Capture of magnetic carriers within large arteries using external magnetic fields

Our overall research goal is to advance the safety and effectiveness of acute ischemic stroke therapy by improving the benefit/risk ratio of thrombolysis and hence, the long-term outcome of acute ischemic stroke victims. Our approach is the development of a novel tissue plasminogen activator (t-PA) delivery system based on t-PA-loaded magnetic nano- and microcarriers guided directly to the site of vascular occlusion by external magnetic fields. Such a t-PA delivery system would conveniently combine the advantages of both intravenous (systemic) and intraarterial (catheter-facilitated) thrombolysis: non-invasiveness - the magnetic t-PA carriers can be injected intravenously and targeted, as drug delivery is magnetically guided to and t-PA focally released at and within the vascular clot to induce lysis. The focus of our discussion are the two necessary, fundamental and interrelated bioengineering steps: the research and development of well-characterized, biocompatible, functionally active and t-PA-loaded (encapsulated) magnetic nano- and microcarriers able to induce effective thrombolysis, and the design of magnetic guidance systems for targeted tPA-delivery allowing also the triggered release of the thrombolytic agent at the clot site. In this paper, we theoretically demonstrated magnetic trapping of blood borne magnetic nano- and microcarriers from human large vessels, especially arteries. Then, some preliminary experiments using primate models (monkeys) were done to identify successful in vivo sequestration of magnetic carriers in large and smaller arterial branches after arterial upstream and systemic venous injection. Histology (hematoxylin-eosin stain) verified intraarterial carrier concentration (identified as black carrier agglomerates on H and E staining) at the arterial region above the surface magnet. The results revealed the feasibility of magnetic drug-targeting at arteries and solidified the proposed t-PA delivery system.     

Flavones. 2. Synthesis and structure-activity relationship of flavodilol and its analogues, a novel class of antihypertensive agents with catecholamine depleting properties

(3-Phenyl-7-flavonoxy)propanolamines have been shown to exhibit antihypertensive activity in spontaneously hypertensive rats. Although they are structurally similar to classical beta-adrenergic blocking compounds, their activity is not due to inhibition of beta-adrenoceptors. In the present study, a series of simple flavonoxypropanolamines was prepared to further explore the structural requirements for the antihypertensive effect of these compounds. A structure-activity relationship of these derivatives indicates that the position of the oxypropanolamine side chain, the hydroxy group of the side chain, steric bulkiness and length of N substituents, degree of the N-substitution, phenyl group at the 2-position of the chromone nucleus, and substituents of the phenyl group or B ring of the flavone play significant roles in imparting pharmacological effects. In addition, there is a good correlation between the antihypertensive activity and depletion of myocardial norepinephrine. Of these analogues tested, the most effective one was flavodilol. Only the 8-substituted analogue 6 was found to be a beta-antagonist. Flavodilol was chosen for in-depth pharmacological, toxicological, and clinical evaluation.     

Staphylococcus aureus--toxic shock syndrome toxin-1 antibody titers in serum of German women

In a prospective study the distribution of Toxic-1 (TSST-1) antibody titers was proved by 236 menstruating, tampon using volunteers. They are divided in 7 different age groups. Up to 11% of the volunteers under 25 years had no TSST-1 antibody-titers at all. Over 25 years of age this could be detected. In the group over 40 years of age 98% were found with antibody-titers up than 1:100. So it may be suggested that there is no general causal relationship between any type of tampon on TSS.     

Is there a link between infant botulism and sudden infant death? Bacteriological results obtained in Central Germany

Despite the fact that botulism was described in Germany for the first time by Kerner in 1820, the disease is almost forgotten in this country. Only about 10-20 cases of classical botulism (intoxication) are recorded every year, including 1-2 cases of clinical infant botulism. As we assumed a high incidence of botulism to be connected with cases of sudden infant death (SID), we undertook the research work presented here. From every case of unexpected infant death up to 12 months of age, standardised specimens (blood, liver and intestine) were taken at autopsy. They were tested for the presence of botulinum neurotoxin (BoNT) and/or bacterial forms of Clostridium botulinum with subsequent BoNT neutralisation tests by the international standard mouse bioassay. Age, sex, pathological findings and season were recorded. Over a 5-year period, 75 samples including 57 SID cases were tested. Free toxin was found in nine and bacterial forms were detected in six samples. Toxin neutralisation revealed the definite presence of BoNT/BoNT producing bacteria (mainly type E), whereas another 11 toxin tests were inconclusive. According to international literature, these 15 cases are to be interpreted as infant botulism. Conclusion: the results show a remarkable incidence of infant botulism without any known previous medical history, partly hidden as sudden infant death. We propose to systematically search for botulism in connection with sudden infant death.     

Prostate preservation by combined external beam and HDR brachytherapy in nodal negative prostate cancer

Purpose

The combined external beam- and high-dose rate brachytherapy (HDR-BT) of localized prostate cancer was introduced at Kiel University in 1986. The aim of this intermediate analysis was to judge the Kiel method of localized prostate cancer radiation treatment after ten years experience.

Patients and Methods

In the past ten years 174 patients with histological proven localized prostate cancer were subjected to combined tele-/HDR-brachytherapy. Local staging in all of the cases by transrectal ultrasound, nodal staging in the majority of the cases by CT or MRI. Average age of the patients was 68.2 years (44–84). According to AJCC/UICC staging T1B, T2, T3 was found in 2, 113 and 59 cases, respectively. Highly differentiated tumors (G1) were found in 27, moderately differentited (G2) in 87, poorly differentiated (G3) in 60 cases. The mean follow-up was 47.1 months with the median of 51.7 months. Total prescribed dose 50 Gy on the small pelvis and 70 Gy on the prostate capsule due to the integration of two, 15 Gy each, HDR-brachytherapy fractions in 6 weeks.

Results

Ten patients died of prostate cancer and 18 of intercurrent diseases resulting in a 5 years overall survival rate of 83% and tumor specific survival rate of 94%. Twenty-one patients showed a clinical progression, of these 14 systemic, 5 local and 2 both systemic and local. Additional 16 patients had PSA elevation only. The 5-years biochemical and/or clinical progression-free survival in the cohort was 79% and 73% for the T3 tumors. Side effects were 27 cases of proctitis/colitis and 20 cases of dysuria/cystitis.

Conclusion

The integrated HDR-BT combined with external beam radiation treatment is a method with excellent tumor control rates at five years superior to those of external beam treatment alone or external beam combined with iodine-125 implants. This form of radiotherapy would appear to be particularly well-suited to treatment of advanced localized (T3) tumors.

     

The femoropatellar endoprosthesis--still of value today?]

PURPOSE: Aim of this study was the examination of clinical middle- and long-term results of total femoropatellar endoprostheses type Lubinus (Link, Germany). METHOD: From 1983 to 1996 12 patients (15 joints) underwent total femoropatellar joint replacement (type Lubinus, Link, Hamburg). All of them have been controlled 7.2 +/- 2.6 years (2 to 12 years) after surgery. The indication was primary osteoarthritis in 6, chondrocalcinosis in 2 and rheumatoid arthritis in 7 cases. In addition to the femoropatellar implants femorotibial endoprostheses have been used in 10 knees: 2 unicondylar medial, 1 unicondylar lateral and 7 bicondylar unicompartimental ones. RESULTS: According to a modified Hungerford knee rating scale 8 knees resulted excellent, 2 fair and 4 poor. One knee was excluded after revision surgery due to a loosened tibial component of a medial unicompartimental knee arthroplasty. The 4 poor outcomes resulted from femoropatellar replacements in chondrocalcinosis (2 cases), rheumatoid arthritis and osteoarthritis, (one case each), affecting the femorotibial joint as well. CONCLUSIONS: In those cases of simultaneous femorotibial joint affection--even if this is merely slight and beginning and if the femoropatellar complaints are actually clearly dominating--the sole femoropatellar surface replacement seems to be contraindicated according to our experiences. Providing correct and strict indications this endoprosthesis can be recommended for sole femoropatellar osteoarthritis especially since loosening of endoprosthetic components was not been found in this study.     

A 12-year follow-up of ANNA/C-TRUS image-targeted biopsies in patients suspicious for prostate cancer

Purpose

PSA screening has been rehabilitated. PSA is not specific and can be elevated by benign reasons. Additionally, a subgroup of patients with prostate hyperplasia may harbor prostate cancer (PCa). During monitoring, the clinician aims to detect significant tumors in time, submitting patients to minimal psychological and physical burden, especially in men with high serum PSA and repeat biopsies. We aimed to determine long-term outcomes with respect to ANNA/C-TRUS ability to detect PCa with six targeted biopsies.

Methods

A subset of 71 patients were enrolled. During monitoring, they were subjected to primary, secondary, or even multiple prostate biopsies when needed. Protocol monitoring included PSA measurements, digital rectal examination (DRE) and imaging.

Results

The median follow-up was 12 years. Forty-one patients had a history of negative systematic random biopsies (1–3 sessions). Their age ranges 62–85 years, PSA 0.5–47.3 ng/ml, and the median prostate volume 11–255 cc. During monitoring, 15 patients were diagnosed with PCa. Only two harbored aggressive tumors. The median time to diagnosis was 6 years. All PCa patients are free from biochemical relapse. From the remaining 56 patients, 11 did not have any biopsies, 12 had one, 13 had two, and 20 had three or more biopsy sessions.

Conclusions

ANNA/C-TRUS is a useful method monitoring patients with a risk of PCa. 50–75% of the usually performed biopsy cores could be spared and, after 12 years, 97% of the patients were either without evidence of a PCa or were diagnosed with a good prognosis tumor.

     

The influence of normobaric hyperoxia on hepatic oxygenation--experience with an animal model

We investigated the effect of a ventilation with an FiO2 of 1.0 on arterial and hepatic venous oxygenation in 23 G?ttingen minipigs. Under balanced anaesthesia (isoflurane/fentanyl), a fibreoptic catheter was placed into a hepatic vein. The correct position of the tip of the catheter was controlled manually after laparotomy. After measurement of baseline values (arterial and hepatic blood gases, ShvO2), in 13 minipigs normoventilation with an FiO2 of 1.0 was performed for 15 minutes. Thereafter, ventilation was continued with an FiO2 of 0.4. In the control group (n = 10), the animals were oxygenated with an FiO2 of 0.4 permanently. The changes due to hyperoxia were measured in hepatic venous oxygen saturation (ShvbgaO2: from 81.2 +/- 1.43% to 87.5 +/- 1.77%, ShvoximO2: from 82.6 +/- 1.14% to 90.5 +/- 0.90%), arterial (from 217.5 +/- 5.0 mmHg to 467.2 +/- 22.0 mmHg) and hepatic venous (from 51.8 +/- 2.0 mmHg) oxygen partial pressure. We found a correlation between hepatic venous oxygen partial pressure und ShvbgaO2 in the blood (r = 0.84, p < 0.001) and between ShvO2 (ShvbgaO2/ShvoximO2), which was either measured directly in the blood or by a fibreoptic catheter (r = 0.6, p < 0.001). Whereas the increase in ShvO2 during hyperoxia may be a result of increased arterial supply, the decrease in ShvO2 after the end of hyperoxia below baseline values needs further investigations. The continuous fibreoptic measurement of ShvoximO2, also under hyperoxic conditions is a valuable parameter for the monitoring of hepatic venous oxygenation.     

Caspase 8 small interfering RNA prevents acute liver failure in mice

A major concern in therapy of acute liver failure is protection of hepatocytes to prevent apoptosis and maintain liver function. Small interfering RNA (siRNA) is a powerful tool to silence gene expression in mammalian cells. To evaluate the therapeutic efficacy of siRNA in vivo we used different mouse models of acute liver failure. We directed 21-nt siRNAs against caspase 8, which is a key enzyme in death receptor-mediated apoptosis. Systemic application of caspase 8 siRNA results in inhibition of caspase 8 gene expression in the liver, thereby preventing Fas (CD95)-mediated apoptosis. Protection of hepatocytes by caspase 8 siRNA significantly attenuated acute liver damage induced by agonistic Fas (CD95) antibody (Jo2) or by adenovirus expressing Fas ligand (AdFasL). However, in a clinical situation the siRNAs most likely would be applied after the onset of acute liver failure. Therefore we injected caspase 8 siRNA at a time point during AdFasL- and adenovirus wild type (Adwt)-mediated liver failure with already elevated liver transaminases. Improvement of survival due to RNA interference was significant even when caspase 8 siRNA was applied during ongoing acute liver failure. In addition, it is of particular interest that caspase 8 siRNA treatment was successful not only in acute liver failure mediated by specific Fas agonistic agents (Jo2 and AdFasL) but also in acute liver failure mediated by Adwt, which is an animal model reflecting multiple molecular mechanisms involved in human acute viral hepatitis. Consequently, our data raise hope for future successful application of siRNA in patients with acute liver failure.