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Background Limited data are available concerning the safety, optimal administration and benefits of contemporary heart failure therapy in patients after left ventricular assist device (LVAD) implantation. Methods : Between 2015 and 2019, 257 patients underwent LVAD implantation and were included in this observational study. Oral heart failure therapy was initiated and uptitrated during the further course. After propensity matching and excluding patients with immediate postoperative treatment in an affiliated center with different medical standards, hospitalization rates and mortality within 12 months after LVAD implantation were compared between 83 patients who received medical therapy including an angiotensin receptor neprilysin inhibitor (ARNI) and 83 patients who did not receive an ARNI. Results The overall use of heart-failure medications after 12 months was high: prescriptions: beta-blockers, 85%; angiotensin inhibiting drugs, 90% (angiotensin-converting-enzyme inhibitors 30%, angiotensin receptor blockers 23%, ARNI 37%); mineralocorticoid receptor antagonists, 80%. No serious drug-related adverse events occurred. The conditional 1-year survival in the group with ARNIs was 97% (95% CI: 94%-100%) compared to 88% in the group without an ARNI (95% CI: 80%-96%); P = 0.06. Conclusions Contemporary heart failure therapy is safe in patients with LVADs. No increase in serious adverse events was seen in patients receiving ARNIs. No significant difference in the conditional 1-year survival was seen between the ARNI group and the nonARNI group.

OBJECTIVES Various trials have assessed the outcome and reliability of the HeartWare HVAD (HW) and HeartMate 3 (HM3) left ventricular assist devices. A direct comparison of clinical outcomes and of the complication profile of these 2 left ventricular assist devices is lacking. We present a retrospective analysis of patients supported with HM3 and HW as a left ventricular assist device. METHODS Preoperative data, complications and outcomes including a 1-year follow-up of patients supported with the HM3 and HW in a single centre were retrospectively analysed. Both pumps were implanted on- or off-pump, employing standard and minimally invasive techniques. For logistic reasons, the 2 device types were implanted in an alternating manner, thereby reducing the systematic bias for pump selection. We considered this to be an appropriate approach, as no differences in respect of survival or the complication profile of the two device types have been demonstrated. Anticoagulation was similar in patients with both pumps according to our anticoagulation protocol, with a target international normalized ratio of 2.5–3.0, a home monitoring system and blood pressure management with a mean arterial target pressure of 70–80 mmHg. RESULTS Between October 2015 and April 2017, 100 patients underwent implantation of the HW and 100 patients underwent implantation of the HM3. The median time on the device was 0.98 years (range 0–2.23 years). The median age was 58.5 (51–65) versus 57 (49–64) years (P = 0.456); the number of male patients was 87 versus 88 (P = 0.831). Of the HW patients, 73% were rated as having an INTERMACS level I or II, compared to 57% of the HM3 patients (P = 0.018). There were no further differences in preoperative data. A total of 14 patients had pre-, intra- or post-pump blood flow obstruction in the HW group versus 4 in the HM3 group [hazard ratio (HR) 2.5 (0.7–8.8), P = 0.103]. There were no differences regarding gastrointestinal bleeding [HR 1.25 (0.56–2.64), P = 0.624] or driveline infection (0.68 vs 0.8 events per patient-year, P = 0.0789). The incidence of ischaemic stroke was similar in both groups [HR 0.72 (0.25–2.09), P = 0.550]. Cerebral bleeding was more frequent in patients supported with HW [HR 6.79 (1.43–32.20), P = 0.016]. The incidence of cerebrovascular accidents, on the other hand, was similar in both groups [HR 1.85 (0.83–4.19), P = 0.13]. The incidence of haemocompatibility-related adverse events, however, was significantly higher in the HW group (113 points corresponding to 1.28 events per patient-year versus 69 points corresponding to 0.7 events per patient-year, P CONCLUSIONS Our data show that the complication profile differs between the 2 pumps, but that early survival is comparable.

Mechanical circulatory support (MCS) using left ventricular assist devices (LVAD) have considerably improved the quality of life and survival rate of patients with end-stage heart failure. Despite substantial technological progress, major challenges with regard to VAD-specific and VAD-related infections have hitherto hindered the broader application of this promising therapy approach. Driveline infections (DLI) range among the main adverse events experienced in LVAD patients. However, many centers still apply their own protocol for driveline exit site (DLES) care and an international standard on prevention, reduction and early treatment of DLI after the perioperative period has not yet been defined. In March 2019, VAD coordinators and cardiac surgeons from Germany and Austria met to develop a standard of care procedure (SOP) as well as a new staging approach with recommended actions for treatment of VAD carriers. In this Driveline Expert STagINg and carE (DESTINE) study group we developed a 10-step SOP for DLES care with emphasis on essentials such as clean and save preparation, sterile dressing change and secure driveline immobilization. An advanced wound staging approach was defined with recommended actions for prevention, early detection and stage-related management of DLI. Broad consensus was reached on the fact that an interdisciplinary approach both in DLES care and DLES healing disorder awareness is required to prolong infect-free survival times on MCS as well as to ensure high patient compliance and quality of life. In conclusion, a new detailed SOP for appropriate DLES care and an advanced wound staging approach for prevention and management of DLI were defined on an expert level applicable for VAD clinicians, practitioners and care givers in Central Europe.

The handling of left ventricular assist devices (LVADs) can be challenging for patients and requires appropriate training. The devices’ usability impacts patients’ safety and quality of life. In this study, an eye tracking supported human factors testing was performed to reveal problems during use and test the trainings’ effectiveness. In total 32 HeartWare HVAD patients (including 6 pre-VAD patients) and 3 technical experts as control group performed a battery change (BC) and a controller change (CC) as an everyday and emergency scenario on a training device. By tracking the patients’ gaze point, task duration and pump-off time were evaluated. Patients with LVAD support ≥1 year showed significantly shorter BC task duration than patients with LVAD support., Journal of Medical Systems, 45, ISSN:0148-5598, ISSN:1573-689X

Only few patients with heart failure with preserved ejection fraction undergo durable mechanical circulatory support implantation. We identified three patients with heart failure with preserved ejection fraction who needed durable mechanical circulatory support as bridge-to-transplant therapy. In two patients with hypertrophic cardiomyopathy, the hypertrophic papillary muscles and myocardium were resected to allow for subsequent left ventricular assist device implantation. In one patient, all visible parts of the mitral valve were additionally resected. The third patient with restrictive cardiomyopathy underwent Berlin Heart Excor BVAD implantation with left atrial cannulation.

Despite the regenerative capacity of the peripheral nerve system (PNS), functional recovery after mechanical nerve trauma is often incomplete, resulting in motor, sensory, and autonomic deficits. The elucidation of key molecules involved in trauma-induced Wallerian degeneration and the ensuing regeneration processes is a prerequisite for the development of disease modifying drugs. The chemokine (C-X-C motif) receptor 3 (CXCR3) has been implicated in the recruitment of macrophages, the major immune cell population during the process of Wallerian degeneration. In this study, we examined whether deletion of CXCR3 affects macrophage recruitment, the expression of the proinflammatory cytokine tumor necrosis factor (TNF)- α and the CXCR3 agonist interferon gamma-induced protein 10 (CXCL10), and functional recovery in the sciatic nerve crush model. CXCR3 mice displayed significantly reduced macrophage counts preceded by diminished expression of CXCL10 and TNF- α. Furthermore, functional recovery of sciatic nerve motor function was significantly accelerated. In summary, these data indicate that the deletion of CXCR3 leads to a diminished inflammatory response and an accelerated functional recovery following sciatic nerve crush injury. Therefore, CXCR3 may be an interesting target for therapeutic interventions after traumatic nerve lesions.

OBJECTIVES Short-term mechanical circulatory support is a life-saving treatment for acute cardiogenic shock (CS). This multicentre study investigates the preoperative predictors of 30-day mortality in CS patients treated with Impella 5.0 and 5.5 short-term left ventricular assist devices. METHODS Data of patients in CS (n = 70) treated with the Impella 5 (n = 63) and 5.5 (n = 7) in 2 centres in Berlin between October 2016 and October 2019 were collected retrospectively. RESULTS CS was caused by acute myocardial infarction (n = 16), decompensated chronic heart failure (n = 41), postcardiotomy syndrome (n = 5) and acute myocarditis (n = 8). Before implantation 12 (17%) patients underwent cardiopulmonary resuscitation and 32 (46%) patients were ventilated. INTERMACS level 1, 2 and 3 was established in 35 (50%), 29 (41%) and 6 (9%) of patients, respectively. The mean preoperative lactate level was 4.05 mmol/l. The median support time was 7 days (IR= 4–15). In 18 cases, the pump was removed for myocardial recovery, in 22 cases, durable left ventricular assist devices were implanted, and 30 patients died on support. The overall 30-day survival was 51%. Statistical analysis showed that an increase in lactate per mmol/l [odds ratio (OR) 1.217; P = 0.015] and cardiopulmonary resuscitation before implantation (OR 16.74; P = 0.009) are predictors of 30-day survival. Based on these data, an algorithm for optimal short-term mechanical circulatory support selection is proposed. CONCLUSIONS Impella treatment is feasible in severe CS. Severe organ dysfunction, as well as the level and duration of shock predict early mortality. An algorithm based on these parameters may help identify patients who would benefit from Impella 5+ support.

Background Cardiac cachexia and frailty are major complications of advanced heart failure (AHF). Bioelectrical impedance analysis (BIA) may provide valuable information regarding fluid balance, muscle mass and prognosis. The main concerns regarding the use of BIA in AHF patients remain arrhythmias and electromagnetic interferences with cardiac implantable electronic devices (CIEDs). Reliable data regarding patients on continuous-flow ventricular assist device (cf-VAD) remain scarce. The aim of this study is to evaluate the safety of BIA in AHF patients on pro-arrhythmogenic therapy with an implanted CIED and/or with a cf-VAD. Methods We prospectively performed 217 BIA measurements in 143 AHF patients at risk of severe arrhythmias due to inotropic support/a history of ventricular arrhythmias and/or treated with CIED, including 104 patients with an ICD, CRT or pacemaker and 95 patients with a cf-VAD. All patients were under continuous Electrocardiogram (ECG) monitoring and clinical surveillance for 24 hours. Results No adverse events were observed during the 217 BIA measurements: No rhythm disturbances were documented in the telemetric monitoring during or within 30 minutes after the measurement. CIEDs showed no malfunction, regardless of the location measured or the device manufacturer. In particular, no inappropriate shocks were observed. No alarms, flow disturbances, or malfunctions of the cf-VAD occurred during or after the measurements. Conclusion We consider BIA a safe measurement with major clinical relevance in our cohort of AHF patients, despite an increased arrhythmic potential on inotropic support or the presence of implanted electronic devices (ICD, CRT, pacemaker and cf-VAD).

Background Twist of the outflow graft (OG) of the HeartMate 3 left ventricular (LV) assist device (HM3) with subsequent occlusion is a rare, but life-threatening complication. Purpose We evaluated if potential implantation technique dependent mechanisms of OG twist can be predicted by multislice computed tomography (MSCT). Methods We retrospectively analyzed clinical, echocardiographic and MSCT data of 7 patients with angiographically proven and surgically corrected OG twist and of 11 consecutive patients without any type of pump obstruction. MSCT parameters were: position of inflow cannula related to anatomical LV apex (1), angulation of axis of inflow cannula related to LV axis (2), orientation of outflow channel of the pump housing related to LV axis (3), OG course (4). Echocardiographic parameters were LV end-diastolic diameter (LVEDD) and aortic valve opening. Results Mean time from implantation to twist was 563 ± 161 days. Preoperative LVEDD (64.6 ± 9.8 mm vs. 67.4 ± 10.2 mm, p = 0.563) was similar. LVEDD reduction after implantation (20% vs. 28%) and prevalence of aortic valve opening was higher in the twist group (71% vs. 45%). The MSCT measurements showed a high degree of heterogeneity in both groups: (1) differed from superior to infero-lateral; (2) varied from cranial to caudal, lateral and medial; (3) varied from antero-septal to inferior. (4) showed an incidence of non-obstructive kinking of 29% and 36%, respectively. Conclusion Marked heterogeneity of the measured MSCT parameters was observed in both groups. No specific pattern or geometric relation could be attributed to the OG twist phenomenon.

Purpose Nowadays a variety of different circulatory support strategies can be involved in cardiogenic shock therapy. Impella 5.0 and 5.5 microaxial pumps became a reliable instrument at disposal of cardiothoracic surgeons. The aim of this study is to reveal preoperative parameters that may influence the outcomes of Impella support. Methods Data of 85 consecutive patients treated with Impella 5.0 (n=78) and 5.5 (n=7) devices between October 2016 and August 2019 at the German Heart Center Berlin and the Cardiology Department of the Berlin Charite Virchow campus university clinic were collected retrospectively. Results The mean age was 57.4±13.4 years, 86% were male, 26 patients had a BMI g in 8 of these patients ECLS was explanted and Impella continued working as LVAD. Preoperative parameters of 67 patients who received isolated Impella support for CS were included into analysis. Prior to implantation, the mean lactate level was 4.1±3.9 mmol/l, 12 (18%) patients received cardiopulmonary resuscitation (CPR), 53 (79%) received inotropic support (mean inotropic index 5.3±4.1), and 30 (45%) underwent invasive ventilation. The mean support time was 11.5±10.7 days. In 18 cases the pump was removed for myocardial recovery and 20 patients underwent long-term LVAD implantation, 29 died on support. Preoperative lactate level l OR 4.7, p=0.03) and absence of preoperative CPR (survival 58% vs 8%, p=0.001) predicted 30-days survival. Conclusion Temporary MCS with Impella 5+ is a reliable tool for treatment of CS in selected patients. In patients after CPR and with more severe CS, ECLS may be more effective. Further prospective studies should be initiated.

Objectives Extracorporeal life support (ECLS) can be applied as a bridge to diagnosis and decision-making for further treatment with long-term left ventricular assist devices (LVADs). Methods From January 2012 to January 2018, 714 adult patients were treated with ECLS in our institution. During the same period, 618 patients received an LVAD for long-term support. Of them, 100 patients were further supported with a long-term LVAD. We retrospectively analysed the datasets of these 100 consecutive patients with the goal of developing an algorithm to predict outcomes for a rational use of long-term ventricular assist device therapy in this setting. Results The mean age of the 100 patients was 54.1 ± 11.6 years, and 72 were men. Twenty-nine patients had a BMI of >30 kg/m2. In 33 patients, a temporary right ventricular assist device was necessary postoperatively. The 30-day, 1-year and 2-year survival after ventricular assist device implantation was 62.0% [95% confidence interval (CI) 53.2-72.3], 43.0% (95% CI 34.3-53.9) and 37.1% (95% CI 28.2-48.7%), respectively. Penalized multivariable logistic regression analysis showed following predictors for 1-year mortality: bilirubin increase per mg/dl [odds ratio (OR) 1.41, 95% CI 1.12-1.77], C-reactive protein increase per mg/dl (OR 1.11, 95% CI 1.05-1.19), ECLS duration >7 days (OR 4.90, 95% CI 1.66-14.41), BMI >30 kg/m2 (OR 1.41, 95% CI 1.05-8.52) and female gender (OR 3.06, 95% CI 1.02-9.23). On the basis of these data, a nomogram to estimate 1-year mortality after LVAD implantation was created. Conclusions After stabilization of patients experiencing cardiogenic shock using ECLS, LVAD implantation can be performed with elevated mortality in an otherwise futile situation. Liver dysfunction, inflammatory status and obesity increase the risk for mid-term mortality.

Large demyelinating inflammatory central nervous system (CNS) lesions may present with contrast enhancement on magnetic resonance imaging and may mimic CNS tumors such as glioma. In ambiguous cases, new diagnostic tools that may be helpful for distinguishing between demyelinating inflammatory and neoplastic CNS lesions are required. The current study presents the case of a patient with a large contrast-enhanced frontal brain lesion, who was initially diagnosed with tumefactive multiple sclerosis. Following the progression of the brain lesion, an 18F-fluoroethyl-L-tyrosine positron emission tomography (18F-FET PET) was performed, revealing markedly elevated static 18F-FET uptake parameters along with time activity-curves consistent with glioma. Subsequently, a biopsy was undertaken, which confirmed the presence of anaplastic oligoastrocytoma. This case illustrates that 18F-FET PET may provide useful diagnostic information in cases where distinction between neoplastic and demyelinating inflammatory CNS lesions is challenging. However, further systematic and prospective analyses are warranted to explore the value of this method in this setting.

Guillain-Barre syndrome (GBS) is an acute, immune-mediated polyradiculoneuropathy characterized by rapidly progressive paresis and sensory disturbances. Moderate to severe and often intractable neuropathic pain is a common symptom of GBS, but its underlying mechanisms are unknown. Pathology of GBS is classically attributed to demyelination of large, myelinated peripheral fibers. However, there is increasing evidence that neuropathic pain in GBS is associated with impaired function of small, unmyelinated, nociceptive fibers. We therefore examined the functional properties of small DRG neurons, the somata of nociceptive fibers, in a rat model of GBS (experimental autoimmune neuritis=EAN). EAN rats developed behavioral signs of neuropathic pain. This was accompanied by a significant shortening of action potentials due to a more rapid repolarization and an increase in repetitive firing in a subgroup of capsaicin-responsive DRG neurons. Na+ current measurements revealed a significant increase of the fast TTX-sensitive current and a reduction of the persistent TTX-sensitive current component. These changes of Na+ currents may account for the significant decrease in AP duration leading to an overall increase in excitability and are therefore possibly directly linked to pathological pain behavior. Thus, like in other animal models of neuropathic and inflammatory pain, Na+ channels seem to be crucially involved in the pathology of GBS and may constitute promising targets for pain modulating pharmaceuticals.

Purpose Bioelectrical impedance analysis (BIA) is a painless and safe way to measure body composition without radiation. It is feasible in immobile patients and may serve as a measure to assess frailty. BIA may lead to electromagnetic interference with the conduction system of the heart, provoking oversensing in pacemakers and internal cardiac defibrillators or arrhythmias. End-stage heart failure patients are at highest risk for these possible side effects. The aim of this study was to evaluate the safety of BIA in end-stage heart failure patients under pro-arrhythmogenic pharmacologic therapy. Methods We performed 56 BIA measurements in 32 hospitalized patients (28 male, 4 female), suffering from advanced heart failure (20 DCMP; 10 ICMP; 2 other) under constant ECG monitoring. Fourteen measurements were performed while the patient was in need of single inotropic support (9 dobutamine; 5 milrinone), 11 patients received combined inotropic therapy (7 milrinone/dobutamine; 1 dobutamine/noradrenalin; 1 dobutamine/adrenalin; 2 dobutamine, milrinone, noradrenalin, adrenalin). Their mean Inotropic Score was 10.03 (+/- 7.15). During 31 BIA measurements, the patient had an implantable cardiac device (ICD, pacemaker or CRT) in place; one patient had an external defibrillator (LifeVest). Thirty-eight BIA measurements were performed while the patient was receiving antiarrhythmic medication either with amiodarone (15), beta-blockers (26), sotalol (1) or glycosides (4) alone (34) or in combination (4). Eighteen assessments were performed without any antiarrhythmic medication. During 36 assessments, the patient received supplementary potassium and during 12 evaluations, the patient was treated with other medication such as ivabradine or magnesium. Results None of the patients showed any signs of clinically relevant arrhythmias following the BIA under ECG monitoring for 48 hours, but we observed some, probably coincidental, ventricular extrasystoles. No device malfunction was seen, especially no oversensing in ICDs resulting in inadequate shocks. Conclusion BIA measurement can be performed safely in end-stage heart failure patients with pro-arrhythmogenic pharmacologic therapy, who are the most vulnerable to arrhythmias.

Introduction The purpose of this trial was to evaluate the effect of long-term treatment with oral sustained-release hydromorphone, transdermal fentanyl, and transdermal buprenorphine on nausea, emesis and constipation. Patients and methods Randomly selected outpatients with cancer pain receiving one of the study medications were enrolled in a prospective, open-labeled, controlled trial ( n = 174). Mobility, pain, and gastrointestinal symptoms were assessed directly and per selected item on the ECOG (Eastern Cancer Oncology Group), EORTC (European Organisation for Research and Treatment of Cancer) questionnaires, NRS (Numerical Rating Scales), and analyzed statistically. Results Demographic and medical data were comparable in all groups. Only 15% of patients suffered from constipation. 59% took the prescribed laxatives. The incidence of stool free periods >72 h was significantly higher with transdermal opioids (transdermal fentanyl: 22%; transdermal buprenorphine: 21%; oral hydromorphone: 2%; p = 0.003). 21% of patients revealed nausea and emesis. The mean NRS for nausea (transdermal fentanyl:1.3; transdermal buprenorphine: 1.2; oral hydromorphone: 1.5; p = 0.6), the consumption of antiemetics (transdermal fentanyl: 42%; transdermal buprenorphine: 33%; oral hydromorphone: 36%; p = 0.6) and laxatives (transdermal fentanyl:53%; transdermal buprenorphine:66%; oral hydromorphone: 61%; p = 0.2) did not differ significantly, in contrast to the score for emesis (transdermal fentanyl: 16%; transdermal buprenorphine:13%; oral hydromorphone: 33%; p = 0.02). Morphine equivalent opioid doses differed (mg/d transdermal fentanyl: 183; transdermal buprenorphine: 89; oral hydromorphone: 143; p = 0.001), because of obvious tolerance varying after long-term treatment. Conclusions Gastrointestinal symptoms of cancer pain patients undergoing an opioid therapy are related to multifactorial causes. Transdermal opioids showed no benefit over oral controlled-release hydromorphone with regard to gastrointestinal symptoms. The conversion ratios for transdermal fentanyl, transdermal buprenorphine, and oral hydromorphone did not accord to the literature, because of differing occurrences of opioid tolerance after long-term therapy.

Some toxins exert cytotoxicity by assembling into multimeric pores in the membranes of their host cells. The bacterial α-helical toxin cytolysin A, responsible for the haemolytic phenotype of several Escherichia coli and Salmonella enterica strains, is one such pore-forming toxin, whose soluble structure is known. Here Mueller et al. describe the structure of its assembled dodecameric pore. The authors propose a sequential mechanism for the large rearrangements that the monomers undergo to form the α-helical pore. Pore-forming toxins are a class of potent virulence factors that convert from a soluble form to a membrane-integrated pore. The bacterial toxin cytolysin A is one such pore-forming toxin, and it is responsible for the haemolytic phenotype of several Escherichia coli and Salmonella enterica strains. Here, the crystal structure of the assembled pore is reported, and a sequential mechanism for its assembly proposed. Pore-forming toxins (PFTs) are a class of potent virulence factors that convert from a soluble form to a membrane-integrated pore1. They exhibit their toxic effect either by destruction of the membrane permeability barrier or by delivery of toxic components through the pores. Among the group of bacterial PFTs are some of the most dangerous toxins, such as diphtheria and anthrax toxin. Examples of eukaryotic PFTs are perforin and the membrane-attack complex, proteins of the immune system2. PFTs can be subdivided into two classes, α-PFTs and β-PFTs, depending on the suspected mode of membrane integration, either by α-helical or β-sheet elements3. The only high-resolution structure of a transmembrane PFT pore is available for a β-PFT—α-haemolysin from Staphylococcus aureus4. Cytolysin A (ClyA, also known as HlyE), an α-PFT, is a cytolytic α-helical toxin responsible for the haemolytic phenotype of several Escherichia coli and Salmonella enterica strains5,6,7,8. ClyA is cytotoxic towards cultured mammalian cells, induces apoptosis of macrophages and promotes tissue pervasion9,10,11. Electron microscopic reconstructions demonstrated that the soluble monomer of ClyA12 must undergo large conformational changes to form the transmembrane pore13,14. Here we report the 3.3 A crystal structure of the 400 kDa dodecameric transmembrane pore formed by ClyA. The tertiary structure of ClyA protomers in the pore is substantially different from that in the soluble monomer. The conversion involves more than half of all residues. It results in large rearrangements, up to 140 A, of parts of the monomer, reorganization of the hydrophobic core, and transitions of β-sheets and loop regions to α-helices. The large extent of interdependent conformational changes indicates a sequential mechanism for membrane insertion and pore formation.

In up to 31% of cases, nonsurgical treatment of midshaft clavicular fractures leads to unsatisfactory results such as nonunion, brachial plexus irritation, shortening and limited function of the shoulder. To date, various implants have been developed for open reduction including intramedullary wires, screws, and plates. This study discusses elastic stable intramedullary nailing of midshaft clavicular fractures.Between 2000 and 2005, 31 midshaft clavicular fractures were treated by intramedullary nailing with a titanium elastic nail (TEN). Subjective and clinical outcome were evaluated after an average follow-up of 26 (6-46) months. Patients were divided into three groups: patients with isolated clavicular fractures (group 1, n = 9); patients with additional injuries (group 2, n = 15), and patients with multiple injuries (group 3, n = 7).Nonunion was not observed. No patient sustained a refracture after TEN removal. Medial migration of the TEN in seven patients and iatrogenic perforation of the lateral cortex in one patient required secondary shortening on five occasions. Nail breakage after fracture healing was observed twice. Subjective outcome did not differ significantly between the three groups. Constant and Murley Score and the Disability of the Arm, Shoulder, and Hand Questionnaire Score showed no significant difference in the clinical outcome of the three groups.Intramedullary fixation of midshaft clavicular fractures with a TEN is a safe minimally invasive surgical technique achieving primary stability for practice. It can be seen as an alternative to plate or screw fixation or nonsurgical treatment, as it produces excellent cosmetic and functional results regardless whether patients suffered from isolated clavicular fractures, additional injuries, or multiple traumas.

OBJECTIVE Cochlear implants (CIs) have become the gold standard treatment for deafness. These neuroprosthetic devices feature a linear electrode array, surgically inserted into the cochlea, and function by directly stimulating the auditory neurons located within the spiral ganglion, bypassing lost or not-functioning hair cells. Despite their success, some limitations still remain, including poor frequency resolution and high-energy consumption. In both cases, the anatomical gap between the electrode array and the spiral ganglion neurons (SGNs) is believed to be an important limiting factor. The final goal of the study is to characterize response profiles of SGNs growing in intimate contact with an electrode array, in view of designing novel CI devices and stimulation protocols, featuring a gapless interface with auditory neurons. APPROACH We have characterized SGN responses to extracellular stimulation using multi-electrode arrays (MEAs). This setup allows, in our view, to optimize in vitro many of the limiting interface aspects between CIs and SGNs. MAIN RESULTS Early postnatal mouse SGN explants were analyzed after 6-18 days in culture. Different stimulation protocols were compared with the aim to lower the stimulation threshold and the energy needed to elicit a response. In the best case, a four-fold reduction of the energy was obtained by lengthening the biphasic stimulus from 40 μs to 160 μs. Similarly, quasi monophasic pulses were more effective than biphasic pulses and the insertion of an interphase gap moderately improved efficiency. Finally, the stimulation with an external electrode mounted on a micromanipulator showed that the energy needed to elicit a response could be reduced by a factor of five with decreasing its distance from 40 μm to 0 μm from the auditory neurons. SIGNIFICANCE This study is the first to show electrical activity of SGNs on MEAs. Our findings may help to improve stimulation by and to reduce energy consumption of CIs and thereby contribute to the development of fully implantable devices with better auditory resolution in the future.

The mouse mutant Ozzy, originating from an ENU-mutagenesis programme, displays a head bobbing phenotype. We report here that Ozzy mice show a clear deficit in vestibulo-ocular reflex (VOR). Micro-CT scanning of the inner ears showed narrowing and truncations of at least one of the semicircular canals and loss of the ampullae. Frequency-specific auditory-evoked brainstem response (ABR) tests revealed a slight threshold increase in the middle frequency range compared to wild-type littermates. Linkage analysis localised the gene in a 5.5-cM region on chromosome 2. Subsequently, a 499 T--A missense mutation was identified in Jag1, leading to a substitution of an evolutionary conserved tryptophane (W167R). Mutations in the human homologue of Jag1 cause Alagille syndrome (AGS), an autosomal dominant disorder associated with liver, heart, eye and skeletal abnormalities, accompanied by a characteristic facies. In human patients, it occasionally affects other organ systems like the kidney or the inner ear. Liver disease is the main diagnostic factor for AGS. Ozzy mice showed significantly less intrahepatic bile ducts than wild-type littermates. Thirty-seven percent of Ozzy mice showed heart defects. No eye or vertebral abnormalities could be detected. In conclusion, Ozzy mice show two of the major and one minor characteristic of AGS.

Granulocyte colony-stimulating factor (G-CSF), alone or in combination with stem cell factor (SCF), can improve hemodynamic cardiac function after myocardial infarction. Apart from impairing the pump function, myocardial infarction causes an enhanced vulnerability to ventricular arrhythmias. Therefore, we investigated the electrophysiological effects of G-CSF/SCF and the underlying cellular events in a murine infarction model. G-CSF/SCF improved cardiac output after myocardial infarction. Although G-CSF/SCF led to a twofold increased, potentially proarrhythmic homing of bone marrow (BM)-derived cells to the area of infarction

Background/Aims: In an ovine meniscal repair model, the patellofemoral (PF) osteoarthritis due to a non-sutured tear or failed repair was investigated. Methods: A radial meniscus tear was either sutured with polydioxanone (PDS), with a slow degrading polylactide long-term suture(LTS) or left without treatment. Knee joint cartilage in the PF and medial compartment was evaluated compared to normal knees (healthy controls). Results: Retropatellar osteoarthritis in the non-sutured and sutured animals was intense in contrast to the control knees after 6 months in all groups (p < 0.001), and after 12 months in the PDS group (p < 0.001), LTS group and non-sutured animals (p < 0.05). Conclusion: Non-sutured meniscus tears and failed repair lead fast to intense PF osteoarthritis corresponding with tibial damage of the injured compartment.

Resident microglia and hematogenous macrophages play crucial roles in the pathogenetic cascade following cerebral ischemia but may functionally differ regarding neuroprotective and cytotoxic properties. Distinction between these cells has not been possible due to a lack of discriminating cellular markers. We generated bone marrow chimeric mice by transplanting bone marrow from green fluorescent protein (GFP) transgenic mice into irradiated wild-type recipients. Transient focal cerebral ischemia was induced by transient middle cerebral artery occlusion (MCAO) for 30 min. Resident microglia and infiltrating macrophages were identified by immunohistochemistry and GFP fluorescence after 1-28 days. The first blood-derived cells infiltrating the infarct area were seen on Day 1 and identified as granulocytes. Hematogenous GFP(+) macrophages were rarely observed on Day 2, reached peak numbers on Day 7, and decreased thereafter. In contrast, resident GFP(-) microglial cells rapidly became activated already on Day 1 after MCAO. Even on Days 4 and 7, most macrophage-like cells remained GFP(-), indicating their derivation from resident microglia. Hematogenous macrophages were able to acquire a ramified morphology indistinguishable from resident microglia while microglial cells could develop into a phagocytic phenotype indistinguishable from infiltrating macrophages. The vast majority of macrophages in the infarct area are derived from local microglia, revealing a remarkable predominance of local defense mechanisms over immune cells arriving from the blood. GFP bone marrow chimeric mice are a powerful tool to further differentiate the function of resident microglia and hematogenous macrophages following cerebral ischemia.

Whereas local microglial cells of the CNS rapidly respond to injury, little is known about the functional role of resident macrophages of the peripheral nervous system in nerve pathology. Using bone marrow chimeric rats, we recently identified individual resident endoneurial macrophages that rapidly became activated after nerve injury. However, the extent of local macrophage activation and its quantitative contribution to the total macrophage response is unknown. We now have created chimeric mice by transplanting bone marrow from green fluorescent protein (GFP)-transgenic mice into irradiated wild-type mice, allowing easy differentiation and quantification of hematogenous and resident endoneurial macrophages. After sciatic nerve crush injury, both GFP(-) and GFP(+) resident macrophages, the latter having undergone physiological turnover from the blood before injury, rapidly underwent morphological alterations and increased in number. Proliferating GFP(-) and GFP(+) resident macrophages were abundant and peaked 3 days after injury. A major lesion-induced influx of hematogenous macrophages with a disproportionate increase of GFP(+) macrophages was not observed until Day 4. Throughout all time points examined, GFP(-) resident macrophages were strikingly frequent, reaching maximum numbers 9.5-fold above baseline. There was also a notable proportion of GFP(-) resident endoneurial macrophages phagocytosing myelin and expressing major histocompatibility complex class II. Our results demonstrate for the first time that the rapid response of resident endoneurial macrophages to nerve injury is quantitatively important and that local macrophages contribute significantly to the total endoneurial macrophage pool during Wallerian degeneration.

Background Chronic low back pain (CLBP) is a serious health problem in industrialised countries and the efficacy of current treatment options is unsatisfying. Objective The present study examines the effects of a combined intervention that utilizes visual feedback, motion and sensory discrimination training in CLBP patients. Methods Thirty patients of an outpatient orthopaedic rehabilitation unit were randomly assigned to either feedback or control group. In addition to standard treatment, patients of the feedback group received 6 feedback sessions where they watched the image of their back during a brief 2-point discrimination training and, after that, while they were tilting their pelvis up and down on the left and right side using their lumbar musculus multifidus solely. The control group received 6 sessions consisting of 2 units of physiotherapy, relaxation training and movement training (walking) each. Results A significant effect on self-reported pain and sensory discrimination threshold could be found for the feedback intervention, while, as expected, other pain related variables, like pain anxiety, pain vigilance, depression and cognitive appraisal of pain remained unchanged. Conclusions These findings imply that very simple feedback interventions without major technical requirements could be a valuable supplement to standard treatment in CLBP.

Macrophages play a central role in the pathogenesis of peripheral neuropathy but the role of resident endoneurial macrophages is undefined because no discriminating markers exist to distinguish them from infiltrating hematogenous macrophages. We identified and characterized resident endoneurial macrophages during Wallerian degeneration in radiation bone marrow chimeric rats created by transplanting wild-type Lewis rat bone marrow into irradiated TK-tsa transgenic Lewis rats. In such animals, resident cells carry the transgene, whereas hematogenous cells do not. As early as 2 days after sciatic nerve crush and before the influx of hematogenous macrophages, resident transgene-positive endoneurial macrophages underwent morphological and immunophenotypic signs of activation. At the same time, resident macrophages phagocytosing myelin were found, and proliferation was detected by bromodeoxyuridine incorporation. Continuous bromodeoxyuridine feeding revealed that resident endoneurial macrophages sequentially retracted their processes, proliferated, and expressed the ED1 antigen, rendering them morphologically indistinguishable from hematogenous macrophages. Resident endoneurial macrophages thus play an early and active role in the cellular events after nerve lesion before hematogenous macrophages enter the nerve. They may thus be critically involved in the pathogenesis of peripheral neuropathy particularly at early stages of the disease and may act as sensors of pathology much like their central nervous system counterparts, the microglial cells.

Alexander disease is a leukodystrophy characterized by Rosenthal fiber accumulation, which is caused by mutations in the gene coding for glial fibrillary acidic protein (GFAP) [1]. Depending on the age at onset, three subtypes (infantile-, juvenile-, and adult-onset) can be distinguished [1], characterized by different phenotypes. Once considered a rare condition, recent studies reveal an increasing number of cases of the adult-onset condition with pseudobulbar signs, ataxia, and spasticity and abnormalities in the medulla and upper cervical cord on neuroimaging [2, 3]. We present MR imaging of a patient with a novel mutation in the GFAP gene and CSF inflammatory signs that broadens the clinical spectrum of adult-onset Alexander disease. A 43 year old woman was admitted to the Department of Neurology at the University Hospital Bonn complaining about recurrent singultus for 1 year and left-sided tonic seizures for 1 month. Cerebrospinal fluid analysis revealed CSF-specific oligoclonal bands without pleocytosis. MRI showed hyperintense T2 and FLAIR signal in the brainstem (Fig. 1a–e) and cervical cord (Fig. 1g) and a contrast-enhancing lesion in the medulla oblongata (Fig. 1f). Taking into account the CSF results, the diagnosis of a chronic inflammatory CNS disease was discussed. However, the patient did not respond to an i.v. course of methylprednisolone. The patient’s condition deteriorated slowly over the next year. She subsequently developed dysphagia, and recurrent vomiting. Repeated brain MRIs over 11 months did not show relevant change. Based on the MRI imaging, adult-onset Alexander disease was suspected. Subsequent genetic analysis of the GFAP gene revealed a novel missense mutation in exon 6 (c.1051G [ C; p.D351H positions according to RefSeq NM_002055) in heterozygous state. This mutation results in an amino acid exchange in codon 351 from aspartate to histidine and it was not detected in 1,038 control chromosomes in a cohort of ethnically matched healthy blood donors from Germany. Analysis of this new amino acid exchange is predicted as ‘‘disease causing’’ using the web-based mutation taster analysis tool [4]. In addition, one sequence variant in intron 3 in heterozygous state (c.619-35_-21del; 1/965 control chromosomes) as well as one polymorphism in exon 2 in heterozygous state (rs59291670) were detected, for which pathogenic impact is unlikely. H. J. Tschampa (&) S. Greschus H. Urbach Departments of Radiology and Neuroradiology, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany e-mail: Henriette.Tschampa@ukb.uni-bonn.de

Co-localization of proteins and nucleic acid sequences by in situ hybridization and immunohistochemistry is frequently difficult as the process necessary to detect the target structure of one technique may negatively affect the target of the other. Morphological impairment may also limit the application of the two techniques on sensitive tissue. To overcome these problems we developed a method to perform in situ hybridization and immunohistochemistry on semithin sections of methyl methacrylate-embedded tissue. Microwave-stimulated antigen retrieval, signal amplification by catalyzed reporter deposition, and fluorescent dyes were used for both techniques, yielding high sensitivity and excellent morphological preservation compared to conventional paraffin sections. Co-localization of in situ hybridization and immunohistochemistry signals with high morphological resolution was achieved on single sections as well as on adjacent multiple serial sections, using computerized image processing. The latter allowed for the co-localization of multiple antigens and a specific DNA sequence at the same tissue level. The method was successfully applied to radiation bone marrow chimeric rats created by transplanting wild-type Lewis rat bone marrow into TK-tsa transgenic Lewis rats, in an attempt to trace and characterize TK-tsa transgenic cells. It also proved useful in the co-localization of multiple antigens in peripheral nerve biopsies.

Osteosynthesis of clavicular fractures is sometimes indicated. Since plate fixation may lead to complications, we have used elastic stable intramedullary nailing and report our experience of midclavicular fractures in 32 adults.From 2000 to 2005, we treated 32 adults (26 men), median age 40 (19-66) years, by intramedullary nailing with a titanium elastic nail (TEN). All patients were re-examined after median 27 (12-59) months.Nonunion was not observed. 20 clavicles healed without shortening. 12 clavicles healed with shortening of more than 5 mm. Migration of the TEN in 8 patients required secondary shortening of the nail in 5 of them. Nail breakage after fracture healing was observed twice. The nails were removed in 29 patients after a median of 6 (1.3-15) months postoperatively. No patient sustained a re-fracture after TEN removal. The mean Constant score was 95 (SD 1.9) points and the mean DASH score was 5 (SD 2.3) points.Intramedullary stabilization of midclavicular fractures with a titanium elastic nail is a minimally invasive technique with good cosmetic and functional results. Intramedullary fixation can be seen as an alternative to plate fixation and nonoperative treatment.

The purpose of this study was to analyse cartilage changes after traumatic meniscal lesions and to provide a detailed description of the model used with a view to reducing the number of animals used in future studies. The sheep's knee was chosen, as ovine biomechanics are similar to that of humans. In two groups of 10 animals each, a radial tear in the medial meniscus was either sutured with polydioxanone (PDS) or left untreated (sham-operated). Half of the animals in each group were sacrificed after six months, the other half after one year. The time periods to achieve weight bearing, meniscus healing, joint effusion (magnetic resonance imaging scan) and knee cartilage in the medial, lateral and patellofemoral compartments were evaluated in comparison to the opposite knee (control). Osteoarthritis (OA) was assessed by a modified Outerbridge classification and confirmed by scanning electron microscopy. Only one sutured meniscus remained completely adapted. In all other meniscus lesions, the rupture healed with a scar. In the PDS and sham-operated groups, OA was significantly higher in the medial knee compartment than in the lateral compartment and in controls ( P < 0.001). In the operated groups, joint effusion was higher in the right hindlimb knee than in the normal left hindlimb knee (control) after six and 12 months ( P < 0.001). Non-treated, displaced and even adapted sutured radial ovine meniscus tears produced intense OA within less than six months. Therefore, this animal model is suitable for assessment of new therapeutic regimens in meniscal surgery.

Incidence of meniscus injury has increased in today's active society. Arthroscopical refixation yields better results than partial meniscectomy. The best healing rates are achieved by sutures. As non-degradable sutures are permanent foreign bodies, slow absorbable materials are needed. A slow degradable suture with high concentration of polylactide acid, the so-called "long-term suture" (LTS, Panacryl), has been suggested to produce a higher inflammatory response than conventional polymer sutures [Vicryl, Dexon or polydioxanone (PDS)]. The aim of the study was to assess LTS for meniscus repair after a traumatic lesion and to evaluate immunological response, biodegradation and healing.In 24 randomised sheep, a radial tear of the medial meniscus was sutured by either PDS or LTS. Twelve sham-operated animals served as control. Half of the sheep were killed after 6 months, the other half after 12 months. The medial and lateral meniscus, synovial membrane, articular cartilage and ascendant lymph nodes up to the kidney were examined. Joint effusion was evaluated by MRI.The synovial membrane was significantly thinner in the LTS group (6 months 85 +/- 10 microm, 1 year 100 +/- 28 microm) than in the PDS group (6 months 165 +/- 10 microm, 1 year 175 +/- 23 microm, P0.001) and the controls (6 months 150 +/- 17 microm, 12 months 192 +/- 21 microm, P0.001). The joint effusion was higher in the PDS than in the LTS group after 6 months, and tended to be higher in controls. In controls, effusion tended to be higher than in the LTS group. In all medial departments, osteoarthritis evolved much more intensely than in the lateral knee departments (P0.01). Bilateral lymph nodes from the groin up to the kidneys were larger (crosscut area) after 6 months in the controls (2.28 +/- 0.7 mm(2)) and PDS treated animals (2.3 +/- 0.7 mm(2)) than in the LTS group (1.3 +/- 0.3 mm(2), P0.001). After 1 year, node size differed significantly between controls and animals from the LTS group (1.98 +/- 0.4 mm(2) vs. 1.5 +/- 0.2 mm(2), P0.05), and between animals from the PDS and the LTS group (2.5 +/- 0.1 mm(2) vs. 1.5 +/- 0.2 mm(2), P0.001).The polylactide thread LTS causes less immunological reaction and synovitis than a polydioxanone suture (PDS).LTS may serve as an alternative to PDS for repair of slow healing structures such as tendons and menisci.

OBJECTIVE. We sought to evaluate the efficiency of 18FDG PET, CT, and MRI for the preoperative staging of squamous cell carcinoma (SCC) of the head and neck region.CONCLUSION. MRI is recommended as the method of choice in the preoperative evaluation of SCC of the oral cavity and the oropharynx. PET can provide relevant diagnostic information in case of equivocal findings by MRI or CT. Routine use of PET, however, does not appear to be necessary if optimized MRI is available.

A complex mutation in DFNA5, resulting in exon 8 skipping, causes autosomal dominant hearing impairment, which starts in the high frequencies between 5 and 15 years of age and progressively affects all frequencies. To study its function in vivo, Dfna5 knockout mice were generated through the deletion of exon 8, simultaneously mimicking the human mutation. To test the hearing impairment, frequency-specific Auditory Brainstem Response (ABR) measurements were performed at different ages in two genetic backgrounds (C57Bl/6J and CBA/Ca), but no differences between Dfna5-/- and Dfna5+/+ mice could be demonstrated. Morphological studies demonstrated significant differences in the number of fourth row outer hair cells between Dfna5-/- mice and their wild-type littermates. These results were obtained in both genetic backgrounds, albeit with opposite effects. In contrast to the results obtained in Dfna5-/- zebrafish, we did not observe different UDP-glucose dehydrogenase and hyaluronic acid levels in Dfna5-/- mice when compared to Dfna5+/+ mice.

We investigate interfacial properties between two highly incompatible polymers of different stiffness. The extensive Monte Carlo simulations of the binary polymer melt yield detailed interfacial profiles and the interfacial tension via an analysis of capillary fluctuations. We extract an effective Flory-Huggins parameter from the simulations, which is used in self-consistent field calculations. These take due account of the chain architecture via a partial enumeration of the single chain partition function, using chain conformations obtained by Monte Carlo simulations of the pure phases. The agreement between the simulations and self-consistent field calculations is almost quantitative, however we find deviations from the predictions of the Gaussian chain model for high incompatibilities or large stiffness. The interfacial width at very high incompatibilities is smaller than the prediction of the Gaussian chain model, and decreases upon increasing the statistical segment length of the semi-flexible component., Comment: to appear in J.Chem.Phys

Information on responses of auditory nerve fibers in birds is generally limited to the low and mid‐frequency ranges of hearing, due to anatomical constraints using the standard ganglion cell approach through the opened tympanic recess. Intracranially recorded responses of single units from the auditory nerve and the overlying cochlear nuclei in the pigeon (Columba livia) were compared to those recorded from the ganglion. Characteristic frequencies (CFs) of auditory units ranged from 0.08–5.7 kHz with intracranial compared to 0.06–1.6 kHz with intrascalar recordings. Response properties were qualitatively and quantitatively comparable in the overlapping CF ranges (0.08–1.6 kHz). Mean spontaneous firing rate decreased monotonically with CF. The CF thresholds were lowest (0–5 dB SPL) in the CF range 0.6–1.5 kHz. Mean sharpness of tuning (Q10 dB) varied nonmonotonically with CF, with a maximum near 2 kHz. In addition, Q10 dB of pigeon auditory units up to CFs of 2 kHz was much higher than that of gerbil (Meriones unguiculatus) primary fibers in the same CF range, recorded in the same setup. As it is highly improbable that mechanical tuning in birds would by far exceed that in mammals, this finding is further evidence for a difference in avian and mammalian tuning mechanisms. [Work supported by the DFG, SFB 269.]