Combination of bevacizumab and 2-weekly pegylated liposomal doxorubicin as first-line therapy for locally recurrent or metastatic breast cancer. A multicenter, single-arm phase II trial (SAKK 24/06).

BACKGROUND: Pegylated liposomal doxorubicin (PLD) and bevacizumab are active agents in the treatment of metastatic breast cancer (MBC). We carried out a multicenter, single-arm phase II trial to evaluate the toxicity and efficacy of PLD and bevacizumab as first-line treatment in MBC patients. METHODS: Bevacizumab (10 mg/kg) and PLD (20 mg/m(2)) were infused on days 1 and 15 of a 4-week cycle for a maximum of six cycles. Thereafter, bevacizumab monotherapy was continued at the same dose until progression or toxicity. The primary objective was safety and tolerability, and the secondary objective was to evaluate efficacy of the combination. RESULTS: Thirty-nine of 43 patients were assessable for the primary end point. Eighteen of 39 patients (46%, 95% confidence interval 30% to 63%) had a grade 3 toxicity. Sixteen (41%) had grade 3 palmar-plantar erythrodysesthesia, one had grade 3 mucositis, and one severe cardiotoxicity. Secondary end point of overall response rate among 43 assessable patients was 21%. CONCLUSIONS: In this nonrandomized single-arm trial, the combination of bimonthly PLD and bevacizumab in locally recurrent and MBC patients demonstrated higher than anticipated toxicity while exhibiting only modest activity. Based on these results, we would not consider this combination for further investigation in this setting.

Atrovastatin-loaded hydrogel affects the smooth muscle cells of human veins

Les pontages veineux restent actuellement un traitement de choix dans les pathologies vasculaires occlusives. Cependant, plusieurs problèmes sont liés à ce type de revascularisation. Premièrement, l'hyperplasie intimale (HI) qui cause une resténose dans 20 à 50% des pontages, conduisant à un échec de la revascularisation. Ce processus est dû à la prolifération et à la migration des cellules musculaires lisses vasculaires vers l'intima, ainsi qu'à une sécrétion de protéines de la matrice extracellulaire conduisant à un épaississement de l'intima, principalement au niveau des anastomoses. Deuxièmement, bien qu'il existe des substances connues pour inhiber l'HI, leur administration systémique répétée est associée à une augmentation de leurs effets secondaires. Aucun dispositif ne permet actuellement la libération d'une telle substance localement au site d'une anastomose vasculaire. Nous avons donc développé un hydrogel d'acide hyaluronique compatible avec une application locale au niveau des anastomoses vasculaires et pouvant être chargé en atorvastatine (ATV) (inhibiteur de la 3-hydroxy-3-methylglutaryl-CoA réductase), substance connue pour inhiber l'HI, dans le but de diminuer le fléau de la resténose. Nous avons tout d'abord testé l'effet de ce gel chargé en ATV sur la prolifération, la migration et la transmigration de cellules musculaires lisses primaires en culture provenant de veines saphènes humaines. Ensuite, nous avons étudié son effet sur différents gènes impliqués dans l'HI. Ceci a permis de montrer que l'ATV diminue la prolifération, la migration et la transmigration des cellules musculaires lisses humaines de façon similaire qu'elle soit ajoutée directement au milieu de culture ou qu'elle soit libérée par l'hydrogel chargé. De même, l'ATV régule de manière simultanée mais différentielle les gènes, en interférant avec le développement de l'HI. Nos expériences montrent que l'HI peut être diminuée in vitro grâce à cet hydrogel d'acide hyaluronique chargé en ATV. Ceci ouvre la porte au développement de futur dispositif permettant de relâcher des substances antisténotiques de façon continue, sur une durée prolongée, et in vivo.

Islands of euchromatin-like sequence and expressed polymorphic sequences within the short arm of human chromosome 21.

The goals of the human genome project did not include sequencing of the heterochromatic regions. We describe here an initial sequence of 1.1 Mb of the short arm of human chromosome 21 (HSA21p), estimated to be 10% of 21p. This region contains extensive euchromatic-like sequence and includes on average one transcript every 100 kb. These transcripts show multiple inter- and intrachromosomal copies, and extensive copy number and sequence variability. The sequencing of the "heterochromatic" regions of the human genome is likely to reveal many additional functional elements and provide important evolutionary information.

Origin of CO2 and carbonate veins in mantle-derived xenoliths in the Pannonian Basin

The origin and evolution of CO2 inclusions and calcite veins in peridotite xenoliths of the Pannonian Basin, Hungary, were investigated by means of petrographic investigation and stable isotope analyses. The fluid inclusions recovered in paragenetic olivine and clinopyroxene belong to distinct populations: type A (texturally early) inclusions with regular shapes (often with negative crystal forms) forming intragranular trails, type B (texturally late) inclusions defining randomly oriented trails that reach grain boundaries Type B inclusions are often associated with silicate melt (type C) inclusions Stable carbon isotope compositions in inclusion-hosted CO2 were obtained by vacuum crushing followed by conventional dual inlet as well as continuous flow mass spectrometry in order to eliminate possible lab artifacts. Olivines, clino- and orthopyroxenes of the host peridotite have oxygen isotope compositions from 5.3 to 6.0 parts per thousand (relative to V-SMOW). without any relationship with xenolith texture. Some of the xenoliths contained calcite in various forms veins and infillings in silicate globules in veins, secondary carbonate veins filling cracks and metasomatic veins with diffuse margins The former two carbonate types have delta C-13 values around -13 parts per thousand (relative to V-PDB) and low Sr contents (<05 wt %), whereas the third type,veins with high-temperature metasomatic features have a delta C-13 value of -5 0 parts per thousand and high Sr contents up to 34 wt.% In spite of the mantle-like delta C-13 value and the unusually high Sr content typical for mantle-derived carbonate, trace element compositions have proven a crustal origin. This observation supports the conclusions of earlier studies that the carbonate melt droplets found on peridotite xenoliths in the alkaline basalts represent mobilized sedimentary carbonate. The large delta C-13 range and the C-12-enrichment in the carbonates can be attributed to devolanlization of the migrating carbonate or infiltration of surficial fluids containing C-12-rich dissolved carbon Carbon isotope compositions of inclusion-hosted CO2 range from -17 8 to -4.8 parts per thousand (relative to V-PDB) with no relation to the amount of CO2 released by vacuum crushing. Low-delta C-13 values measured by stepwise heating under vacuum suggest that the carbon component is pristine and not related to surficial contamination, and that primary mantle fluids with delta C-13 values around -5 parts per thousand were at least partly preserved in the xenoliths Tectonic reworking and heating by the basaltic magma resulted in partial CO2 release and local C-13-depletion. (C) 2010 Elsevier B V All rights reserved

Distribution of arm velocity and frequency of arm usage during daily activity: objective outcome evaluation after shoulder surgery.

In clinical settings, functional evaluation of shoulder movement is primarily based on what the patient thinks he/she is able to do rather than what he/she is actually performing. We proposed a new approach for shoulder assessment based on inertial sensors to monitor arm movement in the daily routine. The detection of movement of the humerus relative to the trunk was first validated in a laboratory setting (sensitivity>95%, specificity>97%). Then, 41 control subjects and 21 patients suffering from a rotator cuff tear were evaluated (before and after surgery) using clinical questionnaires and a one-day measurement of arm movement. The quantity of movement was estimated with the movement frequency and its symmetry index (SIFr). The quality of movement was assessed using the Kolmogorov-Smirnov distance (KS) between the cumulative distribution of the arm velocity for controls and the same distribution for each patient. SIFr presented differences between patients and controls at 3 month follow-up (p<0.05) while KS showed differences also after 6 months (p<0.01). SIFr illustrated a change in dominance due to the disorder whereas KS, which appeared independent of the dominance and occupation, showed a change in movement velocity. Both parameters were correlated to clinical scores (R(2) reaching 0.5). This approach provides clinicians with new objective parameters for evaluating the functional ability of the shoulder in daily conditions, which could be useful for outcome assessment after surgery.

Traitement des varices et des télangiectasies [Treatment of varicose veins and telangiectasias].

Dermatologic surgery has evolved enormously within the past few years especially for the treatment of varicose veins and telangiectasias. New minimally-invasive techniques have been developed: lasers, echo-sclerosis, surgery with tumescent anesthesia and endovascular treatment of saphenous veins. Most interventions can be performed with local anesthesia in the office setting. These new treatments are intended to decrease the risks of surgery, reduce medical costs and the necessity for hospitalization, and improve functional and esthetic results.

Combining chromosomal arm status and significantly aberrant genomic locations reveals new cancer subtypes.

Many types of tumors exhibit characteristic chromosomal losses or gains, as well as local amplifications and deletions. Within any given tumor type, sample specific amplifications and deletions are also observed. Typically, a region that is aberrant in more tumors, or whose copy number change is stronger, would be considered as a more promising candidate to be biologically relevant to cancer. We sought for an intuitive method to define such aberrations and prioritize them. We define V, the "volume" associated with an aberration, as the product of three factors: (a) fraction of patients with the aberration, (b) the aberration's length and (c) its amplitude. Our algorithm compares the values of V derived from the real data to a null distribution obtained by permutations, and yields the statistical significance (p-value) of the measured value of V. We detected genetic locations that were significantly aberrant, and combine them with chromosomal arm status (gain/loss) to create a succinct fingerprint of the tumor genome. This genomic fingerprint is used to visualize the tumors, highlighting events that are co-occurring or mutually exclusive. We apply the method on three different public array CGH datasets of Medulloblastoma and Neuroblastoma, and demonstrate its ability to detect chromosomal regions that were known to be altered in the tested cancer types, as well as to suggest new genomic locations to be tested. We identified a potential new subtype of Medulloblastoma, which is analogous to Neuroblastoma type 1.

Lexan Gate Arm, HR-536, 1987

Innovative Rail Ltd. of Cedar Rapids, Iowa produced a new rail/highway crossing gate arm that shows promise in two areas: a. Minimizing arm breakage, and b. Added target value to motorists. The new gate was demonstrated to the Chicago and North Western Transportation Company, and that railroad has requested its use at two crossings on an "experimental basis" to determine if its installation provides relief in those areas. On April 18, 1986, the Department observed a test of the material under field conditions with the Transportation Company. The gate received four mid-center strikes at 5 MPH by a company truck while in the lowered position, and showed no damage. In a fifth mid-center strike at 15 MPH, the gate was visibly damaged at the connection to its raising mechanism, but continued to function though at a 5-10 degree drop. Several pictures of the gate and its saddle mechanism are shown in Appendix A of this report. Innovative Rail established distributorships in the United States and Canada, and has since gone out of business.

Atorvastatin-loaded hydrogel affects the smooth muscle cells of human veins.

Intimal hyperplasia (IH) is the major cause of stenosis of vein grafts. Drugs such as statins prevent stenosis, but their systemic administration has limited effects. We developed a hyaluronic acid hydrogel matrix, which ensures a controlled release of atorvastatin (ATV) at the site of injury. The release kinetics demonstrated that 100% of ATV was released over 10 hours, independent of the loading concentration of the hydrogel. We investigated the effects of such a delivery on primary vascular smooth muscle cells isolated from human veins. ATV decreased the proliferation, migration, and passage of human smooth muscle cells (HSMCs) across a matrix barrier in a similar dose-dependent (5-10 µM) and time-dependent manner (24-72 hours), whether the drug was directly added to the culture medium or released from the hydrogel. Expression analysis of genes known to be involved in the development of IH demonstrated that the transcripts of both the gap junction protein connexin43 (Cx43) and plasminogen activator inhibitor-1 (PAI-1) were decreased after a 24-48-hour exposure to the hydrogel loaded with ATV, whereas the transcripts of the heme oxygenase (HO-1) and the inhibitor of tissue plasminogen activator were increased. At the protein level, Cx43, PAI-1, and metalloproteinase-9 expression were decreased, whereas HO-1 was upregulated in the presence of ATV. The data demonstrate that ATV released from a hydrogel has effects on HSMCs similar to the drug being freely dissolved in the environment.

Reactive rise in blood pressure upon cuff inflation: cuff inflation at the arm causes a greater rise in pressure than at the wrist in hypertensive patients.

OBJECTIVE: Cuff inflation at the arm is known to cause an instantaneous rise in blood pressure, which might be due to the discomfort of the procedure and might interfere with the precision of the blood pressure measurement. In this study, we compared the reactive rise in blood pressure induced by cuff inflation when the cuff was placed at the upper arm level and at the wrist. PARTICIPANTS AND METHODS: The reactive rise in systolic and diastolic blood pressure to cuff inflation was measured in 34 normotensive participants and 34 hypertensive patients. Each participant was equipped with two cuffs, one around the right upper arm (OMRON HEM-CR19, 22-32 cm) and one around the right wrist (OMRON HEM-CS 19, 17-22 cm; Omron Health Care Europe BV, Hoofddorp, The Netherlands). The cuffs were inflated in a double random order (maximal cuff pressure and position of the cuff) with two maximal cuff pressures: 180 and 240 mmHg. The cuffs were linked to an oscillometric device (OMRON HEM 907; Omron Health Care). Simultaneously, blood pressure was measured continuously at the middle finger of the left hand using photoplethysmography. Three measurements were made at each level of blood pressure at the arm and at the wrist, and the sequence of measurements was randomized. RESULTS: In normotensive participants, no significant difference was observed in the reactive rise in blood pressure when the cuff was inflated either at the arm or at the wrist irrespective of the level of cuff inflation. Inflating a cuff at the arm, however, induced a significantly greater rise in blood pressure than inflating it at the wrist in hypertensive participants for both systolic and diastolic pressures (P<0.01), and at both levels of cuff inflation. The blood pressure response to cuff inflation was independent of baseline blood pressure. CONCLUSIONS: The results show that in hypertensive patients, cuff inflation at the wrist produces a smaller reactive rise in blood pressure. The difference between the arm and the wrist is independent of the patient's level of blood pressure.

Transjugular liver biopsy: prospective evaluation of the angle formed between the hepatic veins and the vena cava main axis and modification of a semi-automated biopsy device in cases of an unfavorable angle.

In cases of transjugular liver biopsies, the venous angle formed between the chosen hepatic vein and the vena cava main axis in a frontal plane can be large, leading to technical difficulties. In a prospective study including 139 consecutive patients who underwent transjugular liver biopsy using the Quick-Core biopsy set, the mean venous angle was equal to 49.6 degrees. For 21.1% of the patients, two attempts at hepatic venous catheterization failed because the venous angle was too large, with a mean of 69.7 degrees. In all of these patients, manual reshaping of the distal curvature of the stiffening metallic cannula, by forming a new mean angle equal to 48 degrees , allowed successful completion of the procedure in less than 10 min.

Oxygen-isotope thermometry of quartz-calcite veins - Unraveling the thermal-tectonic history of the subgreenschist facies Morcles nappe (Swiss Alps)

Combined structural analysis and oxygen isotope thermometry of syntectonic quartz-calcite fibrous veins can be used to correlate the thermal history of deformed rocks,vith specific structural and tectonic events. Results are presented for the Mercies nappe in the western Helvetic Alps, Switzerland, where mineral parageneses, illite `'crystallinity,'' and fluid inclusion chemistry record an apparent peak metamorphic temperature gradient that increased across the Morcles nappe from anchizonal conditions in the foreland to epizonal conditions in its hinterland root zone. Twenty-seven quartz-calcite veins were analyzed in this study in order to determine the temperatures of veining during formation and deformation of the nappe, Peak metamorphic temperatures ranged from approximate to 260 to 290 degrees C in the shallower, foreland localities and to approximate to 330 to 350 degrees C in the deeper, more hinterland localities at the end of S1-foliation formation, related to large-scale folding. Temperatures gradually decreased throughout the nappe during subsequent development of the S2 foliation and S3 crenulation cleavage, Uplift and erosion of the overlying nappe pile resulted in slow cooling of the Morcles nappe during the waning stages of the Alpine Orogeny. The dominant foliation-forming deformation of the Morcles nappe occurred at elevated temperatures over the course of 10 to 15 Ma. Combined structure-oxygen isotope analyses of quartz-calcite veins yield better temperature and temporal constraints on the thermal histories of subgreenschist vein-bearing tectonites than do other geothermometers.

Is my hand connected to my body? The impact of body continuity and arm alignment on the virtual hand illusion

When a rubber hand is placed on a table top in a plausible position as if part of a person"s body, and is stroked synchronously with the person"s corresponding hidden real hand, an illusion of ownership over the rubber hand can occur (Botvinick and Cohen 1998). A similar result has been found with respect to a virtual hand portrayed in a virtual environment, a virtual hand illusion (Slater et al. 2008). The conditions under which these illusions occur have been the subject of considerable study. Here we exploited the flexibility of virtual reality to examine four contributory factors: visuo-tactile synchrony while stroking the virtual and the real arms, body continuity, alignment between the real and virtual arms, and the distance between them. We carried out three experiments on a total of 32 participants where these factors were varied. The results show that the subjective illusion of ownership over the virtual arm and the time to evoke this illusion are highly dependent on synchronous visuo-tactile stimulation and on connectivity of the virtual arm with the rest of the virtual body. The alignment between the real and virtual arms and the distance between these were less important. It was found that proprioceptive drift was not a sensitive measure of the illusion, but was only related to the distance between the real and virtual arms.

Effect of repetitive arm cycling following botulinum toxin injection for poststroke spasticity: evidence from FMRI.

BACKGROUND AND OBJECTIVE: Investigations were performed to establish if repetitive arm cycling training enhances the antispastic effect of intramuscular botulinum toxin (BTX) injections in postischemic spastic hemiparesis. Effects on cerebral activation were evaluated by functional magnetic resonance imaging (fMRI). METHODS: Eight chronic spastic hemisyndrome patients (49 ± 10 years) after middle cerebral artery infarction (5.5 ± 2.7 years) were investigated. BTX was injected into the affected arm twice, 6 months apart. Spasticity was assessed using the Ashworth Scale and range of motion before and 3 months after BTX injections. Images were analyzed using Brain Voyager QX 1.8, and fMRI signal changes were corrected for multiple comparisons. RESULTS: During passive movements of affected and nonaffected hands, fMRI activity was increased bilaterally in the sensorimotor cortex (MISI), secondary somatosensory areas (SII), and supplementary motor area predominantly in the contralesional hemisphere, compared with the rest. Following repetitive arm cycling, fMRI activity increased further in MISI of the lesioned hemisphere and SII of the contralesional hemisphere. For patients with residual motor activity, treatment-related fMRI activity increases were associated with reduced spasticity; in completely plegic patients, there was no fMRI activity change in SII but increased spasticity after training. CONCLUSION: Increased activity in SII of the contralesional hemisphere and in MISI of the lesioned hemisphere reflect a treatment-induced effect in the paretic arm. It is hypothesized that the increased BOLD activity results from increased afferent information related to the antispastic BTX effect reinforced by training.

Measurement with an automated oscillometric wrist device with position sensor leads to lower values than measurements obtained with an automated oscillometric arm device from the same manufacturer in elderly persons.

OBJECTIVE: Home blood pressure (BP) monitoring is recommended by several clinical guidelines and has been shown to be feasible in elderly persons. Wrist manometers have recently been proposed for such home BP measurement, but their accuracy has not been previously assessed in elderly patients. METHODS: Forty-eight participants (33 women and 15 men, mean age 81.3±8.0 years) had their BP measured with a wrist device with position sensor and an arm device in random order in a sitting position. RESULTS: Average BP measurements were consistently lower with the wrist than arm device for systolic BP (120.1±2.2 vs. 130.5±2.2 mmHg, P<0.001, means±SD) and diastolic BP (66.0±1.3 vs. 69.7±1.3 mmHg, P<0.001). Moreover, a 10 mmHg or greater difference between the arm and wrist device was observed in 54.2 and 18.8% of systolic and diastolic measures, respectively. CONCLUSION: Compared with the arm device, the wrist device with position sensor systematically underestimated systolic as well as diastolic BP. The magnitude of the difference is clinically significant and questions the use of the wrist device to monitor BP in elderly persons. This study points to the need to validate BP measuring devices in all age groups, including in elderly persons.