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Biomedical subjects

J Engel

Publications and source records attributed to J Engel.

At least 55 records · Page 3Linked to original sources
PubMed2002

Primary breast cancer therapy in six regions of Germany.

Studies from six regions of Germany (Aachen (W1), Dresden (E1), Jena (E2), Marburg (W2), Munich (W3), and Stuttgart (C1)) have been compared to verify and assess the quality of healthcare using breast cancer as an example. All of the data collection was carried out in comprehensive cancer centres and is population-based, with the exception of C1. Classic prognostic factors and the initial treatment of 8661 women with breast cancer, diagnosed between 1996 and 1998, were examined. Primary therapy, breast conserving therapy (BCT), and the use of subsequent local radiation and/or systemic therapy (chemotherapy or hormonal therapy) were analysed. BCT was performed on 39.3-57.7% of patients. By pT-category, the proportion of BCT in the six regions were as follows: for pTis between 37.8 and 64.3%, for pT1 between 51.7 and 71.5%, for pT2 between 25.9 and 51.1%, for pT3 between 0 and 13.1% and for pT4 between 0 and 15.2%. Multivariate analyses, adjusted for age and biological factors, showed a significant influence of the treating hospital on the mastectomy rate. The use of radiotherapy after BCT (80%) was quite homogeneous in the six regions. The application of radiotherapy after mastectomy, however, varied between 10.4 and 32.2%. In all regions, for premenopausal patients, the use of adjuvant systemic therapy almost reflected the St. Gallen-Consensus recommendations. In contrast, post-menopausal women with positive lymph nodes were not always treated according to these standards. In all regions, age had an influence on the administration of treatment: elderly breast cancer patients received less BCT, less radiotherapy and less adjuvant therapy than recommended in the St. Gallen-Consensus. Feedback of the results was made available to each hospital, providing a comparative summary of patient care that could be used by the participating hospitals for self-assessment and quality-control.

Age Distribution↗
PubMed2002

Moderate progress for ovarian cancer in the last 20 years: prolongation of survival, but no improvement in the cure rate.

Although ovarian cancer treatment has advanced in the last 20 years, long-term survival remains stable. The purpose of this study was to determine whether survival has improved in line with treatment advances in a population-based prospective cohort of ovarian cancer patients (1978-1997, with a follow-up through to 2000). The 10-year overall survival rate for cancer patients was similar before and after 1988: 32.2% (n=1661) and 34.4% (n=2089). For patients after 1988, a 12-month prolongation of median survival was observed. In terms of stage according to the International Federation of Gynecology and Obstetrics (FIGO), only FIGO I and FIGO II patients showed, in addition to a prolongation in survival, an absolute improvement of 12.9 and 12.6% after 5 years and of 13.2 and 8.6% after 10 years. This hardly affected the survival of the total sample. For the most frequent stage FIGO III patients and for FIGO IV patients, a prolongation in survival time, but no improvement in survival rate, was seen after five or 10 years. The progress in FIGO I and II patients may be due to more accurate staging. More effective chemotherapy may also explain some of the improvement. The prolongation in FIGO-stages III-IV may be due to more radical surgery. Patient selection criteria, not only the treatment modalities, may be responsible for the superior results reported in clinical trials. Cancer registries are important for evaluating the quality of healthcare delivery.

Aged↗
PubMed2002

Wrist arthrodesis: modified Gill's technique.

Twenty-five wrist arthrodesis procedures were performed on 24 patients, applying a modification of Gill's technique, which used a corticocancellous strut graft from the distal radius. Patients were followed up until solid bony fusion was established. Union was achieved in 21 of 25 wrists and was subsequently achieved with a further procedure in the remaining four wrists. We have found that the modified Gill's technique is a reliable, simple procedure with a low complication rate which does not require the harvest of a distant bone graft.

Adult↗
PubMed2002

[Risk predictors, scoring systems and prognostic models in anesthesia and intensive care. Part I: anesthesia].

Risk predictors and scoring systems are commonly used in medicine to provide a reliable and objective estimation of disease prognoses, probability of adverse events and outcome. Furthermore, they were designed to classify severity of illness or the course of diagnostic and therapeutic interventions and to perform a risk stratification for scientific studies in a standardized way. In quality management and cost control, scoring systems and predictors are used for risk adjustment and evaluation of care performance. The aim of this review article was to describe common risk indices and scoring systems in anesthesia (part I) and intensive care (part II), and to point out their possible benefits and limitations. Different scoring systems and classifications are available to stratify perioperative risk and adverse events in anesthesia. Especially in cardiac surgery, an increasing interest in risk-adjusted outcome studies led to the modeling and validation of different prognostic systems for postoperative morbidity, mortality and length of stay. Furthermore, there are scoring-systems for special events, such as difficult laryngoscopy or postoperative nausea and vomiting (PONV). Risk check lists and risk indices are superior to the ASA classification of physical status in providing more exact results and the possibility of statistic risk calculation. Nevertheless, they are not frequently used in clinical routine. Because of its simplicity and easy handling the ASA classification has worldwide popularity and recent studies demonstrated at least equal prognostic performance.

Anesthesia↗
PubMed2002

[Risk predictors, scoring systems and prognostic models in anesthesia and intensive care. Part II. Intensive Care].

The aim of the second part of this review article was to describe common scoring systems in intensive care, and to point out their possible benefits and limitations. Intensive care medicine multipurpose scoring-systems are currently used to estimate severity of illness, mortality and the amount of treatment required. Costs (only commercial available scores e.g. Acute Physiology and Chronic Health Evaluation [APACHE] III) and time needed for calculation have to be taken into consideration. Prognostic models of the third generation (APACHE III, Simplified Acute Physiology Score [SAPS] II, Mortality Prediction Model [MPM] II) should be preferred having better prognostic performance compared to scoring systems of prior generations. Although no prospective study exists comparing these three common scoring systems, it appears that all three systems are able to provide useful information to the clinician and researcher. These scoring systems were designed to classify severity of illness or the course of diagnostic and therapeutic interventions and to perform a risk stratification for scientific studies in a standardized way. In quality management and cost control, scoring systems and predictors are used for risk adjustment and evaluation of care performance.

APACHE↗
PubMed2001

Treatment of American cutaneous leishmaniasis with miltefosine, an oral agent.

There is no recognized oral treatment for American cutaneous leishmaniasis. A rising-dose, open-label phase I/II trial of the oral agent miltefosine against Colombian cutaneous leishmaniasis was conducted. Seventy-two male Colombian soldiers (mean weight, 67 kg) received miltefosine at 50-100 mg/day for 3 weeks (for 32 evaluable patients) or at 133-150 mg/day for 3-4 weeks (for 32 evaluable patients). The per-protocol cure rate for 50-100 mg/day was 21 (66%) of 32 patients. The per-protocol cure rate for 133-150 mg/day was 30 (94%) of 32 patients (P =.01, by use of Fisher's exact test). The historic per-protocol cure rate for standard injections of antimony is 93%. "Motion sickness" that did not interfere with normal duties was experienced by 40% of patients and was dose related. Vomiting and diarrhea were reported on approximately 2% of treatment days. In this uncontrolled study of oral miltefosine for treatment of patients with American cutaneous leishmaniasis, a dosage of approximately 2.25 mg/kg/day for 3-4 weeks was effective and tolerated.

Administration, Oral↗
PubMed2001

Sarcolipin, the shorter homologue of phospholamban, forms oligomeric structures in detergent micelles and in liposomes.

The human 31-amino acid integral membrane protein sarcolipin (SLN), which regulates the sarcoplasmic reticulum Ca-ATPase in fast-twitch skeletal muscle, was chemically synthesized. Appropriate synthesis and purification strategies were used to achieve high purity and satisfactory yields of this hydrophobic and poorly soluble protein. Structural and functional properties of SLN were analyzed and compared with the homologous region of human phospholamban (PLB) comprising residues Ala(24)-Leu(52) (PLB-(24-52)), the regulatory protein of the cardiac sarcoplasmic reticulum Ca-ATPase. Circular dichroism spectroscopy showed that SLN is a predominantly alpha-helical protein and that the secondary structure is highly resistant to SDS and thermal denaturation. In this respect SLN is remarkably similar to PLB-(24-52). However, SLN is monomeric in SDS gels, whereas PLB-(24-52) shows a monomer-pentamer equilibrium typical for native PLB. Analytical ultracentrifugation experiments revealed that SLN oligomerizes in the presence of the nonionic detergents octylpolyoxyethylene and octyl glucoside in a concentration-dependent manner. No plateau was observed, and a pentameric state was only reached at much higher protein concentrations compared with PLB-(24-52). Chemical cross-linking showed that also in liposomes SLN has the ability to self-associate to oligomers. PLB-(24-52) specifically oligomerized to pentamers in the presence of octylpolyoxyethylene as well as in liposomes at low protein concentrations. In the presence of octylpolyoxyethylene pentamers were the main oligomeric species, whereas in liposomes monomers and dimers were predominant. Increasing the protein concentration led to self-association of PLB-(24-52) pentamers in the presence of octylpolyoxyethylene. Functional reconstitution of Ca-ATPase with PLB-(24-52) and SLN in liposomes showed that both proteins regulate the Ca-ATPase in a similar manner.

Amino Acid Sequence↗
PubMed2001

A switch in disulfide linkage during minicollagen assembly in Hydra nematocysts.

The smallest known collagens with only 14 Gly-X-Y repeats referred to as minicollagens are the main constituents of the capsule wall of nematocysts. These are explosive organelles found in Hydra, jellyfish, corals and other Cnidaria. Minicollagen-1 of Hydra recombinantly expressed in mammalian 293 cells contains disulfide bonds within its N- and C-terminal Cys-rich domains but no interchain cross-links. It is soluble and self-associates through non-covalent interactions to form 25-nm-long trimeric helical rod-like molecules. We have used a polyclonal antibody prepared against the recombinant protein to follow the maturation of minicollagens from soluble precursors present in the endoplasmic reticulum and post-Golgi vacuoles to the disulfide-linked insoluble assembly form of the wall. The switch from intra- to intermolecular disulfide bonds is associated with 'hardening' of the capsule wall and provides an explanation for its high tensile strength and elasticity. The process is comparable to disulfide reshuffling between the NC1 domains of collagen IV in mammalian basement membranes.

Amino Acid Sequence↗
PubMed2001

Stabilization of short collagen-like triple helices by protein engineering.

Recombinant expression of collagens and fragments of collagens is often difficult, as their biosynthesis requires specific post-translational enzymes, in particular prolyl 4-hydroxylase. Although the use of hydroxyproline-deficient variants offers one possibility to overcome this difficulty, these proteins usually differ markedly in stability when compared with the hydroxyproline-containing analogs. Here, we report a method to stabilize collagen-like peptides by fusing them to the N terminus of the bacteriophage T4 fibritin foldon domain. The isolated foldon domain and the chimeric protein (GlyProPro)(10)foldon were expressed in a soluble form in Escherichia coli. The recombinant proteins and the synthetic (ProProGly)(10) peptide were characterized by circular dichroism (CD) spectroscopy, differential scanning calorimetry, and analytical ultracentrifugation. We show that the foldon domain, which comprises only 27 amino acid residues, forms an obligatory trimer with a high degree of thermal stability. The CD thermal unfolding profiles recorded from foldon are monophasic and completely reversible upon cooling. Similar Van't Hoff and calorimertic enthalpy values of trimer formation indicated a cooperative all-or-none transition. As reported previously, (ProProGly)(10) peptides form collagen triple helices of only moderate stability. When fused to the foldon domain, however, triple helix formation of (GlyProPro)(10) is concentration independent, and the midpoint temperature of the triple helix unfolding is significantly increased. The stabilizing function of the trimeric foldon domain is explained by the close vicinity of its N termini, which induce a high local concentration in the range of 1 M for the C termini of the collagen-like-peptide. Collagen-foldon fusion proteins should be potentially useful to study receptor-collagen interactions.

Amino Acid Sequence↗
PubMed2001

Plasminogen-activator-inhibitor-1 4G/5G promoter polymorphism and prognosis of severely injured patients.

A single base pair insertion/deletion (4G/SG) promoter polymorphism in the plasminogen-activator-inhibitor-1 (PAI-1) gene is thought to play a part in prognosis after severe trauma. We investigated the relation between outcome of severe trauma, PAI-1 concentrations, and PAP-1 genotype in 61 patients who had been severely injured. 11 (58%) of 19 patients with genotype 4G/4G did not survive, whereas only eight (28%) of 29 patients with heterozygous genotype 4G/SG, and two (15%) of 13 patients with genotype 5G/5G died. The PAI-1 4G allele is associated with high concentrations of PAI-1 in plasma and a poor survival rate after severe trauma.

Alleles↗
PubMed2001

Synergistic growth inhibition of prostate cancer cells by 1 alpha,25 Dihydroxyvitamin D(3) and its 19-nor-hexafluoride analogs in combination with either sodium butyrate or trichostatin A.

Prostate cancer is a major cause of male cancer death. In vitro and in vivo data support a role for 1 alpha,25 Dihydroxyvitamin D(3) (1 alpha,25(OH)(2)D(3)) in regulating the growth and differentiation of the normal prostate gland yet prostate cancer cells appear significantly less sensitive to this action. Vitamin D(3) receptor (VDR) content or mutational status do not correlate clearly with the antiproliferative effects of 1 alpha,25(OH)(2)D(3) and therefore it is unclear why prostate cancer cell lines are significantly less sensitive to this action. We hypothesized that the antiproliferative responses of prostate cancer cells to 1 alpha,25(OH)(2)D(3) are suppressed by a process involving histone deacetylation. Sodium butyrate (NaB) and trichostatin A (TSA) are inhibitors of histone deacetylase (HDAC) activity. Low doses of NaB or TSA (300 microM and 15 nM respectively), which alone were relatively inactive, synergized with 1 alpha,25(OH)(2)D(3) in liquid and semi-solid agar to inhibit the growth of LNCaP, PC-3 and DU-145 prostate cancer cells. Still greater synergy was observed between vitamin D(3) hexafluoride analogs and either NaB or TSA. The mechanism appeared to involve neither the cyclin-dependent kinase inhibitor, p21((waf1/cip1)) nor cell cycle arrest, but rather induction of apoptosis. These data suggest that cells dysregulate the normal pro-apoptotic signals of 1 alpha,25(OH)(2)D(3) during prostate cancer development by a mechanism involving histone deacetylation. Combination therapy with potent vitamin D(3) analogs and clinically approved HDAC inhibitors may overcome this lesion and improve the treatment of both androgen-dependent and independent prostate cancer.

Antineoplastic Agents↗
PubMed2001

alpha 1D (Cav1.3) subunits can form l-type Ca2+ channels activating at negative voltages.

In cochlea inner hair cells (IHCs), L-type Ca(2+) channels (LTCCs) formed by alpha1D subunits (D-LTCCs) possess biophysical and pharmacological properties distinct from those of alpha1C containing C-LTCCs. We investigated to which extent these differences are determined by alpha1D itself by analyzing the biophysical and pharmacological properties of cloned human alpha1D splice variants in tsA-201 cells. Variant alpha1D(8A,) containing exon 8A sequence in repeat I, yielded alpha1D protein and L-type currents, whereas no intact protein and currents were observed after expression with exon 8B. In whole cell patch-clamp recordings (charge carrier 15-20 mm Ba(2+)), alpha1D(8A) - mediated currents activated at more negative voltages (activation threshold, -45.7 versus -31.5 mV, p < 0.05) and more rapidly (tau(act) for maximal inward currents 0.8 versus 2.3 ms; p < 0.05) than currents mediated by rabbit alpha1C. Inactivation during depolarizing pulses was slower than for alpha1C (current inactivation after 5-s depolarizations by 90 versus 99%, p < 0.05) but faster than for LTCCs in IHCs. The sensitivity for the dihydropyridine (DHP) L-type channel blocker isradipine was 8.5-fold lower than for alpha1C. Radioligand binding experiments revealed that this was not due to a lower affinity for the DHP binding pocket, suggesting that differences in the voltage-dependence of DHP block account for decreased sensitivity of D-LTCCs. Our experiments show that alpha1D(8A) subunits can form slowly inactivating LTCCs activating at more negative voltages than alpha1C. These properties should allow D-LTCCs to control physiological processes, such as diastolic depolarization in sinoatrial node cells, neurotransmitter release in IHCs and neuronal excitability.

Amino Acid Sequence↗
PubMed2001

[A model for primary and secondary metastasis in breast cancer and the clinical consequences].

BACKGROUND: An adjuvant locoregional radiotherapy after radical surgery results in a survival advantage for breast cancer patients. The advantage starts with a delay and reaches about 10% 15 years after diagnosis. What could explain such a delayed efficacy? METHODS: A population-based cohort from 1996 to 1998 and the Munich Cancer Registry with courses of breast cancer disease since 1977 are the empirical basis. The analysis concerns survival rates and survival times in respect to metastases, local and lymph node recurrencies. A metastatic model is derived from the data. RESULTS: A cohort of 9,347 patients with a mean follow-up of 6.5 years and 2,587 courses with metastases and/or local recurrencies were registered. The overall survival after 15 years was for pT1 57.6%, pT2 37.9%, pT3 24.4% and for pT4 10.5%. Five years after metastasization 20.1 to 12.4% survived, 10 years 6% independent on pT. Ten years after local recurrencies the survival was dependent on pT of the primary tumor: pT1 36.3%, pT2 21.0%, pT3 13.1% und pT4 4.6%. A local recurrency is a prognostic factor for metastasization of the primary tumor, but local recurrencies can also cause metastases. The mean survival time after metastasization of the primary pT1 tumor is estimated about 61 months, after metastasization by local recurrencies about 99 months with a mean time to local recurrencies of 38 months. Further results of the metastatic model are: the development of metastasization is homogeneous and independent on pT-category, the metastatic initiation starts up to 5 years before diagnosis, metastatic-free survival time and progression survival time are independent and an impact of lymph node recurrencies on survival could not be detected. CONCLUSIONS: The reduction of local recurrencies by high-quality primary therapy with radiotherapy and also the early detection of local recurrencies may reduce secondary metastasization and therefore improve survival. The metastasization model also explains the limitation of the therapeutical strategies and the almost mandatory chance of early detection programs of breast cancer.

Aged↗
PubMed2001

The surgical discharge summary: a lack of substantial clinical information may affect the postop treatment of rectal cancer patients.

BACKGROUND AND AIMS: The discharge summary is crucial for patient aftercare as it is the main document for communicating information on patient data between the hospital and the primary care practitioner. The aim of this study was to assess the completeness of hospital discharge summaries and to determine whether the inclusion or omission of specific items of clinical information may affect further patient care. PATIENTS/METHODS: A population based cohort study including patients with rectal cancer from April 1996 through March 1998 in the Munich region. Five hundred and thirty-seven discharge summaries were evaluated for completeness of clinical- and tumor-related information. In addition, the association between recommendation for (discharge summary) and initiation of adjuvant therapy after discharge was evaluated. RESULTS: Information about T and N category was given in 98%, about metastasis in 90%, and about residual tumor in 73% of all discharge summaries. Follow-up was recommended in only 68% of the summaries. No adjuvant therapy was administered to 5/5 patients with N+, T1/2 tumors nor to 14/17 patients with N+, T3/4 tumors if correspondent recommendations were missing. CONCLUSION: Lack of crucial information in surgical discharge summaries is not only surprisingly common, but may also negatively affect patient aftercare.

Cohort Studies↗
PubMed2001

Development status of miltefosine as first oral drug in visceral and cutaneous leishmaniasis.

An oral treatment for visceral and cutaneous leishmaniasis has been searched for over the last decades. An oral drug would facilitate treatment and lower costs. Oral miltefosine (Zentaris/ASTA Medica AG, Germany), an alkylphosphocholine, is under clinical development for treatment of leishmaniasis. Phase I, II and III clinical trials have been performed in visceral leishmaniasis in India; the overall response rate with 100 mg/day over 4 weeks is 96%. A first clinical trial in New World cutaneous leishmaniasis has shown a final cure rate of 94% at a dose of 150 mg/day over 3 or 4 weeks. Side effects are mainly gastrointestinal (vomiting, diarrhoea). Furthermore, transient elevation of transaminases or urea/creatinine has been observed. The clinical results suggest that miltefosine is the first oral therapy that is effective and safe in visceral and cutaneous leishmaniasis.

Administration, Oral↗