Current status of percutaneous PFO closure.

The clinical significance of persistent patent foramen ovale (PFO) is not well defined. Empirically, PFO has been associated with many clinical conditions. In cryptogenic stroke, migraine, and orthodeoxia/platypnea, a plausible biologic mechanism exists to support PFO closure as a possible treatment. Although transcatheter closure of PFO has been available for over 2 decades, it has remained controversial due to a paucity of evidence to guide patient and device selection. Contemporary studies investigating PFO closure as treatment for patients with these conditions have been published recently and longitudinal data regarding the safety and efficacy of the devices is now available. In this review, we aim to describe the potential clinical significance of a patent foramen in the adult, appraise the newest additions to the body of evidence, and discuss the safety, benefit, patient selection, and future of transcatheter treatment of PFO.

Long-term follow-up of high-dose chemotherapy with autologous stem-cell transplantation and response-adapted whole-brain radiotherapy for newly diagnosed primary CNS lymphoma: results of the multicenter Ostdeutsche Studiengruppe Hamatologie und Onkologie OSHO-53 phase II study.

BACKGROUND: We previously reported the results of a phase II study for patients with newly diagnosed primary central nervous system lymphoma treated with autologous peripheral blood stem-cell transplantation (aPBSCT) and response-adapted whole-brain radiotherapy (WBRT). Now, we update the initial results. PATIENTS AND METHODS: From 1999 to 2004, 23 patients received high-dose methotrexate. In case of at least partial remission, high-dose busulfan/thiotepa (HD-BuTT) followed by aPBSCT was carried out. Patients refractory to induction or without complete remission after HD-BuTT received WBRT. Eight patients still alive in 2011 were contacted and Mini-Mental State Examination (MMSE) and the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire (QLQ)-C30 were carried out. RESULTS: Of eight patients still alive, median follow-up is 116.9 months. Only one of nine irradiated patients is still alive with a severe neurologic deficit. In seven of eight patients treated with HD-BuTT, health condition and quality of life are excellent. MMSE and QLQ-C30 showed remarkably good results in patients who did not receive WBRT. All of them have a Karnofsky score of 90%-100%. CONCLUSIONS: Follow-up shows an overall survival of 35%. In six of seven patients where WBRT could be avoided, no long-term neurotoxicity has been observed and all patients have an excellent quality of life.

Fast and robust hydrogen sensors based on discontinuous palladium films on polyimide, fabricated on a wafer scale.

Fast hydrogen sensors based on discontinuous palladium (Pd) films on supporting polyimide layers, fabricated by a cost-efficient and full-wafer compatible process, are presented. The films, deposited by electron-beam evaporation with a nominal thickness of 1.5 nm, consist of isolated Pd islands that are separated by nanoscopic gaps. On hydrogenation, the volume expansion of Pd brings initially separated islands into contact which leads to the creation of new electrical pathways through the film. The supporting polyimide layer provides both sufficient elasticity for the Pd nanoclusters to expand on hydrogenation and a sufficiently high surface energy for good adhesion of both film and contacting electrodes. The novel order of the fabrication processes involves a dicing step prior to the Pd deposition and stencil lithography for the patterning of microelectrodes. This allows us to preserve the as-deposited film properties. The devices work at room temperature, show response times of a few seconds and have a low power consumption of some tens of nW.

A single nanotrench in a palladium microwire for hydrogen detection.

The hydrogen sensing characteristics of a single nanotrench fabricated by focused ion beam milling (FIB) in an evaporated palladium microwire are presented. In situ atomic force microscopy (AFM) measurements proved that, in the presence of H(2), the trench closes and electrically connects the initially separated parts of the wire due to the increase in volume of the material. Therewith, an electrical current can be switched through the wire. With experiments under various H(2) concentrations and a mathematical model, we describe the closing mechanism of the trench with respect to various parameters, including the substrate material, film thickness, trench size and wire dimensions. Results have been compared with those from equivalent continuous wires. Thin SiO(2) and polyimide (PI) layers on silicon were used to study the effect of substrate elasticity. Sufficient lateral expansion of Pd to close trenches of up to 70 nm in width has only been observed on PI, which we attribute to its advantageous elastic properties. The scale of the response times allowed the observation of two superposing effects: the chemical conversion of Pd to PdH(x) and the mechanical closing of the trench.

Primary central nervous system lymphoma treated with high-dose methotrexate, high-dose busulfan/thiotepa, autologous stem-cell transplantation and response-adapted whole-brain radiotherapy: results of the multicenter Ostdeutsche Studiengruppe Hamato-Onkologie OSHO-53 phase II study.

BACKGROUND: We investigated the efficacy and safety of tandem high-dose methotrexate (HD-MTX) induction followed by high-dose busulfan/thiotepa (HD-BuTT) with autologous peripheral blood stem-cell transplantation (aPBSCT) and response-adapted whole-brain radiation therapy (WBRT) in patients with newly diagnosed primary central nervous system lymphoma. PATIENTS AND METHODS: Twenty-three patients were treated with HD-MTX on days 1 and 10. In case of at least a partial remission (PR), HD-BuTT followed by aPBSCT was given. Patients without response to induction or without complete remission (CR) after HD-BuTT received WBRT. RESULTS: Sixteen patients received HD-MTX and HD-BuTT achieving a CR/PR rate of 69%/13%. CR/PR rates for all patients (n = 23) were 70%/13%. There were three deaths during therapy. With longer follow-up three neurotoxic deaths occurred in irradiated patients (n = 9), while no persistent neurotoxicity was seen after HD-BuTT without subsequent WBRT. At a median follow-up of 15 months (range 1-69) median event-free survival (EFS) and overall survival (OS) for all patients were 17 and 20 months (Kaplan-Meier), after HD-BuTT 27 months and "not reached", respectively. Estimated 2-year EFS and OS were 45% and 48% for all patients versus 56% and 61% for the HD-BuTT group, respectively. CONCLUSION: MTX induction followed by HD-BuTT is an effective and very short time-on-treatment regimen. Median survival for patients treated with high-dose chemotherapy is not reached yet. The induction regimen needs optimisation. In this study WBRT was associated with a high incidence of severe neurotoxicity.

[Chylopericardium following pulmonary tuberculosis]. / Chyloperikard nach Lungentuberkulose.

HISTORY: A 22-year old man was admitted with a large pericardial effusion after he had been successfully treated for tuberculosis of the right lung for 6 months. Treatment had been discontinued according to plan 4 months before the current admission. The patient was only mildly symptomatic with exertional dyspnea of 3 weeks duration. Body temperature, pulse rate and blood pressure were within normal limits. The neck veins were not distended. INVESTIGATIONS AND DIAGNOSIS: Laboratory data were unremarkable. The patient underwent thoracoscopy for pericardial drainage. A large chylous effusion was removed. CLINICAL COURSE: Drainage ceased over the following months after the patient had been on a medium-chain triglyceride diet. On follow-up 9 months later, the patient was asymptomatic and without evidence of cardiopulmonary disease. CONCLUSION: We presume (A) that the tuberculous infection had affected the mediastinal lymph nodes and (B) that the fibrous contraction of perinodal tissue caused a temporary obstruction of the thoracic duct at a later stage in the course of the healing process with subsequent reflux of chyle into the pericardial cavity via lymphatic vessels that normally drain the pericardium.

The modification of high-dose therapy shortens the duration of neutropaenia by delay of leucocyte nadir.

Infections during neutropaenia contribute still significantly to mortality and morbidity after high-dose therapy and autologous stem cell transplantation. Further acceleration of haemopoietic recovery seems impossible for biological reasons. Another approach to shorten neutropaenia could be to remove drugs from high-dose therapy protocols with strong contribution to immunosuppression and neutropaenia and unproven antineoplastic activity. In this retrospective matched-pair analysis, conventional busulphan/cyclophosphamide (Bu/Cy) high-dose therapy was compared to single-agent busulphan conditioning before autologous stem cell transplantation. This modification led to a significant shorter neutropaenic interval by protraction of cell decrease and to a significant mitigation of neutropaenia. After single-agent busulphan conditioning, leucocytes dropped below 1/nl at median 1.5 days later when compared to the patients from the busulphanBu/Cy control group (P=0.001). In a significant percentage of patients (n=6, 60%) leucocytes did not fall below 0.5 cells/nl at any time. In contrast, all patients from the Bu/Cy control group experienced deep neutropaenia (P=0.004). Thrombocytopaenia and requirement for transfusions of platelets or red cells were not influenced. Antineoplastic activity seemed to be preserved as determined by survival analysis. In conclusion, modification of high-dose regimen with the intention to shorten neutropaenia with preserved antitumour activity could be an approach to reduce infection-related morbidity and mortality and to consider economic necessities.

Regression of NMU-induced mammary tumors with the combination of melatonin and 9-cis-retinoic acid.

A significant increase in tumor regression was induced in N-nitroso-N-methylurea-induced mammary tumors in rats treated with the combination of melatonin and 9-cis-retinoic acid (9cRA). Treatment groups included: control (ethanolic saline), 9cRA (30 mg/kg chow/day), melatonin 500 microg/day, melatonin 1000 microg/day, melatonin 500 microg/day+9cRA and melatonin 1000 microg/day+9cRA. Rats treated with the lower dose of melatonin 500 microg+9cRA show the greatest degree of tumor regression (78%), with 54% undergoing complete regression and a significant increase in apoptotic cells observed by TUNEL Assay. Furthermore, tumor multiplicity and burden were significantly decreased by the combination of melatonin and 9cRA.

Deep flow in the Madagascar-Mascarene Basin over the last 150,000 years.

The SW Indian Ocean contains at least four layers of water masses with different sources: deep Antarctic (Lower Circumpolar Deep Water) flow to the north, midwater North Indian Deep Water flow to the south and Upper Circumpolar Deep Water to the north, meridional convergence of intermediate waters at 500-1500 m, and the shallow South Equatorial Current flowing west. Sedimentation rates in the area are rather low, being less than 1 cm ka(-1) on Madagascar Ridge, but up to 4 cm ka(-1) at Amirante Passage. Bottom flow through the Madagascar-Mascarene Basin into Amirante Passage varies slightly on glacial-interglacial time-scales, with faster flow in the warm periods of the last interglacial and minima in cold periods. Far more important are the particularly high flow rates, inferred from silt grain size, which occur at warm-to-cold transitions rather than extrema. This suggests the cause is changing density gradient driving a transiently fast flow. Corroboration is found in the glacial-interglacial range of benthic delta18O which is ca. 2 per thousand, suggesting water close to freezing and at least 1.2 more saline and thus more dense glacial bottom waters than present. Significant density steps are inferred in isotope stage 6, the 5e-5d, and 5a-4 transitions. Oxygen isotope data suggest little change by mixing in glacial bottom water on their northward path. Benthic carbon isotope ratios at Amirante Passage differ from glacial Southern Ocean values, due possibly to absence of a local productivity effect present in the Southern Ocean.

Do cancer patients with chemotherapy-induced leukopenia benefit from an antiseptic chlorhexidine-based oral rinse? A double-blind, block-randomized, controlled study.

Patients undergoing cancer chemotherapy frequently suffer from mucositis, particularly if they become leukopenic (leucocytes <1000/microL). To identify a possible benefit from antiseptic rinsing of the oral cavity, 47 patients were randomized to rinse either with a chlorhexidine-based product (chlorhexidine concentration 0.3%; N=24) or with an amine-stannous fluoride combination (control group; N=23). Patients were asked to rinse three times a day for 30s from the beginning of chemotherapy until the end of leukopenia. Before rinsing, as well as during and after leukopenia, aerobic and anaerobic bacteria in the oral cavity were counted. At the same time, the patients were assessed for mucositis. In the chlorhexidine-based group, a significant decrease of the aerobic (P=0.042) and anaerobic (P=0.008) bacterial flora was identified. In the control group, the numbers of aerobic and anaerobic bacteria remained unchanged (P>0.05). Fifteen patients in the chlorhexidine-based group had a C-reactive protein (CRP) increase >50mg/L, compared with only eight patients in the control group [odds ratio: 3.13, confidence interval (CI) 0.82-12.39]. Nine patients in the chlorhexidine-based group but only two patients in the control group developed severe mucositis. This difference was statistically significant with an odds ratio of 6.30 (CI: 1.02-49.67). As not all of the 47 patients developed severe leukopenia, a separate analysis was carried out for patients with <1000 leucocytes/microL for a minimum of three days. The results of the microbial counts were very similar, with a clear reduction in the chlorhexidine group and no major alterations in the control group. Twelve of 15 patients in the chlorhexidine-based group had a CRP >50mg/L whereas only eight of 15 patients did so in the control group, which can be regarded as a slightly elevated risk for a CRP increase in the former group. Seven of 15 patients developed severe mucositis in the chlorhexidine-based group, but only two of 15 patients in the control group. These differences were not significant, but patients treated with chlorhexidine-based product seemed to have more problems with inflammation of the oral mucous membranes, resulting in an elevated mucositis score and a CRP increase. Other parameters such as body temperature or application of antibiotics did not differ between the two groups. We conclude that treatment with the chlorhexidine-based product did not provide a clinical benefit for cancer chemotherapy patients. On the contrary, the risk of mucositis and clinical sequelae seems to be enhanced, although the counts of micro-organisms on the oral mucous membranes are significantly reduced.

Overexpression of the MT1 melatonin receptor in MCF-7 human breast cancer cells inhibits mammary tumor formation in nude mice.

Overexpression of the MT1 melatonin receptor in MCF-7 human breast cancer cells significantly enhances the response of these cells to the growth-inhibitory actions of melatonin. Athymic nude mice implanted with MT1-overexpressing MCF-7 cells developed significantly fewer palpable tumors (60% reduction) compared to mice receiving vector-transfected MCF-7 cells (vt-MCF-7). In response to exogenous melatonin, tumor incidence in the mice receiving the MT1-overexpressing MCF-7 cells was decreased by 80% compared to mice receiving vt-MCF-7 cells. Interestingly, daily melatonin administration did not decrease tumor incidence in mice receiving vt-MCF-7 cells, but rather stimulated overall tumor formation.

Tumor prevention by 9-cis-retinoic acid in the N-nitroso-N-methylurea model of mammary carcinogenesis is potentiated by the pineal hormone melatonin.

Our laboratory has demonstrated that treatment of MCF-7 breast cancer cells with melatonin (Mlt) followed 24h later with physiological concentrations of all-trans retinoic acid (atRA) results in apoptosis. These studies were extended into trials using the N-nitroso-N-methylurea (NMU)-induced rat mammary tumor model. Initial studies conducted by feeding the animals 9-cis-retinoic acid (9cRA in the chow) and administering melatonin by subcutaneous injection in the late afternoon demonstrated that the combination of Mlt and 9cRA was able to significantly prevent tumor development, and that the combination was more efficacious that either Mlt or 9cRA alone. In this report, we conducted studies to determine if lower doses of 9cRA could be used in combination with Mlt while still maintaining anti-tumor activity and if the route of administration of 9cRA (bolus (gavage) v.s. chronic (chow) routes) affected its interaction with Mlt. The studies presented here demonstrate that significantly reduced doses of 9cRA can be used in combination with Mlt while maintaining anti-tumor efficacy. Furthermore, our studies demonstrate that 9cRA is equally effective when it is administered chronically (chow) or as a bolus (gavage). These data demonstrate that the combined use of Mlt and 9cRA produces additive or synergistic effects, which are more efficacious than 9cRA alone. This combination of Mlt and 9cRA could be a potentially useful clinical treatment regimen for breast cancer since it allows the use of lower doses of retinoic acid, thus, avoiding the toxic side effects associated with the use of high dose retinoids.

Involvement of the mt1 melatonin receptor in human breast cancer.

Two putative melatonin receptors have been described including the cell surface G-protein-linked receptors, mt1 and MT2, and the nuclear retinoic orphan receptor alpha (RORalpha). The mt1 receptor, but not the MT2 receptor, is expressed in human breast tumor cell lines, and melatonin-induced growth suppression can be mimicked by the mt1 and MT2 agonist, AMMTC, and blocked by the antagonist, CBPT. RORalpha receptors are also expressed in MCF-7 breast cancer cells and the putative RORalpha agonist CPG-52608 inhibits MCF-7 cell growth but with a very different dose-response than melatonin. Finally, melatonin and AMMTC, but not CPG-52608, can repress RORalpha transcriptional activity in MCF-7 cells.