First report of the International Council of Cardiovascular Prevention and Rehabilitation's Registry (ICRR).

OBJECTIVES: Cardiac rehabilitation - programs comprehensively delivering outpatient secondary prevention - is under-available and under-studied in the resource-poor settings where it is needed most. This report summarizes the governance, participating sites, patient characteristics and outcomes, as well as knowledge translation activities during first year of operation of ICCPR's registry, namely the International Cardiac Rehab Registry. METHODS: A pilot study was undertaken with five centers, demonstrating feasibility, satisfaction with the on-boarding processes, as well as data quality. RESULTS: Fourteen centers have been engaged from all regions but Europe; Data have been entered on >1000 patients (18.1% female; mean age = 57.6), of whom 62.4% completed their programs and 19.9% dropped out for work or clinical reasons. Post-program, completers had significantly better work status, functional capacity, medication adherence, physical activity levels, diet, as well as lower tobacco use than non-completers (all p < 0.05). A site Certification program was developed and piloted, with five centers now recognized for their quality, given they met over 70% of the 13 internationally agreed standards based on Registry data and a virtual site assessment. CONCLUSION: Annual assessments have started. Quality improvement activities will soon be underway. We continue to invite new programs, supporting development in resource-poor settings to the benefit of patients served.

[Pyogenic granuloma with satellitosis]. / Satellitenrezidiv bei Granuloma pyogenicum.

A 16-year-old female developed a satellite-like recurrence of a pyogenic granuloma on her thorax 2 weeks after complete excision. Treatment with a pulsed dye laser led to a complete resolution. BRAF and RAS mutations detected in the pyogenic granuloma are considered major driver mutations. Whether these findings are also of importance for the etiopathogenesis of satellitosis is unknown. In our patient, no BRAF or NRAS mutation could be detected.

[Extramammary Paget disease: successful therapy with imiquimod 5% cream]. / Extramammärer Morbus Paget: Erfolgreiche Therapie mit Imiquimod 5% Creme.

A 90-year-old woman presented with an extensive primary form of extramammary Paget disease localized in the anogenital region. An associated carcinoma could be excluded. Due to the age of the patient, the location and extent of the tumor as well as existing comorbidities, neither a surgical nor a radio-oncological treatment were advisable. A local treatment with imiquimod 5% cream applied 3 times weekly for 2 × 3 weeks led to a clinically and histopathologically complete remission. As also shown by other authors, imiquimod appears to be a treatment option for the primary form of extramammary Paget disease.

[Rhinosporidiosis. A rare cause of nosebleed]. / Rhinosporidiose. Eine seltene Ursache für Nasenbluten.

Due to an increasing number of non-European patients and tourists travelling in endemic aras, "exotic" mycosis and other tropical diseases must be considered in differential diagnosis. In this report we present a patient with epistaxis caused by rhinosporidiosis, an endemic disease in South India and Sri Lanka (Ceylon) and quite rare in Europe. This chronic inflammatory disease characterized by hyperplastic polypoid lesions of the mucous membrane, predominantly nasal, is caused by Rhinosporidium seeberi, a parasite with a complicated life cycle and an uncertain taxonomy. The commonest and often the presenting symptom is epistaxis. The treatment of choice is surgery with risks of recurrence.

[The German Orthopedics Society 1918-1932. Developments and trends]. / Die Deutsche Orthopädische Gesellschaft von 1918-1932. Entwicklungen und Strömungen.

The German Orthopedic Society was founded in 1901. The period between 1918 and 1932 was characterized by the aftermath of World War I. Up to the middle of the 2nd decade, orthopedic surgeons mainly treated soldiers and civilians affected by the war. Almost every congress dealt with amputations and artificial limbs. At the same time, orthopedic surgery became a specialty at the German universities, legitimizing it as a subject of its own. Besides the large number of victims of the First World War who had to be treated by orthopedic surgeons, there was a second group of patients, the so-called cripples. These handicapped people had not previously been treated in general. A new law established in 1920 guaranteed the government's support for treatment and education of these patients. This law was called "Krüppel-Fürsorge-Gesetz," which entailed welfare but also resocialization of the handicapped, including their return to work. The German nation recognized the economic benefit of this law and accepted the financial burden. During this period, German orthopedic surgeons developed many important surgical techniques, diagnostic tests, and technical findings for the production of orthoses and artificial limbs. Some examples of techniques are described in the article: UVirradiation for the treatment of rickets according to K. Huldschinsky, Borggreve's rotationplasty of the leg (Umkehrplastik), hallux valgus arthroplasty according to Brandes, and Bragard's sign.

Calcium-induced calcium release in neurosecretory insect neurons: fast and slow responses.

The dynamics of intracellular free Ca(2+)([Ca(2+)](i)) changes were investigated in dorsal unpaired median (DUM) neurons of the cockroach Periplaneta americana. Activation of voltage-gated Ca(2+) channels caused a steep increase in [Ca(2+)](i). Depolarizations lasting for < 100ms led to Ca(2+) release from intracellular stores as is indicated by the finding that the rise of [Ca(2+)](i) was greatly reduced by the antagonists of ryanodine receptors, ryanodine and ruthenium red. There is a resting Ca(2+)current which is potentiated on application of a neuropeptide, Neurohormone D (NHD), a member of the adipokinetic hormone family. Ca(2+) influx enhanced in this way again caused a rise of [Ca(2+)](i) sensitive to ryanodine and ruthenium red. Such rises developed and relaxed much more slowly than the depolarization-induced signals. Ca(2+)responses similar to those induced by NHD were obtained with the ryanodine receptor agonists caffeine (20mM) and cADP-ribose (cADPR, 100nM). These Ca(2+) responses, however, varied considerably in size and kinetics, and part of the cells did not respond at all to caffeine or cADPR. Such cells, however, produced Ca(2+) rises after having been treated with NHD. Thus, the variability of Ca(2+) signals might be caused by different filling states of Ca(2+) stores, and the resting Ca(2+) current seems to represent a source to fill empty Ca(2+) stores. In line with this notion, block of the endoplasmic Ca(2+) pump by thapsigargin (1 microM) produced either no or largely varying Ca(2+) responses. The Ca(2+) signals induced by caffeine and cADPR displayed different sensitivity to ryanodine receptor blockers. cADPR failed to elicit any response when ryanodine or ruthenium red were present. By contrast, the response to caffeine, in the presence of ryanodine, was only reduced by about 50% and, in the presence of ruthenium red, it was not at all reduced. Thus, there may be different types of Ca(2+) release channels. Block of mitochondrial Ca(2+) uptake with carbonyl cyanide m -chlorophenylhydrazone (CCCP, 1 microM) completely abolished cADPR-induced Ca(2+) signals, but it did not affect the caffeine-induced signals. Taken together our findings seem to indicate that there are different stores using different Ca(2+) uptake pathways and that some of these pathways involve mitochondria.

Evaluation of DNA ploidy and degree of DNA abnormality in benign and malignant melanocytic lesions of the skin using video imaging.

BACKGROUND: Making a morphologic distinction between benign and malignant melanocytic tumors of the skin is frequently difficult, especially because "gray zones" between these lesions often exist. DNA image cytometry as an adjuvant method for the diagnosis and prognostic prediction of premalignant lesions and malignant tumors of many other organs is already well established. The aim of this study was to determine whether DNA image cytometry is helpful in distinguishing benign from malignant melanocytic lesions and whether cytometry would give valid information with which to predict the prognoses associated with malignant melanomas. METHODS: DNA image cytometry was performed on 127 benign and 58 primary maligant melanomas of the skin as well as 11 metastatic melanomas, using an enzymatic single cell solution according to a method described by Heiden et al. in Cytometry (1991;12:614-21). RESULTS: DNA aneuploidy was graded by DNA index (DI) and a 2c deviation index (2cDI). In contrast to benign melanocytic lesions (with 16% DNA aneuploidy), primary and metastatic malignant melanomas had significantly higher frequencies of DNA aneuploidy (86% and 73%, respectively). In the degree of DNA aneuploidy, significant differences between benign and malignant melanocytic tumors could be observed. The mean 2cDI of aneuploid benign lesions was 1.0, whereas the primary malignant melanomas had a mean 2cDI of 2.92 and the metastatic melanomas a mean of 6.9. The frequency of DNA aneuploidy increased with Breslow thickness. Twenty-one patients with primary malignant melanoma developed metastases. All metastasizing primary tumors were aneuploid and showed a significantly higher grade of DNA aneuploidy than nonmetastasizing malignant melanomas. Moreover, none of the diploid malignant melanomas developed metastases. CONCLUSIONS: This study reveals that DNA image cytometry is prognostically and diagnostically relevant to the evaluation of melanocytic lesions of the skin. Nevertheless, it cannot be relied on alone to provide enough information for a diagnosis.

Evaluation and validation of a Crohn's disease inflammatory activity index reflecting pattern of endoscopic severity.

BACKGROUND: This study was designed to investigate objective variables assessing the inflammatory activity of Crohn's disease accessible for routine management and their suitability to act as surrogate indicators for endoscopic alterations. METHODS: Thirty-six patients were included in a prospective study and underwent endoscopic investigation, 18 with clinically exacerbated disease and 18 after acute-phase conservative therapy. The endoscopic findings were classified to define the dependent variable, yielding two categoric levels: acute active disease and remission. The extent of affected mucosal area was not taken into consideration. The serum variables alpha1-antitrypsin, acid alpha1-glycoprotein (AGP), C-reactive protein (CRP), sialic acids, prealbumin (PAB), and albumin were used as independent variables to predict the dependent variable. To compare the results with common indices, the Crohn's Disease Activity Index (CDAI) and van Hees Index were calculated. RESULTS: The following model was calculated by stepwise logistic regression analysis: if AGP (mg/dl) -4.2 x PAB (mg/dl) > or =0.8, then endoscopically active disease will be predicted with a sensitivity of 100% and a specificity of 95% (P < 0.001). The predictive values of the single variables, CDAI, and van Hees Index were lower. For validation of results an analogous study was performed including 44 patients, 29 with active disease and 15 controls. The existence of the model was confirmed, again showing high values for sensitivity (86%) and specificity (100%). CONCLUSIONS: On a qualitative level focusing on clinical relevance, the endoscopic and biologic findings of Crohn's disease are highly associated. In addition to clinical assessment, usage of the developed index as a rationale contributing to therapeutic decisions in the short- and long-term management might be reasonable.

TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors.

Nuclear receptors (NRs) act as ligand-inducible transcription factors which regulate the expression of target genes upon binding to cognate response elements. The ligand-dependent activity of the NR activation function AF-2 is believed to be mediated to the transcription machinery through transcriptional mediators/intermediary factors (TIFs). We report here the cloning of the 160 kDa human nuclear protein TIF2, which exhibits all properties expected for a mediator of AF-2: (i) it interacts in vivo with NRs in an agonist-dependent manner; (ii) it binds directly to the ligand-binding domains (LBDs) of NRs in an agonist- and AF-2-integrity-dependent manner in vitro; (iii) it harbours an autonomous transcriptional activation function; (iv) it relieves nuclear receptor autosquelching; and (v) it enhances the activity of some nuclear receptor AF-2s when overexpressed in mammalian cells. TIF2 exhibits partial sequence homology with the recently isolated steroid receptor coactivator SRC-1, indicating the existence of a novel gene family of nuclear receptor transcriptional mediators.

Ligand-dependent interaction of nuclear receptors with potential transcriptional intermediary factors (mediators).

The activity of the ligand-inducible activation function 2 (AF-2) contained in the ligand binding domain (LBD) of nuclear receptors (NRs) is thought to be mediated by transcriptional intermediary factors (TIFs). We have recently reported the isolation and characterization of two novel mouse proteins, designated TIF1 and mSUG1, that interact in a ligand-dependent fashion with the LBD (region E) of several NRs in vivo as well as in vitro. Remarkably, these interactions require the conserved core motif of the AF-2 activating domain (AF-2 AD) and can be blocked by AF-2 antagonists. TIF1 and mSUG1 might therefore represent TIFs/mediators for the ligand-dependent AF-2 of NRs. By comparing the interaction properties of these two putative TIFs with different NRs including the oestrogen (ER), thyroid hormone (TR), vitamin D3 (VDR), retinoic acid (RAR alpha) and retinoid X (RXR) receptors, we demonstrate that: (i) RXR alpha efficiently interacts with TIF1, but not with mSUG1, whereas TR alpha interacts much more efficiently with mSUG1 than with TIF1, and RAR alpha, VDR and ER efficiently interact with both TIF1 and mSUG1; (ii) the amphipathic alpha helix core of AF-2 AD is differentially involved in the interactions of RAR alpha with TIF1 and mSUG1; and (iii) the AF-2 AD cores of RAR alpha and ER are similarly involved in their interaction with TIF1, but not with mSUG1. Thus the interaction interfaces between the various NRs and either TIF1 or mSUG1 may vary depending on the nature of both the receptor and the putative mediator of its AF-2 function. We discuss the possible roles of TIF1 and mSUG1 as mediators of the transcriptional activity of the AF-2 of NRs.

Differential ligand-dependent interactions between the AF-2 activating domain of nuclear receptors and the putative transcriptional intermediary factors mSUG1 and TIF1.

Using a yeast two-hybrid system we report the isolation of a novel mouse protein, mSUG1, that interacts with retinoic acid receptor alpha (RAR alpha) both in yeast cells and in vitro in a ligand- and AF-2 activating domain (AF-2 AD)-dependent manner and show that it is a structural and functional homologue of the essential yeast protein SUG1. mSUG1 also efficiently interacts with other nuclear receptors, including oestrogen (ER), thyroid hormone (TR), Vitamin D3 (VDR) and retinoid X (RXR) receptors. By comparing the interaction properties of these receptors with mSUG1 and TIF1, we demonstrate that: (i) RXR alpha efficiently interacts with TIF1, but not with mSUG1, whereas TR alpha interacts much more efficiently with mSUG1 than with TIF1, and RAR alpha, VDR and ER efficiently interact with mSUG1 and TIF1; (ii) the amphipathic alpha-helix core of the AF-2 AD is differentially involved in interactions of RAR alpha with mSUG1 and TIF1; (iii) the AF-2 AD cores of RAR alpha and ER are similarly involved in their interaction with TIF1, but not with mSUG1. Thus, the interaction interfaces between the different receptors and either mSUG1 or TIF1 may vary depending on the nature of the receptor and the putative mediator of its AF-2 function. We discuss the possibility that mSUG1 and TIF1 may mediate the transcriptional activity of the AF-2 of nuclear receptors through different mechanisms.

The value of histological analysis of occluded biliary endoprostheses.

BACKGROUND AND STUDY AIMS: Histological diagnosis of biliary strictures remains unsatisfactory, despite the availability of various endoscopic sampling procedures. The aim of our study was to assess the potential diagnostic yield of histological processing of occluded biliary endoprostheses inserted for palliation of malignant biliary stenoses. PATIENTS AND METHODS: Over a period of one year, we prospectively collected biliary endoprostheses at the time of stent removal due to stent obstruction. Thirty-nine stents, inserted a mean of 94 days earlier for presumed malignant biliary strictures, were recovered. Their contents were examined histologically by two independent pathologists. RESULTS: Malignancy was found in 14 of 36 patients (39%). The sensitivity was highest in gallbladder carcinoma (66%), followed by choledochal and ampullary carcinoma (50%), metastatic carcinoma (33%), and pancreatic carcinoma (25%). The specificity of the method was 100%. CONCLUSIONS: We advocate systematic histological or cytological examination, or both, of occluded biliary endoprostheses, since the technique is of low invasiveness, has low costs, and is easy to perform, especially if other methods of tissue diagnosis have failed.

Expression of p53 protein in malignant melanoma: clinicopathological and prognostic implications.

In the present study, we investigated the expression of the tumour suppressor protein p53 in 113 primary and 43 metastatic malignant melanomas by immunohistochemistry, and correlated the findings with clinicopathological parameters such as histological melanoma subtype, thickness of primary melanomas (Breslow thickness) and patient outcome. In primary melanomas, the polyclonal anti-p53 antibody CM-1 detected immunoreactivity in 70% of the lesions, predominantly in the cytoplasm. Signals were observed in this cellular compartment in 57% of the melanomas, whereas in 32% nuclear p53 over-expression was detected. Immunohistochemistry, using the monoclonal antibody DO-1, revealed lower staining frequencies. However, both antibodies showed congruent results in approximately 80% of the cases. Overall, immunoreactivity was observed in 73% of superficial spreading melanomas, but only in 52% of lentigo maligna melanomas. This difference (P < 0.001) was mainly due to a lower frequency of cytoplasmic immunoreactivity (P < 0.002). There was no difference with respect to cytoplasmic and nuclear immunoreactivity between thin (< 1 mm thickness) and thicker primary melanomas. Staining frequencies detected in metastatic lesions seemed to be lower than in primary tumours. In 103 primary melanomas, follow-up data for at least 5 years were available. In 71% (54 of 76) of the primary melanomas which did not recur, and in 78% (21 of 27) of tumours with subsequent metastases, p53 over-expression was detected by CM-1. However, this difference was not statistically significant. The results of the present study indicate that immunoreactivity to anti-p53 antibodies is a common observation in malignant melanomas, with staining signals predominantly found in the cytoplasm of cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Malignant proliferating trichilemmal cyst.

We report a case of a metastasizing proliferating trichilemmal cyst. A 78-year-old man had multiple common and two proliferating trichilemmal cysts, one of which showed malignant transformation as evidenced by lymph node metastases. Despite surgical removal of the malignant tumor, extensive metastatic disease rapidly occurred. This case exemplifies the difficulties in diagnosis and treatment of these rare tumors and their unpredictable course.

Mutation and expression of TP53 in malignant melanomas.

Mutations of the TP53 gene are the most common genetic alterations in human malignancies. Overexpression of the p53 protein has been reported in high frequencies in all types of skin cancer. To determine the role of TP53 in the pathogenesis of malignant melanoma, we investigated the expression of p53 in 12 cell lines and 145 primary and metastatic lesions by immunohistochemistry. Overexpression of p53 was predominantly detected in the cytoplasm of the cells in 96 (66%) tumor and 12 (93%) cell lines. In contrast to findings in other tumor types, in melanomas immunoreactive cells were found in clusters or as scattered single cells. In primary melanomas, the frequency of p53 overexpression did not correlate with tumor thickness. Nucleotide sequencing of TP53 genes of 24 melanoma tumors/cell lines demonstrated point mutations in seven samples, all coding for mutant p53 protein species. The frequency of TP53 alterations of 20%-30% is lower than in other skin tumor types. Notably, immunohistochemistry was not a suitable method to distinguish overexpression of wild-type p53 from mutant species, since cell lines/tumors with TP53 mutations did not show distinctive staining patterns. The mutation pattern in six out of seven lesions was similar to that caused by ultraviolet light damage. This finding may be regarded a further indication for a pathogenetic role of UV light damage in at least a subgroup of malignant melanomas.

Differential diagnosis of keratoacanthomas and squamous cell carcinomas: diagnostic value of DNA image cytometry and p53 expression.

DNA-cytometry and immunohistochemistry with the anti-p53 antibody DO-1 was performed in 24 keratoacanthomas (KA) and 21 squamous cell carcinomas (SCC) (13 well-differentiated, 8 moderately differentiated) to establish the possible value of these methods for the differential diagnosis of both epithelial tumors. Aneuploidy was detected in 1 (4%) KA and 12 (57%) SCC (p < 0.05). In the latter tumors, histologic grade was associated with an abnormal DNA-content. Six (46%) well and 6 (75%) moderately differentiated SCC were shown to be aneuploid. Over-expression of p53 protein was found in 16 (76%) SCC and 14 (66%) KA (p > 0.05; not significant). However, quantification of p53 expression by evaluating both the intensity of immunostaining and the number of cells with over-expression by means of an immunoreactivity score (IRS) showed significant differences (p < 0.05). There was no correlation of p53 over-expression and aneuploidy in the tumors examined. The analysis of ploidy and immunostaining with anti-p53 antibodies may give useful additional information regarding the differential diagnosis of SCC and KA, if only aneuploidy or a high IRS are considered.