[Serous vascularized pigment epithelial detachment in exudative AMD. Morphological typing and risk of tears in the RPE]. / Seröse vaskularisierte Pigmentepithelabhebungen bei exsudativer altersbedingter Makuladegeneration : Morphologische Typisierung und Risiko eines Einrisses im retinalen Pigmentepithel.

PURPOSE: Are there any morphological parameters in pigment epithelial detachment (PED) in eyes with age-related macular degeneration (AMD), which could identify the development of tears (RIP) in the retinal pigment epithelium (RPE) before initiation of anti-vascular endothelial growth factor (VEGF) therapy? METHODS: Retrospectively, the spectral domain optical coherence tomography (SD-OCT), FLA and near infrared (NIR) images of 98 eyes with PED in exudative AMD before treatment (ranibizumab or bevacizumab) were analyzed. Eyes in which a tear in the RPE (RIP group) could be observed during treatment were compared to eyes without the development of RIP (PED group) in the following morphological parameters of PED: height, number of peaks, presence of hyporeflective fissures at the base of the PED, structure of the RPE, presence of floating structures in the PED with maximum hyperreflectivity, amount and localization of hyperreflectivity in the PED and hyperreflectivity in the NIR images. RESULTS: In the 80 eyes of the PED group the mean PED height was 373.7± 197 µm and in the 18 eyes of the RIP group the mean PED height was higher (694.2± 284.3 µm, p < 0.0001). A difference was also seen in the number of peaks per PED (PED group 43%, RIP group 72%, p = 0.039) and in the hyperreflectivity in NIR images (PED group 68%, RIP group 94%, p = 0.033). There were no significant differences in the other morphological parameters. A classification into four types of PED was found by the parameters height and number of peaks. The PED type with a height > 350 µm and one peak (RIP 43%) developed tears more often (p = 0.001) than the PED type < 350 µm with one peak (RIP 0%, p = 0.001). A trend in the visual acuity over 156 weeks was seen: in PED types with heights > 350 µm there was a lower increase in the visual acuity than in PED types < 350 µm (rm ANOVA p = 0.18; ɛ HH = 0.88). Furthermore, in PED types > 350 µm with multiple peaks the total number of injections necessary was higher than in the other PED types (p = 0.032). CONCLUSION: Morphological parameters, such as PED height, number of peaks per PED in OCT images and hyperreflectivity in NIR images are prognostic factors for RPE tears in exudative AMD. The PED height and number of peaks per PED are useful for classification of PED in the daily routine.

Suppression of PTEN function increases breast cancer chemotherapeutic drug resistance while conferring sensitivity to mTOR inhibitors.

Ectopic expression of mutant forms of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) lacking lipid (G129E) or lipid and protein (C124S) phosphatase activity decreased sensitivity of MCF-7 breast cancer cells, which have wild-type PTEN, to doxorubicin and increased sensitivity to the mammalian target of rapamycin (mTOR) inhibitor rapamycin. Cells transfected with a mutant PTEN gene lacking both lipid and protein phosphatase activities were more resistant to doxorubicin than cells transfected with the PTEN mutant lacking lipid phosphatase activity indicating that the protein phosphatase activity of PTEN was also important in controlling the sensitivity to doxorubicin, while no difference was observed between the lipid (G129E) and lipid and protein (C124S) phosphatase PTEN mutants in terms of sensitivity to rapamycin. A synergistic inhibitory interaction was observed when doxorubicin was combined with rapamycin in the phosphatase-deficient PTEN-transfected cells. Interference with the lipid phosphatase activity of PTEN was sufficient to activate Akt/mTOR/p70S6K signaling. These studies indicate that disruption of the normal activity of the PTEN phosphatase can have dramatic effects on the therapeutic sensitivity of breast cancer cells. Mutations in the key residues which control PTEN lipid and protein phosphatase may act as dominant-negative mutants to suppress endogenous PTEN and alter the sensitivity of breast cancer patients to chemo- and targeted therapies.

Vitamins as hormones.

Vitamins A and D are the first group of substances that have been reported to exhibit properties of skin hormones, such as organized metabolism, activation, inactivation, and elimination in specialized cells of the tissue, exertion of biological activity, and release in the circulation. Vitamin A and its two important metabolites, retinaldehyde and retinoic acids, are fat-soluble unsaturated isoprenoids necessary for growth, differentiation and maintenance of epithelial tissues, and also for reproduction. In a reversible process, vitamin A is oxidized IN VIVO to give retinaldehyde, which is important for vision. The dramatic effects of vitamin A analogues on embryogenesis have been studied by animal experiments; the clinical malformation pattern in humans is known. Retinoic acids are major oxidative metabolites of vitamin A and can substitute for it in vitamin A-deficient animals in growth promotion and epithelial differentiation. Natural vitamin A metabolites are vitamins, because vitamin A is not synthesized in the body and must be derived from carotenoids in the diet. On the other hand, retinoids are also hormones - with intracrine activity - because retinol is transformed in the cells into molecules that bind to and activate specific nuclear receptors, exhibit their function, and are subsequently inactivated. The mechanisms of action of natural vitamin A metabolites on human skin are based on the time- and dose-dependent influence of morphogenesis, epithelial cell proliferation and differentiation, epithelial and mesenchymal synthetic performance, immune modulation, stimulation of angiogenesis and inhibition of carcinogenesis. As drugs, vitamin A and its natural metabolites have been approved for the topical and systemic treatment of mild to moderate and severe, recalcitrant acne, photoaging and biologic skin aging, acute promyelocytic leukaemia and Kaposi's sarcoma. On the other hand, the critical importance of the skin for the human body's vitamin D endocrine system is documented by the fact that the skin is both the site of vitamin D (3)- and 1,25-dihydroxyvitamin D (3) [1, 25(OH) (2)D (3)]-synthesis and a target organ for 1,25(OH) (2)D (3). 1,25(OH) (2)D (3) is not only essential for mineral homeostasis and bone integrity, but also for numerous further physiologic functions including regulation of growth and differentiation in a broad variety of normal and malignant tissues, including cells derived from prostate, breast and bone. In keratinocytes and other cell types, 1,25(OH) (2)D (3) regulates growth and differentiation. Consequently, vitamin D analogues have been introduced for the treatment of the hyperproliferative skin disease psoriasis. Other newly detected functions of vitamin D analogues include profound effects on the immune system as well as protection against cancer and other diseases, including autoimmune and infectious diseases, in various tissues. Current investigation of the biological effects of vitamin D analogues are likely to lead to new therapeutic applications that, besides cancer prevention, may include the prevention and treatment of infectious as well as of inflammatory skin diseases. This review summarizes existing knowledge on vitamins A and D, the major vitamin-hormones of the skin.

[New relevance of vitamin D3 metabolism in the skin]. / Neue Aspekte zur Bedeutung des Vitamin-D(3)-Stoffwechsels in der Haut.

Epidermal keratinocytes are the site of both UVB-induced photochemical conversion of 7-dehydrocholesterol to vitamin D(3) (25 OHD(3)) and the enzymatically controlled hydroxylation via 25-hydroxyvitamin D(3) to the biologically active final product 1alpha,25-dihydroxy vitamin D(3) (1alpha,25(OH)(2)D(3), calcitriol). The epidermal synthesis of calcitriol is of fundamental relevance because calcitriol regulates important cellular functions in keratinocytes and dermal immunocompetent cells. Calcitriol and other vitamin D-analogues are effective in the treatment of psoriasis because of their anti-proliferative and pro-differentiation effects. One mechanism for UVB-light therapy in psoriasis could be the induction of calcitriol synthesis. A better understanding of the metabolism of vitamin D(3) in the skin opens new perspectives for potential therapeutic applications of vitamin D analogues in inflammatory skin diseases. Further studies investigating the role of vitamin D(3) metabolism in the prevention of malignant skin disorders are needed.

Expression of vitamin D3 25-hydroxylase (CYP27) mRNA after induction by vitamin D3 or UVB radiation in keratinocytes of human skin equivalents--a preliminary study.

The presence of both 1alpha-hydroxylase activity and 25-hydroxylase activity is a biochemical prerequisite for the enzymatic generation of 1alpha,25(OH)2D3 from vitamin D3 in keratinocytes. In contrast to 1alpha-hydroxylase, however, activity of a 25-hydroxylase in keratinocytes has not previously been demonstrated. In this study, using RT-PCR we detected vitamin D3 25-hydroxylase mRNA in human keratinocytes. The expression of vitamin D3 25-hydroxylase mRNA in keratinocytes was identical to that of CYP27 expressed in mitochondria of human hepatoma HepG2 cells. CYP27 mRNA in keratinocytes is not constitutively expressed but is inducible both by vitamin D3 (780 nM) and by UVB radiation (300 nm, 30 mJ/cm2).

[New cytostatic drugs--indications and costs]. / Neue Zytostatika--Indikationen und Kosten.

In the last decade six new chemotherapeutic agents including the vinca alcaloid vinorelbine, the taxanes paclitaxel and docetaxel, the antimetabolite gemcitabine and the two topoisomerase I-inhibitors irinotecan and topotecan were shown to be active in several phase II- and randomized phase III-trials. This article reviews their mode of action, their efficacy, their side effects and their indications. Their state of registration and reimbursement by insurance companies in Switzerland are summarized. Finally, their costs and cost-effectiveness in a time of increasing financial restraint in health care budgets are analyzed.

Determination of total cysteamine in human serum by a high-performance liquid chromatography with fluorescence detection.

A convenient, reliable and rapid method for determination of total cysteamine in human plasma by high-performance liquid chromatography with fluorescence detection is reported. This assay involves reduction of samples with dithiothreitol, derivatization of total cysteamine by addition of monobromobimane and protein precipitation by perchloric acid. The calibration curve was linear in the range 2-150 nmol ml-1 and the detection limit was 0.5 nmol ml-1. This method was successfully applied for a pharmacokinetic study of three cysteamine derivatives in healthy volunteers without any interference from coexisting substances.

Clinical response to local delivery of tetracycline in relation to overall and local periodontal conditions.

The purpose of this study was to determine the clinical response to local delivery of tetracycline in relation to clinical and microbiological conditions of the other teeth. 4 deep pockets were monitored in 19 subjects with multiple deep periodontal lesions and high counts of P. gingivalis. In 9 patients (LT) only 2 of the selected lesions were treated by placement of tetracycline fibers (Actisite), while the rest of the dentition was left untreated. In the other 10 patients, all teeth were supragingivally scaled and then treated by application of polymeric tetracycline HCl containing fibers, the whole dentition was subject to full mouth scaling and root planing, and the patients rinsed with 0.2% chlorhexidine (FT). A significant reduction in mean PPD was observed in all treated sites after two months. This reduction was maintained over the following 4 months. The magnitude of the effect was significantly greater in the FT group (1.74 mm) than in the LT group (0.88 mm). The mean attachment level changes were similar after 2 months in locally and fully treated subjects. A tendency of relapse was noted for treated sites in LT patients from month 2 to 6. A level of statistical significance was not reached for this effect. Data from measurements recorded at 6 sites around all teeth in the full mouth treated patients were analyzed using multiple linear regression. This analysis showed local changes in PPD and AL were significantly and strongly correlated with the baseline value of the respective parameter at the same site. In addition, more pocket depth reduction was noted if a site was not bleeding on probing at 6 months, if the location of a site was not approximal and if the tooth was not a second molar. Sites located on second molars showed also less AL gain than sites located on other teeth. Smokers showed significantly less reduction in PPD and significantly less AL gain. Furthermore, if subjects had a high % of pockets deeper than 4 mm at baseline they showed significantly less attachment gain.

[Examination of the ovarian activity of mares using progesterone profiles]. / Uberprüfung der Ovaraktivität bei Stuten mittels Progesteronverlaufsprofilen.

By means of clinical and analytical procedures (enzyme immuno assay for progesterone with microtiterplate method) the ovarian activity from 27 mares was tested over a period of several weeks. The measurement of the progesterone level to determine the time of ovulation was proved as suitable in the period of 1-2 days after ovulation. In normocyclic mares (n = 17) a different development of the progesterone profile was detected, so that an insufficient development of the corpus luteum (35%) could be considered. By means of continuous measurement of progesterone (> or = 30 days) six of ten mares with aberrations in estrous cycle were considered carrying a persistent corpus luteum. Four of them showed a complete inactivity of the ovaries. The clinical importance of the determination of progesterone levels as a mean of routine diagnostic in mares with gynaecological problems is discussed.

Treatment of an early implant failure according to the principles of guided tissue regeneration (GTR).

The present case report demonstrates the application of guided tissue regeneration (GTR) in combination with antimicrobial therapy for the treatment of an early implant failure. This treatment approach both prevented further loss of bone as well as led to the regeneration of lost bone. By means of color-converted digital subtraction images, remodelling of the tissues adjacent to the defect was documented as early as one month postsurgically. The images demonstrated "bone-fill" in the apical portion of the defect and resorptive changes at the bone crest. This case report demonstrates that combined regenerative and antimicrobial therapy may be a successful treatment approach restoring osseointegration of dental implants following loss of bone due to infection. Continuously increasing bone-fill inside the defect was documented when comparing the radiograph obtained immediately before the GTR procedure and at months 1, 2, 4, 5 and 6 of the healing period, respectively. Clinical measurement obtained at the time of the surgery and at the time of the membrane removal confirmed the radiographic evidence of bone-fill by demonstrating new tissue resistant to probing in close contact to the implant surface at the site of the previous defect. Antimicrobial therapy included an antibiotic regimen during the 1st month of healing as well as topical rinses with an antiseptic (chlorhexidine) over the entire healing period of 6 months. As a result of this treatment approach, the implant was saved and could be used as an abutment for a bridge reconstruction.

Transformation and degradation of leukotriene B4, 12-hydroxyeicosatetraenoic acid and 5-hydroxyeicosatetraenoic acid induced by ultraviolet radiation.

To reveal the underlying mechanisms in the therapeutic effectiveness of ultraviolet (UBV)- and psoralen plus UVA phototherapy, the photostability of leukotriene B4 (LTB4), 12-hydroxyeicosatetraenoic acid (12-HETE) and 5-HETE was investigated in the presence and absence of photosensitizers (8-methoxypsoralen and 5-methoxypsoralen). Arachidonic lipoxygenase products were irradiated with doses of narrow-band UVB (311 nm) ranging from 0.5-3.2 J/cm2, UVB and UVA (305-400 nm) ranging from 0.6-6.3 J/cm2 and UVA ranging from 5.0-60.0 J/cm2, respectively. High-performance liquid chromatography demonstrated a dose-dependent decrease of LTB4, 12-HETE, and 5-HETE. The photostability of 12-HETE was much higher than that of LTB4 and 5-HETE. Two products of transformation of LTB4 were identified as 5(S), 12(R)-dihydroxy-(6E, 8E, 10E, 14Z)-eicosatetraenoic acid [6-trans-LTB4] and 5(S), 12(R)-dihydroxy-(6E, 8Z, 10E, 14Z)-eicosatetraenoic acid [5(S), 12(R)-DiHETE]. There was no significant increase in photodegradation after addition of photosensitizing psoralens.

[Short TR--short TE and UTSS sequences compared in a NMR study of focal neoplastic pathology in the liver]. / Sequenze "short TR--short TE" e "UTSS" a confronto nello studio NMR della patologia neoplastica focale del fegato.

From December 1987 to January 1989, 66 patients were studied by liver MR imaging: 38 of them were found to have liver tumors, and 28 were studied as a control group. The authors' purpose was to compare the diagnostic accuracy of 0.5 T MR imaging to that of other techniques (CT and US), using mixed Spin-Echo and Inversion Recovery sequences (UTSS). Spin-Echo sequences were used first, with very short repetition times (TR 260, TE 20). Mixed sequences (UTSS) followed, both T1-weighted, lasting 12' and 13' respectively, and then T2-weighted Multiecho sequences lasting 9'. T1-weighted Inversion Recovery sequences provided with good contrast between normal and neoplastic parenchyma, and demonstrated all the lesions shown by other techniques. UTSS proved to be the most sensitive sequence in exactly defining the lesion and its relationship to hepatic vessels. Signal characteristics of T2-weighted Multiecho sequences allowed some neoplastic types to be distinguished that were found to have a particular behavior, especially hemangiomas. T1 and T2 maps were used to characterize the different lesions.

[Influence of endotoxin on the synthesis of lipoxygenase products formed from arachidonic acid by rat alveolar macrophages]. / Zum Einfluss von Endotoxin auf die Synthese von Lipoxygenaseprodukten der Arachidonsäure in Alveolarmakrophagen der Ratte.

Alveolar macrophages of normal and endotoxin--treated rats were stimulated in suspension by calcium ionophore A 23187. After solid phase extraction and isocratic separation by HPLC the lipoxygenase products (Leukotriene B4, 5-hydroxyeicosatetraenoic acid and 12-hydroxyeicosatetraenioc acid) were quantified. Unlike alveolar macrophages of control animals, alveolar macrophages of endotoxin treated rats showed an increased synthesis of lipoxygenase products (Leukotriene B4: 1.6fold; 5-hydroxyeicosatetraenoic acid: 2.1fold; 12-hydroxyeicosatetraenoic acid: 1.3fold). Our results suggest that in vivo endotoxin disturbs the mechanisms of arachidonic acid liberation in alveolar macrophages.

[Retrospective analysis of 31 cases of soft tissue tumors. Comparison of MR and surgical and anatomo-pathological findings]. / Analisi retrospettiva su 31 casi di tumori delle parti molli. Quadri RM, reperti chirurgici e anatomo-patologici a confronto.

Twenty-five patients (16 with malignant soft-tissue tumors and 9 with suspected recurrence), previously studied with conventional radiography and Computed Tomography (CT), were examined with Magnetic Resonance (MR) imaging. MR findings were surgically and anatomo-histopathologically confirmed. Six more patients with benign lesions were examined for differential diagnosis. MR capabilities are here evaluated to detect and eventually characterize the lesion, and to assess its exact location. No false positives were found, and there was only one false negative, in a case of recurrent Malignant Fibrous Histiocytoma (MFH). In another case of MFH the infiltration of the adjacent vessels and nerves was not imaged. After a careful review of all the examinations, MR imaging appears to be able to provide much information for surgical planning about tumor extent and margins, thanks to its contrast resolution between tumor and surrounding anatomical structures. Therefore, MR imaging can be reasonably employed as the examination of choice when a soft-tissue tumor is clinically suspected, because of the multi-planar images it provides with and of its differential imaging parameters.

Signal suppression of normal liver tissue by phase corrected inversion recovery: a screening technique.

A new pulse sequence characterized by simultaneous multislice spin echo (SE) and short inversion time (TI) with inversion recovery (STIR) acquisitions is demonstrated. For the STIR component, a repetition time of 1,000 ms and TI of 210 ms were chosen to suppress the signal from normal liver at 0.5 T and create a fast sequence suitable for screening purposes. Phase correction of the STIR with the SE's signal as a reference resulted in high contrast real IR images that were free of phase error artifact. In 13 min the entire liver could be imaged in 14 adjacent slices, each slice portrayed in an ensemble of four images: a T1-weighted SE image, IR real and modulus images, and a T1 map. Forty-one patients with liver pathology and 10 normal volunteers were examined with the sequence implemented on a commercially available 0.5 T imager (Gyroscan; Phillips). Images demonstrated high liver-lesion contrast and sensitivity to liver lesions. Lesions of less than 1 cm in diameter and lymphomatous lesions, commonly occult to magnetic resonance, were detected.

[Practice relevant rapid tests for milk progesterone in cattle compared with a laboratory-connected routine method]. / Vergleich praxisrelevanter Milchprogesteron-Schnelltests mit einer laborgebundenen Routinemethode beim Rind.

Four commercially available semiquantitative milk progesterone tests (Ovucheck-Praxistest: Cambridge Veterinary Science/Smith Kline), Progestassay-Milchprogesteron (Pitman-Moore/Janssen), Reprostrip-Progesteron-Schnelltest (Noctech/Albrecht), Enzygnost-Milchprogesteron (IQ, 'Bio' UK/Hoechst Veterinär) were examined for their accuracy by using them for the determination of progesterone levels of 64 milk samples, i.e. 1556 single assays. Several test series were performed, using codified samples and changing sequences. Three or four test persons respectively, performed the tests independently and classified the samples semiquantitatively. These test results were then compared to the results acquired by measuring the progesterone levels of the same samples by means of an approved quantitative, labor-bound progesterone test (Hormonost: Biolab). These control tests were performed at a specialized routine labor, by different personnel and at a different location. Lastly, in 48 out of the 64 sampled animals the reproductive status could be evaluated clinically and was taken into account as well. Samples yielding high progesterone levels, i.e. greater than or equal to 9 ng/ml were classified correctly in 84.4 to 96.5% of the cases, whereas samples with low levels (less than or equal to 2.5 ng/ml) were classified correctly in 68.8 to 90.0% of the cases only. Samples ranging between this spectrum (greater than 2.5 less than 9 ng/ml) were classified correctly only in 42.1 to 52.6% of the cases. However, this range appears to be of the most interest for the veterinary practitioner since cows in proestrus or early interestrus tend to have mild progesterone levels within these values. On the other hand, clinical findings are often insufficient for a proper diagnosis just in these animals.(ABSTRACT TRUNCATED AT 250 WORDS)

[Chromatographic separation of activated proteases from human plasma]. / Zur chromatographischen Trennung aktivierter Proteasen aus menschlichem Plasma.

After separation of aceton and dextran sulfate activated human plasma by column chromatography on DEAE-cellulose three esterolytically and amidolytically active fractions, respectively, were obtained, which were assigned to the following species: plasma kallikrein (PK), PK.alpha-macroglobulin.HMW-Kininogen. Their percentage in the whole activity is variable. The proportion of free PK is low (0.11). For characterization of the products we studied inhibition by different polyvalent inhibitors. The Michaelis constant (Km) with p-toluene-sulfonyl-L-arginine methyl ester (TAME) were determined. For simulation of in vivo conditions dextran sulfate activated plasma was inactivated at 37 degrees C. The residual activity and the spontaneous activity in plasma from patients with shock are produced by different active protease inhibitor complexes.

[Relaxation times and proton density of the healthy kidney and its lesions and graphic view of T2 decay]. / Relaxationszeiten und Protonendichte der gesunden Niere sowie ihrer Läsionen und graphische Betrachtung des T2-Zerfalls.

Kidney diseases, healthy kidney tissue and adjacent organs like liver, musculature and fatty tissue were evaluated in respect to their T1-, T2-relaxation times and proton density values. In addition the results of an evaluation of T2-short, T2-long, Rho-short, Rho-long, which were calculated from the T2-relaxation times, are reported. The T2-times are very sensitive in demonstrating differences between the tissues, as significantly different values for healthy kidney tissue and hypernephromas could be found. Different values could be seen dependent on the calculation mode, whereby the calculations had been made from double echo and multiple echo sequences. The T1-relaxation times were less sensitive, differences could be also found between the calculations from the IR and SE mode. The values of T2-long and T2-short and the proton density values differed very much for the same organ in the examined groups of patients, therefore these additionally calculated values unlikely will help in the differential diagnosis of unknown kidney diseases.