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.

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.

Neuropathic central pain: epidemiology, etiology, and treatment options.

BACKGROUND: Nociceptive pain is a major problem in clinical neurology. Peripheral nerve injury may change the physiology of the dorsal horn so that pain becomes progressively centralized. OBJECTIVE: To review mechanisms underlying the plasticity of dorsal root ganglia and dorsal horn neurons that lead to central pain from a peripheral nerve injury. RESULTS: Evidence is reviewed that points to molecular changes in nociceptive terminals, ectopic firing of afferent pain fibers at the level of the dorsal root ganglia, and physiologic changes of the N-methyl-D-aspartate receptor that cause chronic nociceptive pain. CONCLUSIONS: Central sensitization is the physiologic manifestation of many severe peripherally induced pain states. It is maintained by nociceptive input and a physiologic change in the N-methyl-D-aspartate receptor. It consists of: (1) hypersensitivity at the site of injury; (2) mechanoallodynia; (3) thermal hyperalgesia; (4) hyperpathia; (5) extraterritoriality in the case of complex regional pain syndrome/reflex sympathetic dystrophy; and (6) associated neurogenic inflammation, autonomic dysregulation, and motor phenomena.

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.

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.

Chemoprevention of NMU-induced rat mammary carcinoma with the combination of melatonin and 9-cis-retinoic acid.

In experimental trials using the N-nitroso-N-methylurea (NMU)-induced rat mammary tumor model, a significant decrease in tumor incidence (to 5%) was observed in rats treated with melatonin and 9-cis-retinoic acid (9 cRA) compared to controls (55%). Although 9cRA alone decreased tumor incidence to 26%, this response did not reach statistical significance. Tumor incidence was significantly inhibited to 20% in the animals that received melatonin and 9cRA on alternating days. Latency to tumor onset was prolonged in animals receiving either of the combination treatments compared with controls, and tumor multiplicity was also significantly decreased.

Identification of an enhancer element in the estrogen receptor upstream region: implications for regulation of ER transcription in breast cancer.

The estrogen receptor (ER) serves as a diagnostic marker for the treatment of breast cancer. Patients with ER-positive breast tumors are likely to respond to hormonal therapies, while ER-negative breast cancers are resistant to endocrine therapies. Most ER-negative tumors do not express detectable levels of ER transcript, highlighting the importance of transcriptional regulation. A novel regulatory element which resembles a steroid hormone response element has been identified in the 5'-flanking region of the human ER gene. We observed 3- to 5-fold higher specific binding to this element in nuclear extracts from ER-expressing MCF-7 breast cancer cells compared to ER-negative MDA-MB-231 breast tumor cells. We termed the factor(s) which bind to this cis-element estrogen receptor upstream binding factor-1 (ERUBF-1). In transient transfection assays in MCF-7 cells, the ERUBF-1 binding site elicited a 20-fold increase in luciferase activity over the ER P1, promoter. This enhancer element was significantly more active in the ER-positive MCF-7 cell line compared to the ER-negative MDA-MB-231 cell line. These data indicate that ERUBF-1 plays an important role in the transcriptional regulation of the ER gene in breast cancer.

Estrogen receptor transactivation in MCF-7 breast cancer cells by melatonin and growth factors.

The pineal hormone, melatonin, inhibits proliferation of estrogen receptor (ER)-positive MCF-7 human breast cancer cells, modulates both ER mRNA and protein expression, and appears to be serum dependent, indicating interaction between melatonin and serum components. To examine the effects of melatonin on ER activity, ER transactivation assays were performed by transiently transfecting MCF-7 cells with an ERE-luciferase reporter construct. MCF-7 cells pre-treated with melatonin for as little as 5 min followed by either epidermal growth factor (EGF) or insulin resulted in the estrogen-independent transactivation of the ER. None of the compounds when used alone transactivated the ER. The ability of melatonin and EGF to transactivate the ER was abolished by the addition of the antiestrogen, ICI 164384, suggesting that melatonin and EGF co-operate to transactivate the ER. The modulation of ER transactivation was associated with changes in mitogen activated protein kinase activity and ER phosphorylation. This ER transactivation was blocked by pertussis toxin, a Galpha i-protein-coupled receptor inhibitor, suggesting cross talk between the G-protein-coupled melatonin receptor pathway and the EGF/insulin tyrosine kinase receptor pathways in modulating ER transactivation. Exactly how the ability of melatonin in combination with EGF to transactivate the ER relates to melatonin's observed growth suppressive effects is not clear. It is possible that, although melatonin and EGF transactivate the ER, this transactivation does not result in the full transcription of estrogen-responsive genes, but rather, makes the ER refractory to activation by estradiol, thus, blocking the mitogenic actions of estradiol.

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.

Renal artery occlusion model in dogs for the evaluation of thrombolytic agents.

The purpose of this study was to develop a model of renal artery occlusion and to investigate the effects of various thrombolytic agents on an acute occlusion of the renal artery with respect to ischemic tolerance of renal parenchyma. In order to do this, a thrombosis model in dogs (n = 36) was established and a total of 72 dorsal renal arteries occluded using autologous clot material. For the in vitro preparing of a clot, autologous blood (20 mL) was withdrawn and 100 U thrombin immediately added. Then 1 mL of the clot material was injected into the dorsal branch of the exposed renal artery. The dogs were divided into 8 groups (2 control groups, 6 therapy groups with local and systemic thrombolytic therapy). Thrombolysis was performed using urokinase, single-chain urokinase, and recombinant tissue-plasminogen activator. In all cases the clot preparation technique allowed complete and stable occlusion of the renal arteries. Local and systemic application of the thrombolytic agents, however, resulted in complete recanalization of the clot material in all study groups. Recombinant tissue-plasminogen activator turned out to be the most effective agent in terms of recanalization time. The technique described allowed effective and reproducible artery occlusion for in vivo experimental work to study comparatively thrombolytic agents with respect to fibrin specificity, lytic efficacy, and side effects.

Survival of 138 surgically placed straight double-cuff Tenckhoff catheters in patients on continuous ambulatory peritoneal dialysis.

OBJECTIVE: To determine the natural history of a surgically placed Tenckhoff catheter in patients on continuous ambulatory peritoneal dialysis (CAPD). DESIGN: Prospective 7-year study analyzing catheter survival of all catheters using the Kaplan-Meier life table methodology. SETTING: Teaching hospital, department of nephrology. PATIENTS: One hundred and fifteen unselected patients beginning CAPD. INTERVENTIONS: Removal of the catheter required for the following complications: exit-site or tunnel infections or relapsing peritonitis, outflow obstruction, pericatheter leak, and development of hernias. MAIN OUTCOME MEASURES: Period between insertion and removal of the catheter. RESULTS: The cumulative survival of all catheters after 1, 2, and 3 years of CAPD was 87%, 69% and 65%. Catheter survival of the first versus the second catheter after 1 year was significantly longer (p = 0.03). The difference was not significant in relation to diabetes, age, and sex. Infectious complications caused 61% (n = 19) of all 31 catheter failures, mainly due to tunnel infections caused by Staphylococcus aureus (n = 12). "Mechanical" complications accounted for 49% (n = 12) of catheter failures. Eight of 12 mechanical complications were outflow failures. Seven patients had to be transferred to hemodialysis. CONCLUSIONS: The straight Tenckhoff catheter is a reliable peritoneal access device for CAPD in an unselected patient population.

The fate of leached di(2-ethylhexyl)phthalate in patients undergoing CAPD treatment.

OBJECTIVES: To evaluate the degree of exposure to and the fate of di(2-ethylhexyl)phthalate (DEHP) and its major derivatives mono(2-ethylhexyl)phthalate (MEHP), 2-ethylhexanol (2-EH), and phthalic acid (PA) in patients undergoing regular continuous ambulatory peritoneal dialysis (CAPD) during a 4-hour dwell period. DESIGN: Prospective, controlled. SETTING: Teaching hospital, Department of Nephrology. PARTICIPANTS: Seven elderly patients on stable CAPD using Fresenius instruments and dialysate and 6 age-matched healthy controls. INTERVENTIONS: During a routinely performed peritoneal equilibration test (PET), blood and dialysate samples were drawn before and 120 and 240 min after the dwell was started. In addition, blood samples were taken from a group of volunteers participating in a pharmacological study. MEASUREMENTS: Quantitative analysis of DEHP and its hydrolysis products was performed by selected ion-monitoring gas chromatography/mass spectrometry, operating the mass spectrometer in a combined positive and negative ion chemical ionization mode. RESULTS: Serum concentrations of DEHP and PA were significantly higher in patients (median: 0.079 microgram/mL, range: 0.032-0.210 microgram/mL; and 0.167 microgram/mL, range: 0.097-0.231 microgram/mL, respectively) than in controls [0.0195 microgram/mL, range: 0.016-0.025 microgram/mL (p = 0.0027) and 0.0120 microgram/mL, range: 0.006-0.034 microgram/mL (p = 0.0026), respectively]. Concentration of MEHP in the fluid of CAPD bags prior to use was four times higher than that of the parent compound. During the first 4 hours of dwell time, the concentrations of MEHP and 2-EH in dialysate consistently decreased from 0.177 (range: 0.137-0.239 microgram/mL) to 0.022 microgram/mL (range: 0.005-0.058 microgram/mL) (p = 0.017), and from 0.087 (range: 0.075-0.097 microgram/mL) to 0.05 microgram/mL (range: 0.023-0.064 microgram/mL) (p = 0.017), respectively, while the concentration of DEHP remained stable. Remarkably high concentrations of PA (0.129 microgram/mL; range: 0.038-0.466 microgram/mL) were found in CAPD bags prior to use, and these concentrations tended to increase during dwell time, without statistical significance, however (0.135 microgram/mL; range: 0.073-0.659 microgram/mL, p = 0.062). CONCLUSIONS: Patients on CAPD are regularly exposed to considerable amounts of phthalic ester derivatives, mainly to MEHP and PA. MEHP seems to be well absorbed by the peritoneal membrane. The long-term effects of this exposure remain to be elucidated.

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.