Strong Linear Dichroism in Spin-Polarized Photoemission from Spin-Orbit-Coupled Surface States.

A comprehensive understanding of spin-polarized photoemission is crucial for accessing the electronic structure of spin-orbit coupled materials. Yet, the impact of the final state in the photoemission process on the photoelectron spin has been difficult to assess in these systems. We present experiments for the spin-orbit split states in a Bi-Ag surface alloy showing that the alteration of the final state with energy may cause a complete reversal of the photoelectron spin polarization. We explain the effect on the basis of ab initio one-step photoemission theory and describe how it originates from linear dichroism in the angular distribution of photoelectrons. Our analysis shows that the modulated photoelectron spin polarization reflects the intrinsic spin density of the surface state being sampled differently depending on the final state, and it indicates linear dichroism as a natural probe of spin-orbit coupling at surfaces.

Assessment of intravenous pbi-shRNA PDX1 nanoparticle (OFHIRNA-PDX1) in yucatan swine.

PDX1 (pancreatic and duodenal homeobox 1) is overexpressed in pancreatic cancer, and its reduction results in tumor regression. Bi-functional pbi-shRNA PDX1 nanoparticle (OFHIRNA-PDX1) utilizes the endogenous micro-RNA biogenesis pathway to effect cleavage- and non-cleavage-dependent degradation of PDX1 mRNA. We have shown that OFHIRNA-PDX1 reduces pancreatic tumor volume in xenograft models. Thus, we are now exploring biorelevant large animal safety of OFHIRNA-PDX1. Mini pigs were chosen as the biorelevant species based on the similarity of human and pig PDX1 target sequence. In the initial study, animals developed fever, lethargy, hyporexia and cutaneous hyperemia following administration of OFHIRNA-PDX1. Twenty-one days later, the same animals demonstrated less toxicity with a second OFHIRNA-PDX1 infusion in conjunction with a prophylactic regimen involving dexamethasone, diphenhydramine, Indocin and ranitidine. In a new group of animals, PDX1 protein (31 kDa) expression in the pancreas was significantly repressed at 48 and 72 h (85%, P=0.018 and 88%, P=0.013; respectively) following a single infusion of OFHIRNA-PDX1 but recovered to normal state within 7 days. In conclusion, a single intravenous infusion of OFHIRNA-PDX1 in conjunction with premedication in pigs was well tolerated and demonstrated significant PDX1 knockdown.

[Virtual training in head- and neurosurgery]. / Moderne Trainingsmethoden für die Kopfchirurgie.

BACKGROUND: Surgical skill requires training at close-to-reality scenarios. Conventional procedures (practical exercises, anatomical or animal cadavers) are increasingly in conflict with objective parameters (costs of OR, quality management, cadavers availability and cost). Surgical procedures can be covered by using Virtual Surgical Reality (VSR). METHODS: We examined the principle of a VSR system and evaluated the results with 30 probands by the example of modified radical mastoidectomy and ventriculocisternostomy. Probands were divided in experienced (A) and non-experienced surgeons (B). The protocol included time of surgery, collisions and fatal injuries at altogether 15 passages (10 passages - break of 14 days - 5 passages). Additionally the Medical Level of Trust (LOT) describes the confidence into the surgical scenario and thus the quality by volume illustration, texture and haptic data feedback to the user. We used a numeric scale between 0 and 100 and the starting point of 50. RESULTS: The learning effect can be confirmed for both virtual scenarios. The mastoid scenario reaches a total confidence index LOT of 75. The ventricle scenario is evaluated with a total confidence index of 84. The necessary time for the opening of the antrum is reduced from 15.0 minutes (group A) and 22.5 minutes (group B) around 37 % to 9, 5 (group A) and around 56 % to 10.0 minutes (group B). The virtual haptic result was evaluated positive in both scenarios. CONCLUSIONS: VSR systems have the potential to revolutionize surgical training. All surgical experienced probands evaluated the VSR-scenario as near-to-reality. "Suspension of Disbelief" is the major condition for effective virtual reality training systems.

VSOne, a virtual reality simulator for laparoscopic surgery.

The introduction of computer-based training systems for laparoscopic surgery has increased the training quality and made the learning effect measurable with objective criteria. This paper introduces VSOne as a fully-featured virtual reality training system for laparoscopic surgery. VSOne utilizes the state-of-the-art in virtual reality techniques, soft tissue simulation and haptic device control and guarantees realistic training possibilities for various laparoscopic procedures. An authoring software helps to create individual simulation models easily within the shortest time based on real patient data using standardized data formats. We have developed several Basic Task Training (BTT) modules to improve dexterity and complex Surgical Procedure Task (SPT) modules for full training of laparoscopic procedures such as cholecystectomy, tubal sterilization and myomectomy. VSOne has been evaluated in a comparative study with classic training methods and has shown the typical learning curves for inexperienced trainees and the transferability of the learning effect to the real-world situation.

The medical engineering program of Forschungszentrum Karlsruhe.

The research activities of the Forschungszentrum Karlsruhe on minimally-invasive surgery (MIS) have for several years improved techniques and instrumentation for different types of MIS. Many types of instruments and robotic devices have been developed and new techniques implemented. In this paper we present the most recent results from our different projects, such as endoscopic heart surgery, tracking systems, a camera guidance device, telemanipulator systems, minimally-invasive breast biopsy in closed-bore MRI, endoscopic training simulators and developments using smart materials (e.g. Nitinol).

Results of breast conserving therapy for early breast cancer and the role of mammographic follow-up.

PURPOSE: The following article is a review of 23 years of breast-conserving therapy in our hospital. This study was performed to assess and improve the follow-up care of women with early breast cancer and to evaluate whether or not biannual mammogram is useful. METHODS AND MATERIALS: Between 1972 and December 1995, 3072 women with pathological size pT1 and pT2 breast cancer were treated with conservative surgery and radiation therapy. Eighty-five patients developed a recurrence in the treated breast as the first site of failure, 12 of which had positive axillary nodes. In the following patient study, those with an noninvasive recurrence were excluded. A retrospective assessment of the entire mammographic course was made, starting with the mammogram at the time of original diagnosis to the mammogram of the recurrence. RESULTS: In our study group the probability for local failure ranged from 1 to 2% per year. At 5 and 10 years the actuarial rates were 5 and 10%. The median time to recurrence was 41 months (range 8-161). Twenty-six (31%) recurrences were detected by mammography alone, 10 (12%) by clinical examination only, and 35 (41%) by both methods. For the patients with an ipsilateral recurrence, the overall actuarial 5- and 10-year survival after treatment was 87 and 70%, respectively. The 5-year actuarial rate of survival from salvage mastectomy was 61%. CONCLUSION: Considering the high percentage of recurrences detectable by mammography and the possibility of detection within a short-term interval, we think biannual mammographic follow-up is appropriate for the first years following breast-conserving therapy.

CD44 isoforms correlate with cellular differentiation but not with prognosis in human breast cancer.

CD44 is a transmembrane glycoprotein occurring in several isoforms with different extracellular regions. The various transcripts are encoded by one gene locus containing 20 exons, of which at least 10 can be alternatively spliced in nascent RNA. Isoforms encoded by the variant exons (termed CD44v) are highly restricted in their distribution in nonmalignant tissue as opposed to the standard form of CD44 (CD44s) abundant in many tissues. Specific variant isoforms containing exon 6v have been shown to render nonmetastatic rat tumor cells metastatic. Based on the prominent role in rat metastasis formation, CD44v isoforms were suggested to be involved in human tumor progression. Correlations between prognosis and expression of CD44v have been reported for gastric and colon carcinoma, for non-Hodgkin's lymphoma, and recently for breast carcinoma. We evaluated the expression of CD44 isoforms in node-positive (n = 119) and node-negative (n = 108) cases of breast carcinoma by immunohistochemistry using CD44v exon-specific mAbs. In a subset of 43 cases of high-risk patients, reverse transcription-PCR was used to determine the exon composition of the transcripts. Protein and RNA expression data were probed statistically for their correlation to survival of the patients and clinical risk factors. In contrast to recently published data (M. Kaufmann et al., Lancet, 345: 615-619, 1995), in our cohort disease-free and overall survival data did not indicate significant correlations with the expression of the analyzed isoforms in univariate and multivariate analyses. Comparison of CD44 protein expression with established clinical risk factors for survival such as tumor size (pT1+pT2) and histological grading revealed correlations with the presence of CD44s (P = 0.02 and P = 0.03, respectively) and CD44-9v (P = 0.05 for histological grading). Carcinoma tissues with elevated estrogen and progesterone receptor levels showed positive correlation with CD44-6v (P = 0.001), while a trend for significant coexpression of CD44s and CD44-9v isoforms was observed in estrogen receptor-positive tissues (P = 0.08 and 0.06, respectively). In breast cancer, CD44s, CD44-9v, and CD44-6v are apparently markers for cellular differentiation but not for tumor progression. Our data suggest that steroid hormone receptors may be associated with the in vivo expression of CD44-6v-containing isoforms in human mammary carcinoma.

Infraspecific differentiation of garlic (Allium sativum L.) by isozyme and RAPD markers.

Garlic (Allium sativum L.) is a sterile species of considerable variability with respect to morphological and physiological features. The crop presumably originated in West to Middle Asia from its progenitor A. longicuspis Regel and was transported from there to the Mediterranean and other areas of cultivation. In order to clarify older classification schemes, often based on small or biased collections, we used isozyme and RAPD markers to analyze and structure a collection of 300 accessions, many of which were gathered in Middle Asia close to the assumed center of origin. All of the accessions were first investigated with isozymes, and 48 were selected for a RAPD analysis. The resulting molecular markers were used to construct neighbor-joining dendrograms to group the accessions and to indicate the genetic distances between them. Based on the dendrograms and in conjunction with some morphological features, we propose an infraspecific classification of garlic with four major groups. In agreement with the results of other workers, A. longicuspis lies within the range of the species A. sativum. Numerous forms with varying degrees of domestication are part of our longicuspis group, from which presumably the more derived cultivar groups originated. The origin and spreading of the crop are discussed with respect to the geographical distribution and the genetic distances of the accessions.

Human breast cancer: frequent p53 allele loss and protein overexpression.

A sample of 114 primary breast tumors and corresponding constitutional DNA were tested for loss of heterozygosity (LOH) of the YNZ22 and p53 genes, both located in the 17p13 region. Loss of the p53 allele was found in 28 of 44 primary breast carcinomas (64%). In contrast LOH in only 26 of 61 tumors (43%) was detected with the variable number of tandem repeats (VNTR) probe YNZ22 mapping at 17p13.3 close to the p53 locus at 17p13.1. Among 19 tumors informative for both probes allele loss at 17p13.3 never occurred without p53 involvement. These data suggest, that p53 is the target of 17p13 allelic deletions in human breast cancer. Immunohistochemistry showed overexpression of the p53 protein in 25 of 50 cases (50%) presumably reflecting activating point mutations. Overexpression was not correlated with allele loss but seemed to be closely related to the presence of point mutations in this study. No homozygous deletions or rearrangements of the p53 gene were detected. This would argue for an important role of heterozygous p53 mutations in human breast cancer.

Effects of simulated microgravity (HDT) on blood fluidity.

Exposures to microgravity and head-down tilt (HDT) produce similar changes in body fluid. This causes an increase in hematocrit that significantly affects hemorheological values. Lack of physical stimulation under bed rest conditions and the relative immobility of the crew during spaceflight also affects the blood fluidity. A group of six healthy male subjects participated as volunteers, and blood samples were collected 10 days before, on day 2 and day 9, and 2 days after the HDT phase. Blood rheology was quantified by plasma viscometry, red cell aggregability, and red cell deformability. A reduced red cell deformability, an indication of the diminished quality of the red blood cells, was measured under HDT conditions that finally led to the so-called "space flight anemia." Enhanced red cell membrane fragility induced by diminished physical activity and an increase in hemoglobin concentration are responsible for this effect. Plasma viscosity is reduced as a result of diminished plasma proteins. However, despite the reduction in plasma proteins, including fibrinogen, alpha 2-macroglobulin, and immunoglobulin M, red cell aggregation was enhanced, principally because of the increase in hematocrit. Our results of hemorheological alterations under HDT conditions may help to elucidate the formerly documented hematologic changes during spaceflight.

[Follow-up of 551 patients with node-negative breast cancer]. / Krankheitsverlauf bei 551 Patientinnen mit nodal negativem Mammakarzinom.

To evaluate the prognostic significance of established clinical, histological, and biochemical factors, we examined the survival data of 551 node-negative breast cancer patients. At a median follow-up of 5 years, we found 114 recurrences, 79 of them at distant sites. 41 patients died. 84 patients with less than 8 examined lymph nodes, adjuvant systemic treatment, or treatment differing from standard procedures, had a statistically significant shorter overall survival and were excluded from further analysis. With regard to relapse-free and overall survival univariate and multivariate analyses of the remaining 467 patients revealed only few factors with prognostic significance. In multivariate analysis of overall survival by the Cox regression model, statistically significant prognostic value was limited to three factors: lymphangiosis carcinomatosa (relative risk 4.8, 95%-confidence interval 2.0-11.7), postmenopausal status (0.38, 0.17-0.84), and positive progesterone receptor status (0.37, 0.14-1.0). In addition, there was a trend (p = 0.075) of prolonged survival in patients with Bloom and Richardson grade I cancers. The few prognostic factors found were able to identify patients with very good, as well as very bad prognosis. However, for the majority of node-negative breast cancer patients, estimation of prognosis remains unsatisfactory. Therefore, further independent prognostic factors are necessary.

Effect of head-down bedrest on blood/plasma density after intravenous fluid load.

Using the mechanical oscillator technique, the mass density of antecubital venous blood and plasma samples was measured in 6 men before and after infusion of 22 ml/kg isotonic NaCl solution before, on day 7 during, and on day 3 after ten days of 6 degrees head-down bedrest. We studied 1) the distribution volumes of the infused NaCl solution, 2) the magnitude and time-course of induced fluid shifts to the extravascular spaces after rapid volume expansion, and 3) the protein concentration of the translocated fluid. The NaCl distribution volume was 16.7 +/- 2.9% body weight (BW) before, 15.0 +/- 3.0% BW during (P less than 0.05) and 13.0 +/- 1.3% BW after the head-down tilt (HDT) period (P less than 0.01). The volume of fluid shifted 120 min after infusion was not different in the control (12.9 +/- 7.4% plasma volume and 8.3 +/- 3.2% blood volume), during HDT (14.7 +/- 3.8% plasma volume and 7.4 +/- 5.6% blood volume), during HDT HDT conditions (14.6 +/- 2.2% plasma volume, and 8.2 +/- 1.3% blood volume, respectively). The density of the shifted fluid which reflects protein concentration was also unchanged (1004.2 +/- 4.2 g/l, 1002.6 +/- 4.3 g/l and 1003.9 +/- 8.2 g/l in the control, during, and after HDT periods, respectively). The mass density of red cells did not change with any condition. It is concluded that the distribution volume of isotonic saline solution decreases with diminished body mass. Densitometry provides a means of monitoring volume changes and protein shifts under the circumstances of our study.

Effects of head-down tilt and saline loading on body weight, fluid, and electrolyte homeostasis in man.

We studied the effects of head-down tilt bedrest (HDT) on body weight, fluid and sodium homeostasis. A fluid load session with rapid intravenous infusion of 22 ml/kg body weight (BW) isotonic saline was performed before, during and after HDT. During the pre- and post HDT periods the test subjects were given a diet containing 2600 kcal/day. The energy intake was reduced to 2000 kcal/day during HDT. Water intake was kept constant at 40 ml/kg BW, sodium intake was 2.2 mmol/kg BW and protein intake was 1.4 g/kg BW, while the daily fat and carbohydrate intake was reduced during the HDT period. As expected plasma volume and BW changed rapidly in the beginning of HDT and during early recovery. A total body water loss of 0.6 l was observed within the second day after tilting. Plasma volume was reduced by 16% during HDT-bedrest. The time course of the body fluid loss paralleled a decrease in body sodium that then remained fairly constant during the HDT-bedrest period (except for the interference caused by the fluid loading on day S06). A restoration of body fluid and body sodium content occurred early in the recovery period. Fluid loading caused a negative fluid balance of 0.6-0.9 l over a 48 hr period following infusion regardless of the phase of the HDT study. These results demonstrate that under our strictly controlled conditions 1) HDT alters body fluid and sodium balances, 2) a standard fluid loading causes a net negative 3-day fluid balance during all phases of the study.

The effects of a 10-day period of head-down tilt on the cardiovascular responses to intravenous saline loading.

We tested the hypothesis that adaptation to microgravity, simulated by a 10-day period of head-down tilt (HDT), alters the responses to an intravenous fluid load by causing a larger fraction of the infused volume to be retained and magnifying the acute hemodynamic effects. HDT caused a significant (p less than 0.01) decrease in blood volume (-0.72 liters) and weight (-1.6 kg). Rapid infusion (22 ml/kg over 20 min.) of isotonic saline before, during, and after HDT produced a transient blood volume expansion with 18% of the infusate retained intravascularly after 2 hours. HDT had no effect on this response. Control hemodynamics were significantly different with lower cardiac output and higher total peripheral resistance (TPR) during and after HDT. Saline caused significant increases in cardiac output, heart rate, and stroke volume and a decrease in TPR. The magnitude and time course of these changes were not altered by HDT. The results refute the hypothesis and suggest that during HDT new set points or operating points were established for the control of intravascular volume and hemodynamic state.