The number of digital objects (and digital collections) will increase rapidly within the next years since mass digitisation activities have started all over the world. Although it is obvious that these objects are of enormous scientific and cultural value, some crucial aspects of ensuring their long-term preservation and access to them have so far not been thoroughly addressed. This means that there is an urgent need for developing (and implementing) new and reliable models in order to deliver a sound organisational and financial framework for institutions (and enterprises), that are concerned with digitisation and long-term preservation of digital objects. To this purpose the Bavarian State Library (BSB) and the University of the Federal Armed Forces Munich, are carrying out a study, funded by the German Research Foundation (DFG), that explicitly addresses the perceived shortcomings by analysing the current state of long-term preservation in Germany, developing solutions in the form of scalable business and organisational models and clarifying the agenda for further research. Background/Motivation Today, the access to digital cultural heritage is a granted service of the traditional memory organisations. No longer only small projects on the digitisation of specific scientific and aesthetic values of the stocks of our organisations are realized. The focus is rapidly shifting away from pure boutique to mass digitisation projects with several thousands of titles. To secure the availability of this content for the long term is one of the priority tasks of memory organisations. Long-term preservation of the underlying data has been recognized as an absolute necessity, yet infrastructures can change, funds run dry. Therefore sustainable structures have to be created to ensure the preservation of our digital heritage in every case. Apart from reusable technical solutions, in particular stable organisational, legal and financial models have to be developed, which can be harmonised in a strategy for long-term preservation of digital content.

BACKGROUND:There is increasing interest in natural orifice surgery (NOS). Because the lumen of the appendix is connected to the cecum, a minimally invasive method for removing the appendix by colonoscopy may be feasible.OBJECTIVES:Our purpose was to design, develop, and test new devices for inverting and removing the appendix by colonoscopy.DESIGN:Prospective prototype development program.SETTING:University-based study in 25 colons from adult human cadavers.INTERVENTIONS AND METHODS:Various prototypes were evaluated by inserting them into the appendiceal orifice to its luminal tip, with the intent to invert the appendix in a controlled fashion into the lumen of the cecum. The advantage of using a tubular structure as a counterforce to aid inversion of the appendix was evaluated. When inversion was incomplete, the growing tissue strain was relieved by endoluminal incision of the mesenteric side of the appendix. Closure methods with endoloops or ligating loops were studied. Appendiceal resection was completed by snare diathermy, leaving an inverted intraluminal stump.MAIN OUTCOME MEASUREMENT:Ability to invert the appendix into the cecum.RESULTS:The mean appendix length and luminal diameter were 84 +/- 23 mm and 4.9 +/- 1.2 mm, respectively. It was possible to advance various types of inversion devices to the tip of the appendiceal lumen. Partial inversion of the appendix was successful in 22 of 25 tests. Mesenteric tissue tension, tissue volume, and device slippage were the main reasons for incomplete inversion. The complete inversion was achieved with a combination of vacuum, tip grip, counterforce at the appendix base, and eventually endoluminal incision.CONCLUSIONS:The inversion of the human appendix by colonoscopy seems feasible and may be an alternative approach to conventional appendectomy.

We investigated in different human cell types nuclear positioning and transcriptional regulation of the functionally unrelated genes GASZ, CFTR, and CORTBP2, mapping to adjacent loci on human chromosome 7q31. When inactive, GASZ, CFTR, and CORTBP2 preferentially associated with the nuclear periphery and with perinuclear heterochromatin, whereas in their actively transcribed states the gene loci preferentially associated with euchromatin in the nuclear interior. Adjacent genes associated simultaneously with these distinct chromatin fractions localizing at different nuclear regions, in accordance with their individual transcriptional regulation. Although the nuclear localization of CFTR changed after altering its transcription levels, the transcriptional status of CFTR was not changed by driving this gene into a different nuclear environment. This implied that the transcriptional activity affected the nuclear positioning, and not vice versa. Together, the results show that small chromosomal subregions can display highly flexible nuclear organizations that are regulated at the level of individual genes in a transcription-dependent manner.

OBJECTIVE:To study the effects of osteoclast-targeted therapies, such as osteoprotegerin (OPG) and pamidronate, on joint inflammation and bone destruction using a tumor necrosis factor alpha (TNF alpha)-transgenic mouse model.METHODS:Mice were placed into 5 groups that received either OPG, pamidronate, a combination of both agents, infliximab as a positive control, or phosphate buffered saline as a negative control. Treatment was initiated at the onset of arthritis, continued over 6 weeks, and thereafter, the clinical, radiologic, and histologic outcomes were assessed.RESULTS:A significant improvement in clinical symptoms, as assessed by the reduction of paw swelling, was only found in the infliximab group, whereas all other treatment groups failed to show significant improvement. However, when assessing structural damage with radiographic analysis, a significant retardation of joint damage was evident in animals treated with OPG (55% reduction of erosions), pamidronate (50% reduction of erosions) the combination therapy of OPG and pamidronate (64% reduction of erosions), and with infliximab (66% reduction of erosions). Confirming these data, quantitative histologic analysis revealed a significant reduction in the size of bone erosions in all treatment groups (OPG 56%, pamidronate 53%, OPG and pamidronate 81%, and infliximab 46%) compared with the control group. Furthermore, a significant reduction of osteoclast numbers was seen in animals treated with OPG alone or in combination with pamidronate as well as in animals treated with infliximab.CONCLUSION:These data suggest that OPG alone or in combination with bisphosphonates is an effective therapeutic tool for the prevention of TNF alpha-mediated destruction of bone by reducing the number of bone-resorbing cells in the inflammatory tissue.

Previous results of an in vitro guidance test, the stripe assay, have demonstrated the presence of a repulsive axon guidance activity for temporal retinal axons in the posterior part of the vertebrate optic tectum. Ephrin‐A5 and Ephrin‐A2 are ligands for the EphA subfamily of Eph receptor tyrosine kinases, which are expressed in overlapping gradients in the posterior part of the tectum. When recombinantly expressed, both proteins have been shown to guide retinal ganglion cell axons in the stripe assay. While these results suggest that Ephrin‐A5 and Ephrin‐A2 form part of the posterior repulsive guidance activity, they do not elucidate whether they are necessary components. Here we report that soluble forms of the ligands at nanomolar concentrations completely abolish this repulsive activity. Similar results were obtained with the soluble extracellular domain of EphA3, which is a receptor for Ephrin‐A2 and Ephrin‐A5, but not with the corresponding domain of EphB3, a receptor for the transmembrane class of Eph ligands. These experiments show that the repulsive axon guidance activity seen in the stripe assay is mediated by Ephrin‐A ligands.

Extensive proliferation of connective tissue around Vitallium implants can be observed in young patients who had limb salvage for primary malignant bone tumors. The underlying mechanism of excess proliferation and collagen accumulation is not known. We were therefore interested to show whether the alloy of the implant induced proliferation of fibroblasts in vitro, acted by a cytotoxic mechanism or generated free radical cross linking of collagen with subsequent accumulation. In vitro tests for proliferation and cytotoxicity using the implant material which consists of a series of transition metals, ruled out a proliferation-inducing or cytotoxic effect of the implant. Determination of ortho-tyrosine (OT), a marker for hydroxyl radical attack on phenylalanine, in the proliferating tissues surrounding the implants revealed significantly higher aromatic hydroxylation in the vitallium surrounding tissue correlating with tissue collagen content (r = 0.86, p < 0.01). Based upon the findings of increased OT and the presence of higher molecular weight bands on SDS-PAGE, representing more cross linked collagen, we suggest that hydroxyl radical attack lead to free radical mediated cross linking of collagen with subsequent collagen accumulation, as collagen cross-linked to a higher degree is less susceptible to proteolytic degradation.The hydroxyl radical attack seems to having been generated by the many transitional metals of the vitallium-alloy.

Chronotherapy with antineoplastic drugs is a rather new strategy of reducing cytotoxic side effects. Because the circadian timing of 5-fluorouracil (5-FU) was reported to result in a higher efficacy and lower toxicity, the authors conducted a chronopharmacologic Phase I trial with 5-FU and folinic acid (FA).Eight patients with advanced colorectal cancer received 5-FU (initial dose of 500 mg/m2/day) and FA (20 mg/m2/day) as a continuous intravenous infusion over 5 consecutive days. Using a portable, ambulatory drug delivery system, 75% of the daily dose of 5-FU and FA were given from Oh00-7h00, and the remaining 25% from 7h00-24h00. Treatment courses were repeated after 28 days. Dose escalations of 250 mg/m2/day of 5-FU and 10 mg/m2/day of FA per course were performed in the absence of any toxicity greater than WHO (World Health Organization) grade 2.Dose-limiting toxicity WHO grade 3 was observed at a dose of 750 mg/m2/day of 5-FU and 30 mg/m2/day of FA in five, and 1000 mg/m2/day of 5-FU and 40 mg/m2/day of FA in two patients, respectively. One patient tolerated 1000 mg/m2/day of 5-FU and 40 mg/m2/day of FA, but the treatment was stopped before further dose escalation because of rapid disease progression. Mucositis was the dose-limiting toxicity in seven patients and diarrhea in two. Disease stabilization occurred in three patients and disease progression in five. Compared with conventional Phase I/II trials using a 5-day infusion regimen, the maximal tolerated dose of 5-FU and FA was slightly higher but significantly lower than in a chronotherapeutic trial that used a different, sinusoidal mode of drug application.Based on these results, the authors feel justified to caution that the circadian timing of 5-FU plus FA may not always allow the safe application of high dose levels. Future Phase I/II studies need to define whether specific drug delivery systems or schedules are necessary for chronotherapy with 5-FU and FA in patients with colorectal carcinoma.

Sixty‐nine male Sprague Dawley rats were divided into three groups of 23 animals each and osteotomies were performed in group 1 with a power saw, in group 2 with the Erb:Yag laser, and in group 3 with the Hol:YAG laser. Two animals of each group were sacrificed 1 week, 4, 8, and 12 weeks after operation for histologic investigation, and five animals of each group at 4, 8, and 12 weeks after osteotomy for torque testing. Anterior‐posterior (AP) radiographs were taken at the same time points and investigated for callus formation and development of pseudoarthrosis. All tibiae osteotomied with the Ho1:YAG laser (group 3) developed pseudoarthrosis within 12 weeks and, therefore, torque testing could not be performed for this group. Biomechanical measurements of bone treated by power saw or Erb:YAG laser osteotomies, respectively, showed no significant statistical difference in the stability of bone between the two groups. Histologic examination after 1 week exhibited fibrous tissue at the site of osteotomy in rats of all three groups and additionally carbonization in rats of group 3. Saw osteotomies resulted in more callus formation than Erb:YAG osteotomies, but both techniques provoked a certain reunion within 8 weeks. Hol:YAG laser‐treated osteotomies, however, exhibited formation of dense fibrous tissue, carbonization and no callus formation within 12 weeks. Radiographic pictures showed more callus formation for saw osteotomies as compared to those performed with the Erb: YAG laser. For Hol:YAG laser osteotomies pseudoarthrosis was identified also radiologically. © 1994 WiIey‐Liss, Inc.

In this study we report on the clinical, radiological and pathologic data of 42 intraosseous ganglia which had been verified histologically. Of the patients, 26 were male and 16 female. Their mean age was 41.8 years (range 20-71 years). Exclusively solitary ganglia were included in this study; mainly they were located within the lower extremity. In most cases (n = 12), the malleolus medialis was involved. In 40 patients, treatment consisted of curettage, in 39 cases in combination with autologous or homologous bone grafting. In 2 cases, a resection was performed. No local recurrence was observed. Etiology and pathogenesis are discussed.

Background. Chronotherapy with antineoplastic drugs is a rather new strategy of reducing cytotoxic side effects. Because the circadian timing of 5-fluorouracil (5-FU) was reported to result in a higher efficacy and lower toxicity, the authors conducted a chronopharmacologic Phase I trial with 5-FU and folinic acid (FA).Methods. Eight patients with advanced colorectal cancer received 5-FU (initial dose of 500 mg/m(2)/day) and FA (20 mg/m(2)/day) as a continuous intravenous infusion over 5 consecutive days. Using a portable, ambulatory drug delivery system, 75% of the daily dose of 5-FU and FA were given from 0h00-7h00, and the remaining 25% from 7h00-24h00. Treatment courses were repeated after 28 days. Dose escalations of 250 mg/m(2)/day of 5-FU and 10 mg/m(2)/day of FA per course were performed in the absence of any toxicity greater than WHO (World Health Organization) grade 2.Results. Dose-limiting toxicity WHO grade 3 was observed at a dose of 750 mg/m(2)/day of 5-FU and 30 mg/m(2)/day of FA in five, and 1000 mg/m(2)/day of 5-FU and 40 mg/m(2)/day of FA in two patients, respectively. One patient tolerated 1000 mg/m(2)/day of 5-FU and 40 mg/m(2)/day of FA, but the treatment was stopped before further dose escalation because of rapid disease progression. Mucositis was the dose-limiting toxicity in seven patients and diarrhea in two. Disease stabilization occurred in three patients and disease progression in five. Compared with conventional Phase I/II trials using a 5-day infusion regimen, the maximal tolerated dose of 5-FU and FA was slightly higher but significantly lower than in a chronotherapeutic trial that used a different, sinusoidal mode of drug application.Conclusion. Based on these results, the authors feel justified to caution that the circadian timing of 5-FU plus FA may not always allow the safe application of high dose levels. Future Phase I/II studies need to define whether specific drug delivery systems or schedules are necessary for chronotherapy with 5-FU and FA in patients with colorectal carcinoma.

Ho:YAG, Nd:YAG, and Erb:YAG laser ablation of Polymethylmethacrylate (PMMA) was investigated under in vitro and simulated clinical conditions. Ablation rates were measured for all lasers and after ablation, macroscopic and microscopic appearance of the ablation site was investigated. The mean ablation rates of the Erb:YAG, Ho:YAG, and Nd:YAG laser increased from 8 μm per pulse at 100 mJ to 44 μm per pulse at 300 mJ from 100 μm per pulse at 200 mJ to 222 μm per pulse at 800 mJ and from 28 μm per pulse at 100 mJ to 189 μm per pulse at 800 mJ, respectively. Macroscopic investigation exhibited melting of bone cement for the Ho:YAG and Nd:YAG lasers and pulse‐to‐pulse vaporization for the Erb:YAG laser. The width of thermal alteration, however, was comparable for all lasers used. Removal of cement from bone specimens under simulated clinical conditions showed good detachment of cement when the fiber was used parallel; in case of perpendicular use, remainders of cement and carbonization of bone could be observed upon histological investigation. © 1993 Wiley‐Liss, Inc.