[Implementation of Enhanced Recovery after Surgery (ERAS®) protocol in radical cystectomy at the University Medical Center Mainz]. / Implementierung des ERAS®-Protokolls (Enhanced Recovery After Surgery) nach radikaler Zystektomie an der Universitätsmedizin Mainz.

BACKGROUND: In surgical fields there has been a perceivable paradigm shift during the last decade concerning patient pre- and rehabilitation. Current literature suggests close interdisciplinary collaboration after complex procedures such as radical cystectomy in order to optimize perioperative patient care for the benefit of "fast-track" surgery. OBJECTIVES: To compose a catalogue of standardized measures after radical cystectomy based on guidelines set by the ERAS®-Society. RESULTS: The protocol commences with preoperative education in order to improve the physical and psychological condition of the patient. Crucial aspects in peri- and postoperative patient care are gentle surgical technique, adequate pain management, early mobilization and oral food intake, early removal of drains and foreign material and a seamless return to normal, daily life. CONCLUSIONS: Prospective data analysis will be the next step in order to establish the effectiveness of the protocol especially regarding postoperative complications and median duration of hospital stay.

[Patient-centered perioperative vigilance: perioperative process quality, effectiveness of pain treatment and mobilization progress after implementation of a treatment bundle for total knee endoprosthesis]. / Patient*innenzentrierte perioperative Versorgung: perioperative Prozessqualität, Effektivität von Schmerztherapie und Mobilisationsfortschritt nach Implementation eines Maßnahmenbündels bei Knietotalendoprothese.

BACKGROUND: The perioperative surgical home is a patient-centered, team-based model of care developed in the USA to coordinate diagnosis, treatment and follow-up; however, due to different healthcare systems, scientific findings in the USA cannot be simply transferred to Germany. OBJECTIVE: This preliminary study was carried out to evaluate the effects of a new interdisciplinary treatment bundle (patient-centered perioperative vigilance, PPV) in a German university hospital. MATERIAL AND METHODS: After IRB approval and written informed consent, 34 patients (PPV group) undergoing elective endoprosthetic surgery were enrolled after introduction of the PPV bundle (1. preoperative patient education, 2. specific surgical technique, 3. specific anesthesia technique, 4. start of mobilization on day of operation) and compared to historic matched pairs (HMP) for age cohort, ASA-PS, body mass index, and sex. We hypothesized that PPV shortens induction time (primary outcome). Secondary outcomes were length of hospital stay (LOS), resting pain and pain with movement on postoperative day 1 and mobilization progress on postoperative days 1, 3 and 6. Groups were compared with Wilcoxon-Mann-Whitney test for noninferiority. In the case of noninferiority, a Wilcoxon-Whitney-Mann test for superiority was additionally applied. RESULTS: The median anesthesia induction time was 13.5 min for PPV and 60 min for HMP (p < 0.0001). The LOS was 8 days for PPV and 12 days for HMP (p < 0.0001). Resting pain on postoperative day 1 was 20 for PPV (30 for HMP). Pain with movement was identical (median 40). Mobilization progress was better for PPV on days 1, 3 and 6 (p < 0.0001 for each day). CONCLUSION: The concept of patient-centered perioperative vigilance (PPV) shortens induction time and hospital length of stay. Mobilization improves with PPV on day 1. Higher pain scores in PPV seem to be clinically insignificant, which warrants further study.

[Validation of Subjective Estimates of Female Breast Volume and Comparison with Objective Methods]. / Validierung subjektiver Schätzungen des weiblichen Brustvolumen und Vergleich zur objektiven Methode.

INTRODUCTION: To date it remains unclear how well we are doing in subjectively judging breast volume. METHOD: 2 experienced female examiners reviewed images of 88 female breasts and estimated breast volumes. The "true" breast volumes were previously objectively obtained by breast analysis tool (BAT) software. Tests were repeated, and Bland/Altman statistics were utilised. RESULTS: Mean breast volume was at 419±274 cc statistically significantly larger by 59, respectively, 75 cc than estimated breast volume by the 2 examiners. The comparison of the first and second repeated test of subjective estimation of breast volumes revealed a correlation coefficient R of about 0.92 (p<0.001) while the same comparison for the BAT measurements provided a close to perfect correlation coefficient of R>0.99 (p<0.001). With increasing volumes the repeated estimations became less reliable, not so the BAT measurements. Small breast volumes were estimated as too large and large breast volumes were estimated as too small by the examiners and the connection was nearly perfectly linear. The correlation coefficient R between estimations and measurements was lower at 0.86 than in the repeated tests and estimations showed some considerable deviations in individual cases. CONCLUSION: Subjective breast assessments underestimated breast volumes by around 70 cc, with some deviations. Breast volume determination was less reproducible by subjective estimation than by objective measurement with BAT software. With increasing breast volumes the error of the subjective estimations in the repeated tests as well as in comparison to the BAT data increased, not so the error of the BAT data. Small breast volumes were overestimated and large volumes underestimated with some considerable individual deviations. There was a good reliability of the objective measurements without much systematic error, however only limited validity of the subjective method.

Treatment of Giant Fibroadenoma in Young Women: Results after Tumor Excision without Reconstructive Surgery.

Introduction: Giant fibroadenoma (GFA) of the breast is defined as fibroadenoma larger than 5 cm, usually presenting unilaterally and manifesting as breast asymmetry or deformity of the breast. Material and Methods: A retrospective database search was done of all patients with giant fibroadenoma who underwent surgery for GFA in the breast center of Hanover Medical School between 2007 and 2014; all patients with GFA were followed up. Data were analyzed with regard to tumor and patient characteristics and esthetic outcome. Results: A total of 13 patients with symptomatic GFA underwent surgery between 2007 and 2014. Mean patient age was 21.2 years (range 14-31 years). In 8 of 13 patients the tumor had resulted in breast deformity and/or breast asymmetry. Average size of the mass was 10.2 cm (range 8.5-12 cm) and average weight was 203.6 g (range 151.2-323.5 g). Initial clinical suspicion of GFA was confirmed by ultrasound examination. Preoperative core biopsy revealed fibroadenoma in 8/13 cases, cellular fibroepithelial lesions with a differential diagnosis of benign phyllodes tumor in 3 cases and unspecific histological findings in the remaining 2 cases. Conclusion: Excision was done using an inframammary or periareolar approach without reconstructive plasty. The cosmetic results were good, as were the outcomes on follow-up. We therefore favor this surgical technique to treat giant fibroadenoma of similar size to those described above.

Increasing Liability Premiums in Obstetrics - Analysis, Effects and Options.

Whenever people act, mistakes are made. In Germany, it is thought that a total of 40 000 cases of malpractice occur per year. In recent years, costs for liability insurance have risen significantly in almost all spheres of medicine as a whole. Liability in the health care sector is founded on the contractual relationship between doctor and patient. Most recently, case law developed over many years has been codified with the Patients' Rights Act. In obstetrics, the focus of liability law is on brain damage caused by hypoxia or ischemia as a result of management errors during birth. The costs per claim are made up of various components together with different shares of damage costs (increased needs, in particular therapy costs and nursing fees, acquisition damage, treatment costs, compensation). In obstetrics in particular, recent focus has been on massively increased liability payments, also accompanied by higher liability premiums. This causes considerable financial burdens on hospitals as well as on midwives and attending physicians. The premiums are so high, especially for midwives and attending physicians, that professional practice becomes uneconomical in some cases. In recent years, these circumstances have also been intensely debated in the public sphere and in politics. However, the focus here is on the occupation of midwife. In 2014, in the GKV-FQWG (Statutory Health Insurance - Quality and Further Development Act), a subsidy towards the occupational liability premium was defined for midwives who only attended a few deliveries. However, to date, a complete solution to the problem has not been found. A birth will never be a fully controllable risk, but in rare cases will always end with injury to the child. The goal must be to minimise this risk, through good education and continuous training, as well as constant critical analysis of one's own activities. Furthermore, it seems sensible, especially in non-clinical Obstetrics, to look at the current study data more closely. Among the many solutions which have been proposed, such as the development of quality management, risk management and prevention, better remuneration, a waiver on recourse claims by social insurance underwriters, a cap on damage costs of liability insurers, state liability, an indemnity fund, a system change to Medical Treatment Risk Insurance, as well as a discussion on whether or not it makes sense to use non-clinical obstetrics for the prevention of a further increase in premiums, not one stands out as being especially convincing. On the contrary, a meaningful coordination of various concepts should follow. What seems sensible is a higher remuneration per birth, taking into account the liability premiums as well as, in the medium term, the establishment of a liability fund which, from a certain limit upwards, steps in as liable third party.

Breast reconstruction and revision surgery for implant-associated breast deformities using porcine acellular dermal matrix: a multicenter study of 156 cases.

BACKGROUND: Acellular dermal matrix is increasingly used as caudolateral coverage for breast implants in immediate breast reconstruction after skin-sparing mastectomy or in the correction of implant-associated breast deformities. Matrices of human, bovine, and porcine origin are available. The purpose of this retrospective multicenter study was to report experiences with porcine acellular dermal matrices, as only limited data can be found in the literature. METHODS: In the hospital databases of five institutions, 127 patients were identified who underwent breast reconstructions in 156 breasts using an acellular porcine dermal matrix. Medical records were reviewed. Patients were divided into three groups: immediate expander-implant or direct to implant reconstructions (n = 98), delayed expander-implant reconstructions (n = 14), and revision surgery for implant-associated breast deformities (n = 44). RESULTS: With a mean follow-up of 19.6 months, total major complication rate was 7.1 %: implant loss (3.2 %), skin flap necrosis (2.6 %), delayed skin healing (2.6 %), hematoma (1.9 %), seroma (1.3 %), infection (0.6 %), and capsular contracture (0.6 %). Total minor complication rate was 22.9 %, with seroma being the most frequent complication (19.2 %). In the group of immediate breast reconstructions, 20.4 % of the breasts had received radiotherapy in the past. These patients exhibited a significantly higher rate of seroma than patients without prior radiotherapy (35.0 vs. 14.9 %, p = 0.031). CONCLUSIONS: Complication rates using porcine acellular dermal matrix in breast reconstruction are comparable to complication rates reported in studies using human acellular dermal matrices. Thus, porcine acellular dermal matrices can safely be applied in breast reconstructive surgery.

[Papillary lesions of the breast]. / Papilläre Läsionen der Mamma.

Papillary lesions of the breast encompass a spectrum of both benign and malignant lesions despite sharing a similar basic architecture. A reliable distinction between the different entities is possible even in biopsies with precise knowledge of the diagnostic criteria and using immunohistochemistry as a diagnostic adjunct. These include papilloma, papillary ductal carcinoma in situ, encapsulated papillary carcinoma and solid papillary carcinoma. Architectural features, cellular composition and distribution of myoepithelial cells as highlighted by immunohistochemistry are the major diagnostic criteria. In this review the most useful morphological and immunohistochemical criteria for routine diagnostic practice are presented.

Dihydroxythiophenes are novel potent inhibitors of human immunodeficiency virus integrase with a diketo acid-like pharmacophore.

We have identified dihydroxythiophenes (DHT) as a novel series of human immunodeficiency virus type 1 (HIV-1) integrase inhibitors with broad antiviral activities against different HIV isolates in vitro. DHT were discovered in a biochemical integrase high-throughput screen searching for inhibitors of the strand transfer reaction of HIV-1 integrase. DHT are selective inhibitors of integrase that do not interfere with virus entry, as shown by the inhibition of a vesicular stomatitis virus G-pseudotyped retroviral system. Moreover, in quantitative real-time PCR experiments, no effect on the synthesis of viral cDNA could be detected but rather an increase in the accumulation of 2-long-terminal-repeat cycles was detected. This suggests that the integration of viral cDNA is blocked. Molecular modeling and the structure activity relationship of DHT demonstrate that our compound fits into a two-metal-binding motif that has been suggested as the essential pharmacophore for diketo acid (DKA)-like strand transfer inhibitors (Grobler et al., Proc. Natl. Acad. Sci. USA 99:6661-6666, 2002.). This notion is supported by the profiling of DHT on retroviral vectors carrying published resistance mutations for DKA-like inhibitors where DHT showed partial cross-resistance. This suggests that DHT bind to a common site in the catalytic center of integrase, albeit with an altered binding mode. Taken together, our findings indicate that DHT are novel selective strand transfer inhibitors of integrase with a pharmacophore homologous to DKA-like inhibitors.

[BWS-mobility in patients with an impingement syndrome compared to healthy subjects--an inclinometric study]. / Die BWS-Beweglichkeit von Impingementpatienten im Vergleich zu Gesunden -- eine inklinometrische Studie.

AIM: The aim of this study was to analyse the relation between the mobility of the thoracic spine and an impingement syndrome of the shoulder. METHOD: In a prospective study, 50 patients with an impingement syndrome and 50 healthy test subjects were examined for the mobility of their thoracic spines. All patients and test subjects were examined according to a standardized protocol. The experiments were carried out in the biomechanical laboratory of our clinic with the Plurimetercompass and the Inclinometer of Rippstein. RESULTS: In 23 patients a tendinosis calcarea was diagnosed radiologically, 27 patients suffered from a plain impingement without calcification, hence both groups were analyzed separately. The mobility of the thoracic spine in the sagittal and frontal planes and in rotation was significantly different between the three groups. The highest mobility was found in the healthy test subjects, the lowest in patients with a plain impingement. No differences were found concerning the initial posture of the thoracic spine. CONCLUSION: There is a relation between mobility of the thoracic spine and an impingement syndrome. This should be respected in diagnosis and therapy.

Role of STAT3 and PI 3-kinase/Akt in mediating the survival actions of cytokines on sensory neurons.

The binding of cytokines to the gp130 receptor activates the STAT3, MEK/MAPK, and PI3K/Akt signalling pathways. To assess the relative importance of these pathways in promoting the survival of cytokine-dependent neurons, we conditionally inactivated STAT3 in mice and inhibited MEK, PI3K, and Akt in cultured neurons using pharmacological reagents and by expressing specific inhibitory proteins. Inactivation of STAT3 enhanced the death of the cytokine-dependent sensory neurons of the nodose ganglion in vivo and substantially reduced the response of these neurons to CNTF and LIF in vitro. LY294002, an inhibitor of PI3K, but not PD98059, an inhibitor of MEK, markedly reduced the response of these neurons to CNTF, as did dominant-negative PI3K, dominant-negative Akt, and overexpression of Ruk (a natural PI3K inhibitor). These results demonstrate that STAT3 and PI3K/Akt signalling play major roles in mediating the survival response of neurons to cytokines.

[Function of back extensor muscles in upright standing position and during sitting with identical back posture--an electromyography study]. / Die Aktivität der Rückenstreckmuskulatur beim aufrechten Stehen und beim Sitzen mit standidentischer Rumpfhaltung--eine elektromyographische Studie.

PROBLEM: There is a controversial discussion about the loading of the spine by the force of the extending muscles of the back in upright sitting with the back curved as in upright standing. Experimental studies investigating this issue are still lacking. METHODS: In the study presented in this paper we measured in 30 subjects the activity of the extending back muscles both in a natural upright standing posture and in sitting with identical posture of the back as recommended in some back training programs. To this end we recorded the electromyographical surface activity of the back muscles at four levels of the spine in both postures. The EMG activities were intraindividually normalized with reference to the respective activity recorded at maximum voluntary isometric contraction (MVC). RESULTS: At three of the four levels of the spine examined, the group averages of the EMG activity in sitting were significantly higher than in standing (p < 0.001). The maximum activity enhancement evaluated was 48% at Th12. The force of the lower back muscles in sitting with a posture of the back as in natural upright standing could be estimated to be at least greater than 30% of the force at MVC. CONCLUSION: The force needed to enforce in sitting a posture of the back identical to the posture at natural standing entails lower back muscle fatigue in a few minutes. The results of our study agree with recent experimental findings about an increased loading of the spine in lordotic sitting.

Chronic lateral epicondylitis of the elbow: A prospective study of low-energy shockwave therapy and low-energy shockwave therapy plus manual therapy of the cervical spine.

OBJECTIVE: To compare the effects of extracorporeal shockwave therapy (ESWT) alone with a combination of ESWT and manual therapy of the cervical spine in treating chronic tennis elbow. DESIGN: Prospective, matched single-blind control trial. SETTING: University hospital clinic. PATIENTS: Thirty patients with unilateral chronic tennis elbow, an unsuccessful conservative therapy during the 6 months before referral, and clinical signs of cervical dysfunction (eg, pressure pain at the C4-5 and/or C5-6 level, protraction of the head). INTERVENTIONS: Three times at weekly intervals all patients received 1000 shockwave impulses of an energy flux density of.16mJ/mm(2) at the lateral elbow. Additionally, they underwent manual therapy of the cervical spine and the cervicothoracic junction 10 times (group I). For each patient, a control matched by age (3-yr range) and gender at first conservative treatment was drawn at random from 127 patients who had undergone low-energy shockwave therapy in the same unit in the past 3 years (group II). Follow-up examinations took place at 12 weeks and at 12 months. MAIN OUTCOME MEASURES: The Roles and Maudsley outcome score at 12 months, defining an excellent or good result with no or only occasional discomfort without limitation of activity and range of motion. RESULTS: Neither group differed statistically before the study, with a poor rating for all patients (p >.05). At 12 months, there was still no significant difference, with the outcome being excellent or good in 56% in group I, and in 60% in group II (p >.05). Each group showed significant improvement compared with the respective prestudy evaluation (p <.0001). CONCLUSION: ESWT may be an effective conservative treatment method for unilateral chronic tennis elbow. The efficacy of additional cervical manual therapy for lateral epicondylitis remains questionable.

Mice reconstituted with DNA polymerase beta-deficient fetal liver cells are able to mount a T cell-dependent immune response and mutate their Ig genes normally.

The ubiquitously expressed, error-prone DNA polymerase beta (polbeta) plays a role in base excision repair, and the involvement of this molecule in the nonhomologous end joining (NHEJ) process of DNA repair has recently been demonstrated in yeast. Polbeta-deficient mice are not viable, and studies on conditional mutants revealed a competitive disadvantage of polbeta(-/-) vs. wild-type cells. We show here that polbeta-deficient mice survive up to day 18.5 postcoitum, but die perinatally; a circumstance that allowed the investigation of a potential role of polbeta in lymphocyte development by transfer of fetal liver cells (FLC) derived from polbeta(-/-) embryos into lethally irradiated hosts. FLC transfers using mutant cells lead to an almost normal reconstitution of the lymphocyte compartment, indicating that polbeta-deficiency does not prevent V(D)J recombination, which is known to employ factors of the NHEJ pathway. Mice reconstituted with polbeta(-/-) FLC mount a normal T cell-dependent immune response against the hapten (4-hydroxy-3-nitrophenyl) acetyl (NP). Moreover, germinal center B cells from NP-immunized reconstituted mice show normal levels and patterns of somatic point mutations in their rearranged antibody genes, demonstrating that polbeta is not critically involved in somatic hypermutation.

Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress.

Biomechanical stress is a major stimulus for cardiac hypertrophy and the transition to heart failure. By generating mice that harbor a ventricular restricted knockout of the gp130 cytokine receptor via Cre-IoxP-mediated recombination, we demonstrate a critical role for a gp130-dependent myocyte survival pathway in the transition to heart failure. Such conditional mutant mice have normal cardiac structure and function, but during aortic pressure overload, these mice display rapid onset of dilated cardiomyopathy and massive induction of myocyte apoptosis versus the control mice that exhibit compensatory hypertrophy. Thus, cardiac myocyte apoptosis is a critical point in the transition between compensatory cardiac hypertrophy and heart failure. gp130-dependent cytokines may represent a novel therapeutic strategy for preventing in vivo heart failure.

Postnatally induced inactivation of gp130 in mice results in neurological, cardiac, hematopoietic, immunological, hepatic, and pulmonary defects.

The pleiotrophic but overlapping functions of the cytokine family that includes interleukin (IL)-6, IL-11, leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, and cardiotrophin 1 are mediated by the cytokine receptor subunit gp130 as the common signal transducer. Although mice lacking individual members of this family display only mild phenotypes, animals lacking gp130 are not viable. To assess the collective role of this cytokine family, we inducibly inactivated gp130 via Cre-loxP-mediated recombination in vivo. Such conditional mutant mice exhibited neurological, cardiac, hematopoietic, immunological, hepatic, and pulmonary defects, demonstrating the widespread importance of gp130-dependent cytokines.

Regulated expression of gp130 and IL-6 receptor alpha chain in T cell maturation and activation.

The functional receptor for the inflammatory cytokine IL-6 is composed of the ligand binding IL-6 receptor alpha chain (IL-6R alpha) and the signal transducing chain gp130, which is a shared component of multiple cytokine receptors. We analyzed the surface expression of gp130 and IL-6R alpha in thymocytes and peripheral T cells. While all thymocytes expressed gp130 throughout thymic maturation, they gained expression of IL-6R alpha at the CD4 or CD8 single-positive stage. Approximately 10-30% of the CD4-CD8+ and 40-50% of the CD4+CD8- thymocytes expressed IL-6R alpha. Within the CD4+CD8- population, the IL-6R alpha- subpopulation was cortisone sensitive, appeared immature according to the cell surface markers expressed and failed to proliferate after TCR cross-linking. Peripheral T cells were predominantly gp130+ and IL-6R alpha+, but down-regulated gp130 and IL-6R alpha expression upon TCR engagement in vitro and in vivo. Peripheral gp130low/-IL-6R alphalow/- T cells expressed surface markers characteristic of memory T cells. We show that gp130 and IL-6R alpha are expressed in a regulated manner in T cells, depending on the developmental and functional stage.

Bypass of lethality with mosaic mice generated by Cre-loxP-mediated recombination.

BACKGROUND: The analysis of gene function based on the generation of mutant mice by homologous recombination in embryonic stem cells is limited if gene disruption results in embryonic lethality. Mosaic mice, which contain a certain proportion of mutant cells in all organs, allow lethality to be circumvented and the potential of mutant cells to contribute to different cell lineages to be analyzed. To generate mosaic animals, we used the bacteriophage P1-derived Cre-loxP recombination system, which allows gene alteration by Cre-mediated deletion of loxP-flanked gene segments. RESULTS: We generated nestin-cre transgenic mouse lines, which expressed the Cre recombinase under the control of the rat nestin promoter and its second intron enhancer. In crosses to animals carrying a loxP-flanked target gene, partial deletion of the loxP-flanked allele occurred before day 10.5 post coitum and was detectable in all adult organs examined, including germ-line cells. Using this approach, we generated mosaic mice containing cells deficient in the gamma-chain of the interleukin-2 receptor (IL-2R gamma); in these animals, the IL-2R gamma-deficient cells were underrepresented in the thymus and spleen. Because mice deficient in DNA polymerase beta die perinatally, we studied the effects of DNA polymerase beta deficiency in mosaic animals. We found that some of the mosaic polymerase beta-deficient animals were viable, but were often reduced in size and weight. The fraction of DNA polymerase beta-deficient cells in mosaic embryos decreased during embryonic development, presumably because wild-type cells had a competitive advantage. CONCLUSIONS: The nestin-cre transgenic mice can be used to generate mosaic animals in which target genes are mutated by Cre-mediated recombination of loxP-flanked target genes. By using mosaic animals, embryonic lethality can be bypassed and cell lineages for whose development a given target gene is critical can be identified. In the case of DNA polymerase beta, deficient cells are already selected against during embryonic development, demonstrating the general importance of this protein in multiple cell types.

Major histocompatibility complex class I genes of the coelacanth Latimeria chalumnae.

The coelacanth fish Latimeria chalumnae is the sole surviving species of a phylogenetic lineage that was founded more than 400 million years ago and that has changed morphologically very little since that time. Little is known about the molecular evolution of this "living fossil," considered by some taxonomists to be the closest living relative of tetrapods. Here we describe the isolation and characterization of L. chalumnae major histocompatibility complex (MHC) class I genes. The exon-intron organization of these genes is the same as that of their mammalian counterparts. The genes fall into four families, which we designate Lach-UA through Lach-UD. There are multiple loci in all of the families. Genes of the first two families are transcribed. The Lach-UA family bears the characteristics of functional, polymorphic class I genes; the other three families may be represented by nonclassical genes. All the Lach loci arose by duplication from an ancestral gene after the foundation of the coelacanth lineage. Intergenic variation is highest at positions corresponding to the mammalian peptide-binding region. The closest relatives of the Lach genes among the MHC genes sequenced thus far are those of the amphibian Xenopus.