Cardiopulmonary and cerebrovascular acclimatization in children and adults at 3800 m.

Maturational differences exist in cardiopulmonary and cerebrovascular function at sea-level, but the impact of maturation on acclimatization responses to high altitude is unknown. Ten children (9.8 ± 2.5 years) and 10 adults (34.7 ± 7.1 years) were assessed at sea-level (BL), 3000 m and twice over 4 days at 3800 m (B1, B4). Measurements included minute ventilation ( V ̇ E ${\dot{V}}_{\rm{E}}$ ), end-tidal partial pressures of oxygen ( P ETO 2 ${P}_{{\rm{ETO}}_{\rm{2}}}$ ) and carbon dioxide, echocardiographic assessment of pulmonary artery systolic pressure (PASP) and stroke volume (SV) and ultrasound assessment of blood flow through the internal carotid and vertebral arteries was performed to calculate global cerebral blood flow (gCBF). At 3000 m, V ̇ E ${\dot{V}}_{\rm{E}}$ was increased from BL by 19.6 ± 19.1% (P = 0.031) in children, but not in adults (P = 0.835); SV was reduced in children (-11 ± 13%, P = 0.020) but not adults (P = 0.827), which was compensated for by a larger increase in heart rate in children (+26 beats min-1 vs. +13 beats min-1 , P = 0.019). Between B1 and B4, adults increased V ̇ E ${\dot{V}}_{\rm{E}}$ by 38.5 ± 34.7% (P = 0.006), while V ̇ E ${\dot{V}}_{\rm{E}}$ did not increase further in children. The rise in PASP was not different between groups; however, ∆PASP from BL was related to ∆ P ETO 2 ${P}_{{\rm{ETO}}_{\rm{2}}}$ in adults (R2  = 0.288, P = 0.022), but not children. At BL, gCBF was 43% higher in children than adults (P = 0.017), and this difference was maintained at high altitude, with a similar pattern and magnitude of change in gCBF between groups (P = 0.845). Despite V ̇ E ${\dot{V}}_{\rm{E}}$ increasing in children but not adults at a lower altitude, the pulmonary vascular and cerebrovascular responses to prolonged hypoxia are similar between children and adults. KEY POINTS: Children have different ventilatory and metabolic requirements from adults, which may present differently in the pulmonary and cerebral vasculature upon ascent to high altitude. Children (ages 7-14) and adults (ages 23-44) were brought from sea level to high altitude (3000 to 3800 m) and changes in ventilation, pulmonary artery systolic pressure (PASP) and cerebral blood flow (CBF) were assessed over 1 week. Significant increases in ventilation and decreases in left ventricle stroke volume were observed at a lower altitude in children than adults. PASP and CBF increased by a similar relative amount between children and adults at 3800 m. These results help us better understand age-related differences in compensatory responses to prolonged hypoxia in children, despite similar changes in pulmonary artery pressure and CBF between children and adults.

Schatzker II tibial plateau fractures: Anatomically precontoured locking compression plates seem to improve radiological and clinical outcomes.

INTRODUCTION: The design of anatomically precontoured locking compression plates (LCP) allows the placement of angular stable screws right underneath the reduced joint surface fragments. To date, there is a lack of evidence supporting the broad utilization of these implants in split depression fractures to the lateral tibial plateau. Thus, aim of the present matched pair retrospective cohort study was to investigate the radiological and clinical outcomes of anatomically precontoured LCP compared to conventional plate and screw osteosynthesis in Schatzker II fractures. MATERIAL AND METHODS: The institutional databank was searched for Schatzker II fractures from 2010 to 2016. Patients that underwent open reduction and internal fixation with anatomically precontoured 3.5 mm LCP or conventional 4.5 mm l-shaped plates and screws were included. CT scans and radiographs were analyzed. Details of the operative procedures and secondary events were collected. A matched pair analyses was conducted in a best fit manner. The primary outcome parameter was the Rasmussen Radiological Score approximately one year postoperatively. Secondary outcome parameters were the medial proximal tibial angle (MPTA), the Rasmussen Clinical Score and the WOMAC Score after a follow up of at least three years. RESULTS: A total of 50 patients was included. Patient age, gender distribution, size and depression depth of the lateral joint surface fragments, frequency of utilizing bone grafts or substitutes and lateral meniscus repair as well as subsequent implant removal were comparable across the groups. Immediately postoperatively, the Rasmussen Radiological Score revealed no differences. After a mean of 64.2 weeks, the radiological outcome was significantly better in the LCP 3.5 group (RRS 8.2 vs. 6.3 points, p<0.001; MPTA 89.5 vs. 92.0°, p = 0.001). After a mean clinical follow-up of 4.5 years, the Rasmussen Clinical Score (22.9 vs. 27.8 points, p<0.001) and the WOMAC score (24.3 vs. 16.0 points, p = 0.04) revealed significantly impaired results in the conventional group. CONCLUSION: Anatomically precontoured LCP prevent the subsidence of the reduced joint surface fragments more sufficiently and allow for improved patient outcomes compared to conventional plates and screws. The utilization of anatomically precontoured LCP should therefore closely be considered for internal fixation of any split depression fractures to the lateral tibial plateau.

Transfer and retention effects of gait training with anterior-posterior perturbations to postural responses after medio-lateral gait perturbations in older adults.

BACKGROUND: Gait perturbations, occurring in any direction in daily life, may result in a fall. In fall prevention, gait perturbation training is a promising approach. Treadmill perturbations in anterior-posterior direction can easily be applied by accelerations or decelerations of the belt, but it is unknown whether training effects transfer to reactive recovery in medio-lateral direction. We aimed to evaluate the transfer and retention effects of gait training with treadmill perturbations in anterior-posterior direction to medio-lateral reactive recovery. METHODS: 30 community dwelling older adults (>65 years) participated in this study. They were randomly assigned to a treadmill training session either with 16 anterior-posterior perturbations or with treadmill walking. The assessments contained a walking trial with 4 anterior-posterior and 4 medio-lateral perturbations. Deviations in trunk velocity from unperturbed walking were summed over the first three strides after perturbation as a measure of recovery. FINDINGS: An exposure to gait perturbations during the baseline assessment led to significant improvement of recovery responses. For anterior-posterior perturbations, both groups showed better recovery immediately and 1-week post-intervention, and no group x time interaction was found.. For medio-lateral perturbations, both groups showed better recovery immediately and 1-week post-intervention, and again no group × time interaction. INTERPRETATION: Baseline assessment with perturbations in anterior-posterior and medio-lateral directions caused significant improvements that were retained. Short-term training can be effective in dynamic stabilization of one's trunk, but our findings do not exclude that multi-directional perturbations may be needed.

Adaptation to Occupational Exposure to Moderate Endotoxin Concentrations: A Study in Sewage Treatment Plants in Germany.

Acute or chronic inhalation of endotoxin may lead to changes of lung function and inflammatory markers in the airways. Adaptation to workplace exposure may be possible. In this study, we investigated the possible difference in inflammatory markers assessed in nasal lavage fluid (NALF) in chronical exposure compared to voluntary subjects exposed acutely to endotoxin. We sought to define the variability of inflammatory markers in NALF and the dose-related changes after moderate exposure in naïve subjects. Endotoxin exposure (4-1039 EU/m3) resulted from routine work during one shift in sewage treatment plants. Subjects were matched to pairs (8 workers escorted by 10 students). Inflammatory markers were investigated before, directly after, and 16 h after the shift end. Additional NALF samples were collected in students without any specific exposure after 3 days. In NALF, total cell count, and interleukin (IL)-8 and IL-1ß concentrations were significantly higher in workers than in students at all times pointing to workplace-related long-lasting exposure resulting in adaptation. However, concentration of inflammatory markers without specific exposure in students showed a great variability, covering the whole range of values recorded in the workers. The findings of this study make us to recommend a repeated assessment of inflammatory markers in healthy volunteers before the investigation of exposure-related changes and a sample size adequate for statistical analysis.

[What do General Practitioners and Dentists Report about their Cooperation? A Qualitative Exploration]. / Was berichten Hausärzte und Zahnärzte über ihre Zusammenarbeit? Ergebnisse aus einer qualitativen Exploration.

OBJECTIVE: Against the background of well-described associations between oral and general health, the cooperation between general practitioners (GPs) and dentists is crucial. Besides treatment, this includes prevention. Administrative referral between these two professions is not provided by statute. Thus, the study addresses the question: How do dentists and GPs integrate the associations between oral and systemic health in daily routine? METHODS: A total of 28 semi-structured interviews were conducted with GPs and dentists from 3 structurally different regions in the Federal State of Baden-Wurttemberg. Participants were visited in their office. The interviews were recorded, transcribed and analysed by 2 dentists and sociologists using Mayrings' qualitative content analysis. RESULTS: Associations between general and oral health are partially known to both practitioners. However, contact between them is limited. GPs send patients directly to dentists, without contacting them - mainly due to a desolate dental status, rarely due to therapy-resistant headache or facial pain. Dentists contact GPs to clarify mainly medication or anticoagulation medications taken by patients prior to invasive procedures. Preventive aspects play a minor part. Consultation essentially depends on acquaintanceship. CONCLUSION: Separation by statute determines the cooperation. Oral cavity in daily care is demarcated. Holistic patient care is hindered by a lack of knowledge and daily routines.

Addition of rituximab to CHOP-like chemotherapy in first line treatment of primary mediastinal B-cell lymphoma.

BACKGROUND: The addition of rituximab (R) to CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) -like therapy has improved survival in primary mediastinal B-cell lymphoma (PMBCL) patients. However, these results were obtained in young low risk patients and a reevaluation in an unselected patient cohort is warranted. METHODS: In this study, we analyzed 80 PMBCL patients treated with a CHOP-based regimen with and without rituximab. RESULTS: In the non-rituximab cohort 10-year progression free survival (PFS) was 67% and 10-year overall survival (OS) was 72% versus a PFS of 95% and a OS of 92% in the rituximab group, PFS P = 0.001, OS P = 0.023. A subgroup PFS analysis by international prognostic index (IPI) risk revealed that all risk groups benefit from addition of rituximab to induction chemotherapy. In addition, OS probability was higher in the group of non-low risk patients who were treated with rituximab compared to those patients who did not receive rituximab (P = 0.035). In multivariate analysis, only addition of rituximab to induction chemotherapy and reaching complete remission (CR) after first line therapy had a beneficial effect on both PFS and OS, whereas IPI, age, upfront high dose (HD) chemotherapy/autologous blood stem cell transplantation (ABSCT) and rituximab maintenance had no impact on survival. CONCLUSIONS: Our data demonstrate a survival benefit in unselected PMBCL patients treated with CHOP-like induction regimen and additional rituximab independently of the IPI risk score.

The potential of eHealth in otorhinolaryngology-head and neck surgery: patients' perspectives.

The use of modern information and communication technologies (ICT) in daily life has significantly increased during the last several years. These essential online technologies have also found their way into the healthcare system. The use of modern ICT for health reasons can be summarized by the term 'eHealth'. Despite the potential importance of eHealth in the field of otorhinolaryngology (ORL), there is little understanding of patients' attitudes towards the deeper integration of these technologies into intersectoral care. The aim of this study was to gain a better understanding of patients' attitudes towards the use of modern ICT for intersectoral communication and information transfer in the field of ORL. Therefore, a structured interview was developed by an interdisciplinary team of otorhinolaryngologists, public health researchers, and information technology (IT) specialists. Overall, 211 ORL patients were interviewed at the Department of Otorhinolaryngology-Head and Neck Surgery, Tuebingen University Hospital, Germany, and 203 of these patients completed the interview. This study revealed ORL patients' perspectives on the potential of eHealth, especially for appointment scheduling, appointment reminders, and intersectoral communication of personal medical information. Furthermore, this study provides evidence that data security and the impacts of eHealth on the physician-patient relationship and on treatment quality warrant special attention in future research.

GvL effects in T-prolymphocytic leukemia: evidence from MRD kinetics and TCR repertoire analyses.

Allogeneic stem cell transplantation (alloSCT) is used for treating patients with T-prolymphocytic leukemia (T-PLL). However, direct evidence of GvL activity in T-PLL is lacking. We correlated minimal residual disease (MRD) kinetics with immune interventions and T-cell receptor (TCR) repertoire diversity alterations in patients after alloSCT for T-PLL. Longitudinal quantitative MRD monitoring was performed by clone-specific real-time PCR of TCR rearrangements (n=7), and TCR repertoire diversity assessment by next-generation sequencing (NGS; n=3) Although post-transplant immunomodulation (immunosuppression tapering or donor lymphocyte infusions) resulted in significant reduction (>1 log) of MRD levels in 7 of 10 occasions, durable MRD clearance was observed in only two patients. In all three patients analyzed by TCR-NGS, MRD responses were reproducibly associated with a shift from a clonal, T-PLL-driven profile to a polyclonal signature. Novel clonotypes that could explain a clonal GvL effect did not emerge. In conclusion, TCR-based MRD quantification appears to be a suitable tool for monitoring and guiding treatment interventions in T-PLL. The MRD responses to immune modulation observed here provide first molecular evidence for GvL activity in T-PLL which, however, may be often only transient and reliant on a poly-/oligoclonal rather than a monoclonal T-cell response.

Targeting expression to megakaryocytes and platelets by lineage-specific lentiviral vectors.

Essentials Platelet phenotypes can be modified by lentiviral transduction of hematopoietic stem cells. Megakaryocyte-specific lentiviral vectors were tested in vitro and in vivo for restricted expression. The glycoprotein 6 vector expressed almost exclusively in megakaryocytes. The platelet factor 4 vector was the strongest but with activity in hematopoietic stem cells. SUMMARY: Background Lentiviral transduction and transplantation of hematopoietic stem cells (HSCs) can be utilized to modify the phenotype of megakaryocytes and platelets. As the genetic modification in HSCs is transmitted onto all hematopoietic progenies, transgene expression from the vector should be restricted to megakaryocytes to avoid un-physiologic effects by ectopic transgene expression. This can be achieved by lentiviral vectors that control expression by lineage-specific promoters. Methods In this study, we introduced promoters of megakaryocyte/platelet-specific genes, namely human glycoprotein 6 (hGP6) and hGP9, into third generation lentiviral vectors and analyzed their functionality in vitro and in vivo in bone marrow transplantation assays. Their specificity and efficiency of expression was compared with lentiviral vectors utilizing the promoters of murine platelet factor 4 (mPf4) and hGP1BA, both with strong activity in megakaryocytes (MKs) used in earlier studies, and the ubiquitously expressing phosphoglycerate kinase (hPGK) and spleen focus forming virus (SFFV) enhancer/promoters. Results Expression from the mPf4 vector in MKs and platelets was the strongest similar to expression from the viral SFFV promoter, however, the mPf4 vector, also exhibited considerable off-target expression in hematopoietic stem and progenitor cells. In contrast, the newly generated hGP6 vector was highly specific to megakaryocytes and platelets. The specificity was also retained when reducing the promoter size to 350 bp, making it a valuable new tool for lentiviral expression in MKs/platelets. Conclusion MK-specific vectors express preferentially in the megakaryocyte lineage. These vectors can be applied to develop murine models to study megakaryocyte and platelet function, or for gene therapy targeting proteins to platelets.

Deficiency of RITA results in multiple mitotic defects by affecting microtubule dynamics.

Deregulation of mitotic microtubule (MT) dynamics results in defective spindle assembly and chromosome missegregation, leading further to chromosome instability, a hallmark of tumor cells. RBP-J interacting and tubulin-associated protein (RITA) has been identified as a negative regulator of the Notch signaling pathway. Intriguingly, deregulated RITA is involved in primary hepatocellular carcinoma and other malignant entities. We were interested in the potential molecular mechanisms behind its involvement. We show here that RITA binds to tubulin and localizes to various mitotic MT structures. RITA coats MTs and affects their structures in vitro as well as in vivo. Tumor cell lines deficient of RITA display increased acetylated α-tubulin, enhanced MT stability and reduced MT dynamics, accompanied by multiple mitotic defects, including chromosome misalignment and segregation errors. Re-expression of wild-type RITA, but not RITA Δtub ineffectively binding to tubulin, restores the phenotypes, suggesting that the role of RITA in MT modulation is mediated via its interaction with tubulin. Mechanistically, RITA interacts with tubulin/histone deacetylase 6 (HDAC6) and its suppression decreases the binding of the deacetylase HDAC6 to tubulin/MTs. Furthermore, the mitotic defects and increased MT stability are also observed in RITA-/- mouse embryonic fibroblasts. RITA has thus a novel role in modulating MT dynamics and its deregulation results in erroneous chromosome segregation, one of the major reasons for chromosome instability in tumor cells.

Do we still need autopsy in times of modern multislice computed tomography?-Missed diagnoses in the emergency room.

INTRODUCTION: In spite of increasing quality of emergency room (ER) assessment in trauma patients and improved accuracy of modern multislice computed tomography (MSCT), the number of potentially missed diagnoses is still controversial. The aim of this study was to compare the initial findings of ER assessment and MSCT to the findings during autopsy in trauma patients not surviving the first 48 h after admission. We hypothesized that autopsy was more accurate than MSCT in diagnosing potentially fatal diagnoses. PATIENTS AND METHODS: Between January 2004 and September 2007, all trauma patients undergoing ER treatment in our institution who deceased within 48 h after admission were analyzed regarding diagnoses from initial ER assessment, including MSCT, and diagnoses from autopsy. Data were prospectively collected and retrospectively analyzed. Autopsy reports were compared to diagnoses of ER assessment and MSCT. Missed diagnoses (MD) and missed potentially fatal diagnoses (MPFD) were analyzed. RESULTS: Seventy-three patients with a mean age of 53.2 years were included into the study. Sixty-three percent were male. Autopsy revealed at least one missed diagnosis in 25% of the patients, with the thoracic area accounting for 67% of these. At least one MPFD was found in 4.1% of the patients, all of them being located in the thorax. Total numbers of MD and MPFD were significantly lower for the newer CT generation (64 MSCT, N = 11), compared to older one (4 MSCT, N = 26). CONCLUSIONS: As determined by autopsy, modern multislice computed tomography is an accurate method to diagnose injuries. However, 25% of all diagnoses, and 4.1% of potentially fatal diagnoses are still missed in trauma patients, who deceased within the first 48 h after admission. Therefore, autopsy seems to be necessary to determine potentially missed diagnoses for both academic and medicolegal reasons as well as for quality control.

A phase I trial of the trifunctional anti Her2 × anti CD3 antibody ertumaxomab in patients with advanced solid tumors.

BACKGROUND: Ertumaxomab (ertu) is a bispecific, trifunctional antibody targeting Her2/neu, CD3 and the Fcγ-receptors I, IIa, and III forming a tri-cell complex between tumor cell, T cell and accessory cells. METHODS: Patients (pts) with Her2/neu (1+/SISH positive, 2+ and 3+) expressing tumors progressing after standard therapy were treated to investigate safety, tolerability and preliminary efficacy. In this study, ertu was applied i.v. in 2 cycles following a predefined dose escalating scheme. Each cycle consisted of five ascending doses (10-500 µg) applied weekly within 28 days with a 21 day treatment-free interval. If 2 pts experienced a dose limiting toxicity (DLT) at a given dose level, the maximum tolerated dose (MTD) had been exceeded. RESULTS: Fourteen heavily pretreated pts (e.g. breast, rectal, gastric cancer) were enrolled in the four main cohorts. Three (21 %) pts had to be replaced. Two serious adverse events (SAE) with possible relation to the investigational drug were seen, both fully reversible. A DLT was not detected. Consequently, the MTD could not be determined. All adverse events (AE) were transient and completely reversible. Most frequent AEs were fatigue (14/14), pain (13/14), cephalgia (12/14), chills (11/14), nausea (8/14), fever (7/14), emesis (7/14) and diarrhea (5/14). Single doses up to 300 µg were well tolerated (total dose up to 800 µg per cycle). We observed one partial remission and two disease stabilizations after first treatment cycle. CONCLUSIONS: Single doses up to 300 µg could be safely administered in an escalating dose scheme. Immunological responses and clinical activity warrant further evaluation in patients with Her2 over expressing tumors. TRIAL REGISTRATION: EudraCT number: 2011-003201-14; ClinicalTrials.gov identifier: NCT01569412.

Rediscovering the wound hematoma as a site of hemostasis during major arterial hemorrhage.

BACKGROUND: Treatments for major internal bleeding after injury include permissive hypotension to decrease the rate of blood loss, intravenous infusion of plasma or clotting factors to improve clot formation, and rapid surgical hemostasis or arterial embolization to control bleeding vessels. Yet, little is known regarding major internal arterial hemostasis, or how these commonly used treatments might influence hemostasis. OBJECTIVES: (i) To use a swine model of femoral artery bleeding to understand the perivascular hemostatic response to contained arterial hemorrhage. (ii) To directly confirm the association between hemodynamics and bleeding velocity. (iii) To observe the feasibility of delivering an activated clotting factor directly to internal sites of bleeding using a simplified angiographic approach. METHODS: Ultrasound was used to measure bleeding velocity and in vivo clot formation by elastography in a swine model of contained femoral artery bleeding with fluid resuscitation. A swine model of internal pelvic and axillary artery hemorrhage was also used to demonstrate the feasibility of local delivery of an activated clotting factor. RESULTS: In this model, clots formed slowly within the peri-wound hematoma, but eventually contained the bleeding. Central hemodynamics correlated positively with bleeding velocity. Infusion of recombinant human activated factor VII into the injured artery near the site of major internal hemorrhage in the pelvis and axillae was feasible. CONCLUSIONS: We rediscovered that clot formation within the peri-wound hematoma is an integral component of hemostasis and a feasible target for the treatment of major internal bleeding using activated clotting factors delivered using a simplified angiographic approach.

Allogeneic hematopoietic stem cell transplantation for poor-risk CLL: dissecting immune-modulating strategies for disease eradication and treatment of relapse.

To elucidate factors contributing to the effectiveness of allogeneic hematopoietic stem cell transplantation (alloHCT) in high-risk CLL, immune interventions, GvHD and clinical outcome of 77 consecutive patients allografted for CLL were analyzed. Immune modulation (immunosuppression tapering, rituximab-augmented donor lymphocyte infusions) was guided by minimal residual disease (MRD) monitoring and commenced at a median of 91 (22-273) days after alloHCT, resulting in a probability of being event free and MRD-negative 1 year after transplant of 57% (84% in those encountering chronic GvHD). Patients who were event free and MRD-negative at the 12-month landmark had a 4-year PFS of 77% and largely remained durably MRD-negative if MRD clearance had occurred subsequent to immune modulation. Three-year overall survival, PFS, relapse incidence and non-relapse mortality of all 77 patients were 69, 57, 26 and 24%, respectively. Survival was not affected by EBMT risk category but by active disease at alloHCT, which could not be overcome by intensification of conditioning. Twenty-three patients who experienced relapse post alloHCT had a survival of 56% at 2 years after CLL recurrence. In conclusion, MRD-guided immune modulation after alloHCT for high-risk CLL can provide durable MRD clearance in more than half of the patients.

[Psychosomatic Consultation in the Workplace--Description and Modelling of a New Health-Related Service]. / Psychosomatische Sprechstunde im Betrieb--Gestaltungsformen des Angebots.

GOAL OF THE STUDY: In Germany, mental disorders have increasing importance for disability and early retirement. However, patients may have to wait several months before becoming an appointment with a psycho(somatic) therapist. Accordingly, several companies initiated a "psychosomatic consultation in the workplace" (PCIW). This concept has been explored. METHODS: Qualitative data analysis (expert interviews with stakeholders, focus group interviews with occupational health physicians; Mayring's content analysis) focussed on the question of how the concept of a PCIW can be tailored to meet the employees' needs. RESULTS: Concepts and implementation of PCIW differed with regard to the aspects dissemination of information about the consultation, gatekeeping, place of the consultation, and number of appointments with the psycho(somatic) therapist. The concepts of PCIW may be described as more or less "restrictive" or "liberal". The interviewees emphasised the need for PCIW and discussed the involvement of the occupational health physician within this approach. PCIW proved of value. Yet, the interviewees were ambivalent regarding the fact that companies offer and pay for treatment which should be provided within standard health care. CONCLUSION: Shaping company-based elements of standard health care should respect setting-specific needs and involve in-company stakeholders into the process.

[Patient care at the interface between rehabilitation and occupational health physicians--a systematic literature review focusing health care organization]. / Patientenversorgung an der Schnittstelle von Rehabilitation und Betriebsärzten--Systematische Literaturübersicht zur Versorgungsgestaltung.

Principal goal of rehabilitation arrangements for patients in employable age are the preservation of the ability to work, the rehabilitation of employability and the prompt reintegration into the professional life respectively. In practice, the reintegration is achieving unsatisfactory results.The systematic literature research (acquisition period: 1998-2013) was conducted on the basis of defined search keywords in electronic databases, online archives, relevant German magazines (via manual search), and in bibliographies of selected publications. The definition of research results has taken place in consensus procedures on the tier of abstracts.Reasons for the unsatisfying reintegration quota are current temporary latencies and qualitative deficits of rehabilitation discharge reports, unsatisfying communication and cooperation between rehabilitation and company doctors, insufficient presence of company doctors, and trust issues between rehabilitant and company doctor among other things.The company doctors have an objective role as mediator based on their internal knowledge, competences and opportunities to influence, and they are awarded with a role as connecting piece on setting the course for rehabilitation.Since the currently available data are dissatisfactory concerning the medical interfaces in the rehabilitation process, despite the high thematically relevance, research activities should absolutely be intensified in this field of interest.

p21Waf1/Cip1 deficiency causes multiple mitotic defects in tumor cells.

As a multifaceted molecule, p21 plays multiple critical roles in cell cycle regulation, differentiation, apoptosis, DNA repair, senescence, aging and stem cell reprogramming. The important roles of p21 in the interphase of the cell cycle have been intensively investigated. The function of p21 in mitosis has been proposed but not systematically studied. We show here that p21 is abundant in mitosis and binds to and inhibits the activity of Cdk1/cyclin B1. Deficiency of p21 prolongs the duration of mitosis by extending metaphase, anaphase and cytokinesis. The activity of Aurora B is reduced and the localization of Aurora B on the central spindle is disturbed in anaphase cells without p21. Moreover, HCT116 p21-/-, HeLa and Saos-2 cells depleted of p21 encounter problems in chromosome segregation and cytokinesis. Gently inhibiting the mitotic Cdk1 or add-back of p21 rescues segregation defect in HCT116 p21-/- cells. Our data demonstrate that p21 is important for a fine-tuned control of the Cdk1 activity in mitosis, and its proper function facilitates a smooth mitotic progression. Given that p21 is downregulated in the majority of tumors, either by the loss of tumor suppressors like p53 or by hyperactive oncogenes such as c-myc, this finding also sheds new light on the molecular mechanisms by which p21 functions as a tumor suppressor.