Attitudes toward genetic testing, family planning and preimplantation genetic testing in families with a germline CDKN2A pathogenic variant.

Individuals with a germline CDKN2A pathogenic variant (PV) have a highly increased life time risk of melanoma and pancreatic cancer. This cross-sectional study assessed the attitudes among toward genetic testing, family planning, and preimplantation genetic testing (PGT) in confirmed CDKN2A PV carriers and individuals with a 50% risk of the PV (at-risk carriers) using of a one-time questionnaire.A total of 537 individuals were screened for eligibility, of whom 208 of 366 (57%) confirmed carriers (56% female, median age 54 years [IQR 46-63]) and 39 of 171 (23%) at-risk carriers (59% female, median age of 26 years [IQR 22-32]) participated in the study. Primary motivations for genetic testing were to gain control over their personal and children's cancer risk, as well as increasing cancer surveillance practices. In contrast, concerns about obtaining a mortgage and life insurance were frequently cited as reasons for postponing genetic testing. Family planning decisions remained largely unaffected in both confirmed and at-risk carriers; however, the majority of confirmed carriers were still unaware of their familial or personal cancer risk when starting a family. More than 60% of the participants were unfamiliar with PGT and only a minority (19% of confirmed carriers and 10% of at-risk carriers) would be open to considering PGT as a reproductive option. This study found different attitudes toward genetic testing, family planning, and PGT among individuals affected by the CDKN2A PV. Understanding these different attitudes can help clinicians to address the complexities surrounding these issues, especially for younger individuals facing difficult decisions about the timing of genetic testing, family planning, and the potential use of assisted reproductive options.

Longitudinal changes of serum protein N-Glycan levels for earlier detection of pancreatic cancer in high-risk individuals.

BACKGROUND: Surveillance of individuals at risk of developing pancreatic ductal adenocarcinoma (PDAC) has the potential to improve survival, yet early detection based on solely imaging modalities is challenging. We aimed to identify changes in serum glycosylation levels over time to earlier detect PDAC in high-risk individuals. METHODS: Individuals with a hereditary predisposition to develop PDAC were followed in two surveillance programs. Those, of which at least two consecutive serum samples were available, were included. Mass spectrometry analysis was performed to determine the total N-glycome for each consecutive sample. Potentially discriminating N-glycans were selected based on our previous cross-sectional analysis and relative abundances were calculated for each glycosylation feature. RESULTS: 165 individuals ("FPC-cohort" N = 119; Leiden cohort N = 46) were included. In total, 97 (59%) individuals had a genetic predisposition (77 CDKN2A, 15 BRCA1/2, 5 STK11) and 68 (41%) a family history of PDAC without a known genetic predisposition (>10-fold increased risk of developing PDAC). From each individual, a median number of 3 serum samples (IQR 3) was collected. Ten individuals (6%) developed PDAC during 35 months of follow-up; nine (90%) of these patients carried a CDKN2A germline mutation. In PDAC cases, compared to all controls, glycosylation characteristics were increased (fucosylation, tri- and tetra-antennary structures, specific sialic linkage types), others decreased (complex-type diantennary and bisected glycans). The largest change over time was observed for tri-antennary fucosylated glycans, which were able to differentiate cases from controls with a specificity of 92%, sensitivity of 49% and accuracy of 90%. CONCLUSION: Serum N-glycan monitoring may support early detection in a pancreas surveillance program.

[Proton pump inhibitor-induced nephrotoxicity]. / Nefrotoxiciteit van protonpompremmers.

Proton pump inhibitors are widely used, and generally considered safe. In this clinical lesson two cases are presented with a strong suspicion of proton pump inhibitor induced decline of kidney function. This adverse event has only recently been identified in epidemiological studies. Our cases illustrate that chronic proton pump inhibitor nephrotoxicity can manifest subtle and may therefore be difficult to recognize. We discuss the current epidemiological evidence to support these observations, and the pathophysiology and clinical manifestations of proton pump inhibitor nephrotoxicity. In case a subject using a proton pump inhibitor shows kidney function decline, without a clear cause, withdrawal of this medication is advised. Although for an individual patient the risk may not be high, the large number of proton pump users makes that this adverse event is important on a population level.

[Invasive bladder cancer with lymphangiosis carcinomatosa and carcinoma in situ in a 19-year-old female. Case report with 21-year follow-up]. / Invasives Harnblasenkarzinom mit Lymphangiosis carcinomatosa und Carcinoma in situ bei einer 19-jährigen Patientin. Fallbericht mit Langzeitverlauf über 21 Jahre.

We report a 19-year-old female with a grade 2 transitional cell carcinoma of the bladder invading the lamina propria. In addition, lymphangiosis carcinomatosa and a carcinoma in situ were found. The presenting symptom was painless gross hematuria. The patient was treated with transurethral resection. No tumor recurrence occurred during the 21-year follow-up. The literature on bladder tumors in the first two decades of life is reviewed in this article.

[History and personalities at the Department of Urology, University of Magdeburg. From medical academy to university]. / Geschichte und Persönlichkeiten der Urologie an der Hochschule Magdeburg. Von der Medizinischen Akademie zur Universität.

The Medical Academy of Magdeburg was founded in 1954, but at that time the university did not have its own urological department. It was founded in 1957. Chiefs of the department were Hartwig Eggers (through 1958), Gerhard Wilhelm Heise (1958-1976), Gerd-Wolfgang Mueller (1976-1994), and Ernst Peter Allhoff (since 1994). The department has an interesting history. Numerous famous urologists were trained here.

[Radionuclide bone scan in patients with newly diagnosed prostate cancer. Clinical aspects and cost analysis]. / Die Skelettszintigraphie beim neu diagnostizierten Prostatakarzinom. Klinische Aspekte und Kostenanalyse.

BACKGROUND: The indication for a radionuclide bone scan in patients with newly diagnosed, untreated prostate cancer remains controversial. PATIENTS AND METHODS: In this retrospective study we examined 406 patients who had received a staging bone scan irrespective of their PSA serum level and histology. We evaluated different guidelines and recommendations with respect to their usefulness. The costs were calculated according to EBM and GOA. We evaluated the classification systems of bone metastases according to Soloway, Crawford, and Rigaud. RESULTS: The bone scan was positive in 41 (10%) of 406 patients. The EAU guidelines turned out to be useful with respect to both clinical value and cost efficiency. The Rigaud classification of bone metastases predicted outcome better than the Soloway or Crawford classification. CONCLUSIONS: The EAU guidelines from 2005 are a useful tool to decide whether to perform a bone scan in patients with newly diagnosed, untreated prostate cancer. A bone scan should be performed if PSA levels exceed 20 ng/ml in patients with a G1/G2 histology, and in patients with G3 histology and locally advanced disease irrespective of PSA level. Bone scan metastases should be classified according to Rigaud.

Skipper, an LTR retrotransposon of Dictyostelium.

The complete sequence of a retrotransposon from Dictyostelium discoideum , named skipper , was obtained from cDNA and genomic clones. The sequence of a nearly full-length skipper cDNA was similar to that of three other partially sequenced cDNAs. The corresponding retrotransposon is represented in approximately 15-20 copies and is abundantly transcribed. Skipper contains three open reading frames (ORFs) with an unusual sequence organization, aspects of which resemble certain mammalian retroviruses. ORFs 1 and 3 correspond to gag and pol genes; the second ORF, pro, corresponding to protease, was separated from gag by a single stop codon followed shortly thereafter by a potential pseudoknot. ORF3 (pol) was separated from pro by a +1 frameshift. ORFs 2 and 3 overlapped by 32 bp. The computed amino acid sequences of the skipper ORFs contain regions resembling retrotransposon polyprotein domains, including a nucleic acid binding protein, aspartyl protease, reverse transcriptase and integrase. Skipper is the first example of a retrotransposon with a separate pro gene. Skipper is also novel in that it appears to use stop codon suppression rather than frameshifting to modulate pro expression. Finally, skipper and its components may provide useful tools for the genetic characterization of Dictyostelium.

Purification of the 230-kD bullous pemphigoid antigen (BP230) from bovine tongue mucosa: structural analyses and assessment of BP230 tissue distribution using a new monoclonal antibody.

In the epidermis the autoantigen BP230 is a component of the hemidesmosomal plaque. We have developed a procedure for the isolation of BP230 from bovine tongue mucosa using chromatographic means. The identity of the isolated protein was confirmed by its recognition by bullous pemphigoid autoantibodies. A monoclonal antibody (MoAb230), generated against the purified protein, localizes to the region of the plaque of the hemidesmosome with which keratin bundles interact. Furthermore, the tissue distribution of BP230, assessed using MoAb230, suggests that BP230 or an immunologically related protein is a component of all hemidesmosomes. Ultrastructural analyses of the BP230 preparation reveal that the BP230 molecules assemble into macromolecular aggregates. The few images of individual intact molecules that we have observed in platinum replicas of rotary shadowed BP230 preparations suggest that BP230 is an elongate rod-shaped molecule. This is consistent with predictions based on the primary sequence of BP230 deduced from BP230 cDNAs reported by others. We discuss our results in relation to the potential function of BP230. Isolation of BP230 should now allow more rigorous biochemical analyses of potential protein-protein interactions of BP230 in the hemidesmosome.

Eimeria bovis in cattle: colostral transfer of antibodies and immune response to experimental infections.

IgM, IgG1, and IgG2 antibodies to Eimeria bovis first-generation merozoite antigens were determined by enzyme-linked immunosorbent assay and Western blotting in naturally infected cows and in their offspring before and after the uptake of colostrum. In addition, calves were examined following experimental primary and challenge infections. Neonate calves received maternal antibodies via colostrum. All isotypes determined were transmitted, but only IgG1 was concentrated in the colostrum and it occurred at significantly increased levels in sera from the calves as compared with those from the respective dams. Recognition patterns (Western blotting) displayed by related maternal serum and colostrum and those shown by calves that had ingested colostrum were very similar, but marked variations occurred between individual pairs. Experimental infection of 15-week-old calves with 0.7 x 10(5) oocysts caused strong protective immunity against a challenge with 1 x 10(5) oocysts. In contrast, animals that had undergone a weak intercurrent infection were not protected. Experimental infections induced a considerable increase in IgG1 and IgG2 antibody levels, whereas IgM values increased only slightly. The spectrum of merozoite antigens recognized by the sera increased markedly after experimental infection, although high individual variations were found in the calves. However, there was no correlation between the levels of any specific antibody or the recognition patterns and the status of immunity to a severe challenge.

Immunochemical characterization of three components of the hemidesmosome and their expression in cultured epithelial cells.

Treatment of bovine tongue mucosa with 1 M KCl induced a split in the lamina densa of the basement membrane zone (BMZ). The epithelium was then separated from the underlying connective tissue. Electron microscopic analysis of the stripped epithelium revealed that hemidesmosomes and their associated intermediate filaments (IF) remain along the basal surface of the epithelium. This surface was solubilized in an SDS/urea-containing buffer. Characterization of components of this protein mixture was undertaken using human autoantibodies from bullous pemphigoid (BP) patients that have been shown to recognize hemidesmosomal plaque elements (Mutasim, D. F., Y. Takahashi, R. S. Labib, G. J. Anhalt, H. P. Patel, and L. A. Diaz. 1985. J. Invest. Dermatol. 84:47-53) and by production of mAbs. Affinity-purified autoantibodies directed against 180- and 240-kD polypeptides present in the protein preparation generated strong immunofluorescence staining patterns along the BMZ of bovine tongue mucosa. Furthermore, immunogold localization revealed that these two polypeptides are associated with the hemidesmosomal plaque. A mAb preparation directed against a 125-kD polypeptide present in this same protein mixture lamina lucida side of the hemidesmosome. Autoantibodies in BP serum samples, affinity-purified 180-kD autoantibodies and the mAb preparation generated a punctate stain along the substratum attached surface of epithelial cells maintained on glass substrata for approximately 1 wk. The spots appeared to be associated with bundles of IF in cultured mouse keratinocytes. These monospecific antibody probes should prove invaluable for the study of hemidesmosome structure, assembly, and function.

[Today's prognosis of urolithiasis caused by infection calculi in the young child]. / Die Prognose der Urolithiasis durch Infektionssteine beim Kleinkind heute.

In 24 infants (age 1-4 years) with urolithiasis a good and recurrence-free long-term prognosis is shown in 15 patients with infected stones under following conditions: early diagnosis and operative treatment without residual stones, immediate therapy of bacteriuria and close-meshed follow-up controls. In these 15 infants the morbidity peak was in the second year of life. However in the remaining 9 infants with calcium oxalate calculi recurrent stones did occur on an average of 6 years despite of non-infection. The incidence of urolithiasis in the first to sixth year of life was 1:5 in comparison with the school age.

Inverted Y-ureteral duplication with an uterine ectopy as cause of ureteric enuresis.

Presentation of the casuistry of a girl at the age of 3 years with an inverted Y-ureteral duplication in connection with a uterine ectopy and 'urinary incontinence'. Reference to cases of this extremely seldom occurring malformation published so far and embryonic background are given.

[Intracavitary methylene blue dye in the diagnosis of dysplasias and tumors of the urinary bladder]. / Intracavitäre Methylenblaufärbung in der Diagnostik von Dysplasien und Tumoren der Harnblase.

The in vivo staining of the mucosa of the bladder with methylene blue is a non-invasive, technically simple investigation not stressing for the patient by means of which it is possible to gain informations about place and extension of non-papillary plan-like growing carcinomas and severe dysplasias. Apart from this by this means a coarse estimation of the degree of malignity can be done, which in every case requires the cytologic and histopathologic control. Moreover, the already resected part of the tissue can be delimited well markedly from the parts not yet resected, since wound surfaces covered with inflammatory exudate, as they are found after the first resection, get a very intensive strong staining. The in vivo staining of the mucosa of the bladder is an essential supplementation of the formerly existing diagnostic methods in tumours of the urinary bladder.

[Pretherapeutic testing of sensitivity to cytostatic drugs in primary cultures of selected urologic tumors]. / Prätherapeutische Zytostatikasensibilitätstestung an Primärkulturen ausgewählter urologischer Tumoren.

In 30 patients with malignant urologic tumours (scrotal tumours, renal tumours, tumours of the urinary bladder) an in vitro cultivation of the primary tumor was tried. According to the technique of Tannenberger and Bacigalupo 21 primary cell cultures could be applied. This corresponds to an accession rate of 70%. After formation of a cell lawn and addition of cytostatics of the arbitrarily selected medicaments vinblastin, bleomycin, cis-DDP, actinomycin D the reaction of the cells on the drugs was judged light-microscopically and electrophysiologically by measuring the transmembrane potential 24 hours after the application of medicaments. Thus apart from a usual oncobiogram which has as its fundament the morphology of the cells an electrooncobiogram could be established. The authors dealt with the methodology of the TMP-measurement after Redmann as a relatively new method for the pretherapeutic sensitisation test of tumours. The reactions of the cells to the cytostatics mentioned were so multifarious in the 3 groups of tumours that no conclusions of general validity could be drawn. These different modes of reaction are to be regarded as an expression of the biological individuality of human tumours. Apart from answering theoretical questionings the TMP-measurements might be used in the pretherapeutic sensitisation test of cytostatics in malignant renal tumours.