, leasing records as well as patient safety were all detailed. RESULTS: Forty eight of 52 Canadian hospitals utilizing an OC participated. Clinical activity at the surveyed sites of 1996 included 30,642 surgical operations, 9,415 intensive care bed days and 364,529 emergency room visits. The cumulative survey represents 1,026,819 hr of OC operation. During a 24 hr day, OCs operate 55 +/- 3% of the time. Financial analysis was validated at 43 of the 48 hospital sites. During the study the unit cost of oxygen was reduced by 62% (P <.0001). An annual increase in oxygen consumption of 11.5 +/- 2% was documented (P <.0001). No patient care critical incidents related to OCs were reported. CONCLUSION: An OC installation which is CAN/CSA Z305.6-M92 compliant provides a safe, reliable, cost efficient primary hospital source of oxygen.


Subject(s)
Anesthesiology/instrumentation , Oxygen Inhalation Therapy/instrumentation , Oxygen , Anesthesiology/economics , Canada , Evaluation Studies as Topic , Oxygen Inhalation Therapy/economics
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