Etiologies and predictors of mortality in an all-comer population of patients with non-ischemic heart failure.

BACKGROUND: Despite progress in diagnosis and therapy of heart failure (HF), etiology and risk stratification remain elusive in many patients. METHODS: The My Biopsy HF Study (German clinical trials register number: DRKS22178) is a retrospective monocentric study investigating an all-comer population of patients with unexplained HF based on a thorough workup including endomyocardial biopsy (EMB). RESULTS: 655 patients (70.9% men, median age 55 [45/66] years) with non-ischemic, non-valvular HF were included in the analyses. 489 patients were diagnosed with HF with reduced ejection fraction (HFrEF), 52 patients with HF with mildly reduced ejection fraction (HFmrEF) and 114 patients with HF with preserved ejection fraction (HFpEF). After a median follow-up of 4.6 (2.5/6.6) years, 94 deaths were enumerated (HFrEF: 68; HFmrEF: 8; HFpEF: 18), equating to mortality rates of 3.3% and 11.6% for patients with HFrEF, 7.7% and 15.4% for patients with HFmrEF and 5.3% and 11.4% for patients with HFpEF after 1 and 5 years, respectively. In EMB, we detected a variety of putative etiologies of HF, including incidental cardiac amyloidosis (CA, 5.8%). In multivariate logistic regression analysis adjusting for age, sex and comorbidities only CA, age and NYHA functional class III + IV remained independently associated with all-cause mortality (CA: HRperui 3.13, 95% CI 1.5-6.51; p = 0.002). CONCLUSIONS: In an all-comer population of patients presenting with HF of unknown etiology, incidental finding of CA stands out to be independently associated with all-cause mortality. Our findings suggest that prospective trials would be helpful to test the added value of a systematic and holistic work-up of HF of unknown etiology.

Increased C reactive protein, cardiac troponin I and GLS are associated with myocardial inflammation in patients with non-ischemic heart failure.

Inflammatory cardiomyopathy diagnosed by endomyocardial biopsy (EMB) is common in non-ischemic heart failure (HF) and might be associated with adverse outcome. We aimed to identify markers predicting myocardial inflammation in HF. We screened 517 patients with symptomatic non-ischemic HF who underwent EMB; 397 patients (median age 54 [IQR 43/64], 28.7% females) were included in this study. 230 patients were diagnosed with myocardial inflammation, defined as ≥ 7.0 CD3+ lymphocytes/mm2 and/or ≥ 35.0 Mac1 macrophages/mm2 and were compared to 167 inflammation negative patients. Patients with myocardial inflammation were more often smokers (52.4% vs. 39.8%, p = 0.013) and had higher C-reactive protein (CRP) levels (5.4 mg/dl vs. 3.7 mg/dl, p = 0.003). In logistic regression models CRP ≥ 8.15 mg/dl (OR 1.985 [95%CI 1.160-3.397]; p = 0.012) and Troponin I (TnI) ≥ 136.5 pg/ml (OR 3.011 [1.215-7.464]; p = 0.017) were independently associated with myocardial inflammation, whereas no association was found for elevated brain natriuretic peptide (OR 1.811 [0.873-3.757]; p = 0.111). In prognostic performance calculation the highest positive predictive value (90%) was detected for the combination of Global longitudinal strain (GLS) ≥ -13.95% and TnI ≥ 136.5 pg/ml (0.90 (0.74-0.96)). Elevated CRP, TnI and GLS in combination with TnI can be useful to detect myocardial inflammation. Smoking seems to predispose for myocardial inflammation.

e-Health-based management of patients receiving oral anticoagulation therapy: results from the observational thrombEVAL study.

Essentials e-Health based health care by an expert centre may advance management of oral anticoagulation. Outcome of patients was compared between an e-health based coagulation service and regular care. Patients in the coagulation service cohort experienced a significantly better clinical outcome. Lower risk for adverse events was related to anticoagulation-specific and non-specific outcome. SUMMARY: Background Management of oral anticoagulation (OAC) therapy is essential to minimize adverse events in patients receiving vitamin K-antagonists (VKAs). Data on the effect of e-health-based anticoagulation management systems on the clinical outcome of OAC patients are limited. Objectives To compare the clinical outcome of OAC patients managed by an e-health-based coagulation service (CS) with that of patients receiving regular medical care (RMC). Methods The prospective multicenter cohort study thrombEVAL (NCT01809015) comprised 1558 individuals receiving RMC and 760 individuals managed by a CS. Independent study monitoring and adjudication of endpoints by an independent review panel were implemented. Results The primary study endpoint (composite of thromboembolism, clinically relevant bleeding and death) occurred in 15.7 per 100 patient-years (py) with RMC and in 7.0 per 100 py with the CS (rate ratio [RR], 2.3; 95% confidence interval [CI], 1.7-3.1). Rates for major and clinically relevant bleeding were higher with RMC than with the CS: 6.8 vs. 2.6 and 10.1 vs. 3.6 per 100 py, respectively. Thromboembolic events showed an RR of 1.5 (95% CI, 0.8-2.6) comparing RMC with the CS. Hospitalization (RR, 2.6; 95% CI, 2.3-3.0) and all-cause mortality (RR, 4.6; 95% CI, 2.8-7.7) were markedly more frequent with RMC. In Cox regression analysis with adjustment for age, sex, cardiovascular risk factors, comorbidities, treatment characteristics and sociodemographic status, hazard ratios (HR) for the primary endpoint (HR, 2.2; 95% CI, 1.5-3.4), clinically relevant bleeding (HR, 3.1; 95% CI, 1.7-5.5), hospitalization (HR, 2.2; 95% CI, 1.8-2.8) and all-cause mortality (HR, 5.6; 95% CI, 2.9-11.0) favored CS treatment. Conclusions In this study, e-health-based management of OAC therapy was associated with a lower frequency of OAC-specific and non-specific adverse events.

[Gracilis tendon augmented reconstruction of the medial patellofemoral ligament with soft tissue fixation at the patellar insertion site]. / Ersatz des medialen patellofemoralen Ligaments durch autologe Gracilissehne mit implantat- und bohrkanalfreier patellarer Fixation.

OBJECTIVE: Reconstruction of the medial patellofemoral ligament with autologous tendon augmentation and soft tissue fixation at the patellar insertion with resorbable suture material. INDICATIONS: Patellofemoral instability due to insufficiency of the medial passive stabilizers and dysplastic trochlea. CONTRAINDICATIONS: Primary traumatic dislocation of the patella without risk factors for patellar redislocation, severe osteoarthritis of the patellofemoral joint, infection. SURGICAL TECHNIQUE: Diagnostic arthroscopy to evaluate cartilage and shape of trochlea and to treat associated injuries. Harvesting of the gracilis tendon and arming with resorbable suture material. Transfer of the tendon through the medial capsule in the anatomical layer of the MPFL and weaving in u-shape through the capsule and periosteum near the patella. Soft tissue fixation with resorbable suture material. Anatomical reconstruction of the femoral insertion site. Femoral fixation with interference screw. POSTOPERATIVE TREATMENT: For 4 weeks, partial (20 kg) weight bearing with crutches; cast with physiotherapy (limited ROM extension, flexion 0-0-90°). Thereafter free range of motion and full weight bearing. RESULTS: 27 patients (age 12-45 years) with patellofemoral instability underwent reconstruction of the medial patellofemoral ligament. Clinical follow-up was assessed up to 12 months postoperatively. After 1 year, the Kujala and Flandry scores increased from preoperatively 72 points to 95 points and 65.7 points to 89.9 points, respectively. One redislocation was observed. Patient satisfaction was significantly increased at 6 months postoperatively. Reconstruction of the medial patellofemoral ligament shows good clinical results after 12 months.

Relevance of depression for anticoagulation management in a routine medical care setting: results from the ThrombEVAL study program.

BACKGROUND: Depressive symptoms have detrimental effects on quality of life and mortality. Poor adherence to a treatment regimen is a potential mechanism for the increased risk of adverse medical events associated with depression. Regarding oral anticoagulation with vitamin K antagonists, adherence is crucial for the outcome. Little is known about the clinical relevance of current depressiveness for anticoagulation treatment. OBJECTIVES: To examine the impact of current depressiveness on anticoagulation treatment in regular medical care. PATIENTS/METHODS: We examined the association between clinically significant depressiveness as assessed by the Patient Health Questionnaire-2 ≥ 2 (PHQ-2 ≥ 2) with the percentage of time in the therapeutic range (TTR), self-rated compliance, several aspects of health literacy, anticoagulation side-effects and treatment satisfaction in a cross-sectional study of 1790 oral anticoagulation outpatients. RESULTS: Seven hundred and sixteen participants (40.0%) had clinically significant depressive symptoms. Depressed persons reported lower compliance with intake of prescribed medication and regular visits for control of anticoagulation, more unspecific side-effects (e.g. pruritus) and lower satisfaction with the anticoagulation treatment and their doctors' expertise and empathy. Depressed as compared with non-depressed individuals had a lower TTR (-4.67; 95% CI, -8.39 to -0.95). Increasing severity of depressiveness was related with decreasing TTR. However, depressiveness lost its significant impact on TTR after multivariable adjustment (-3.11; 95% CI, -6.88 to 0.66). CONCLUSIONS: Clinically significant depressiveness was highly prevalent and impaired several aspects of anticoagulation treatment. Depressiveness should be regarded as a clinically significant condition that needs to be addressed in the management of anticoagulation patients.

The left parietal and premotor cortices: motor attention and selection.

It is well established that the premotor cortex has a central role in the selection of movements. The role of parts of the parietal cortex in movement control has proved more difficult to describe but appears to be related to the preparation and the redirection of movements and movement intentions. We have referred to some of these processes as motor attention. It has been known since the time of William James that covert motor attention can be directed to an upcoming movement just as visuospatial attention can be directed to a location in space. While some parietal regions, particularly in the right hemisphere, are concerned with covert orienting and the redirecting of covert orienting it may be useful to consider other parietal regions, in the anterior inferior parietal lobule and in the posterior superior parietal lobule, particularly in the left hemisphere, as contributing to motor attention. Such parts of the parietal lobe are activated in neuroimaging experiments when subjects covertly prepare movements or switch intended movements. Lesions or transcranial magnetic stimulation (TMS) affect the redirecting of motor attention. The difficulties apraxic patients experience when sequencing movements may partly be due to an inability to redirect motor attention from one movement to another. The role of the premotor cortex in selecting movements is also lateralized to the left hemisphere. Damage to left hemisphere movement selection mechanisms may also contribute to apraxia. If, however, it remains intact after a stroke then the premotor cortex may contribute to the recovery of arm movements. A group of patients with unilateral left hemisphere lesions and impaired movements in the contralateral right hand was studied. Functional magnetic resonance imaging showed that in some cases the premotor cortex in the intact hemisphere was more active when the stroke-affected hand was used. TMS in the same area in the same patients had the most disruptive effect on movements. In summary, patterns of motor impairment and recovery seen after strokes can partly be explained with reference to the roles of the parietal and premotor cortices in motor attention and selection.

The mental number line and the human angular gyrus.

To investigate the hemispheric organization of a language-independent spatial representation of number magnitude in the human brain we applied focal repetitive transcranial magnetic stimulation (rTMS) to the right or left angular gyrus while subjects performed a number comparison task with numbers between 31 and 99. Repetitive TMS over the angular gyrus disrupted performance of a visuospatial search task, and rTMS at the same site disrupted organization of the putative "number line." In some cases the pattern of disruption caused by angular gyrus rTMS suggested that this area normally mediates a spatial representation of number. The effect of angular gyrus rTMS on the number line task was specific. rTMS had no disruptive effect when delivered over another parietal region, the supramarginal gyrus, in either the left or the right hemisphere.

[Aggression, inanimate objects and fantasy of invulnerability]. / Aggression, unbelebte Objekte und die Phantasie der Unzerstörbarkeit.

Some highly aggressive children prefer to symbolize and express their inner experiences by toys, which represent "things" and not living creatures. The special function of this preference represents a defense structure of deanimation after traumatization. It implicates the phantasy, that inanimated objects are not part of the vivid dialogue and can "survive" every attack. Thus in the transferential relationship the deanimation can slowly be reanimated by borrowing the undestroyable aspects of a thing in combination with the suffering feelings of the therapist.

Application of capillary zone electrophoresis for analyzing biotin in pharmaceutical formulations--a comparative study.

The detection limit and reproducibility of capillary zone electrophoresis (CZE) measurement of biotin were compared to those of a spectrophotometric method and those of the determination of the sulphur content by combustion of the biotin sample followed by coulometric titration of the formed SO2. Drug analysis showed that all three methods gave consistent results and were suitable for the determination of biotin. CZE was found to be the best method for the determination of pharmaceutical formulations containing biotin because of its high separation efficiency, short analysis time, ease of instrumentation and sample preconditioning, and good precision.

Effect of n-3 and n-6 fatty acids on 7,12 dimethylbenz (a) anthracene-induced mammary tumorigenesis.

Numerous studies have consistently shown that vegetable oils containing linoleic acid enhance mammary tumorigenesis more effectively than fish oils containing eicosapentaenoic and docohexaenoic acids. The purpose of this investigation was to study these and additional n-3 and n-6 PUFA, e.g., a-linolenic (a-LN) (18:3 n-3) and gamma-linolenic (GLA) (18:3 n-6) acid. Different oils were used as dietary sources of fatty acids: corn (CO) (61% LA); blackcurrant (BCO) (44% LA, 18% GLA and 16% a-LN); fish oil (FO) (mixed with corn oil, 12% LA and 24% EPA + DPA + DHA). Thirty-five-day-old female Sprague-Dawley rats were divided into 5 dietary treatment groups and were allowed to feed ab libitum on one of the test diets: I. BCO (23.5%); II. CO (23.5%); III. BCO (15.5%) + FO (8%); IV. FO (20.5%) + CO (3%); and V. BCO (20.5%) + FO (3%). From 48 to 52 days of age, rats in all five groups were fed rat chow. At 50 days of age, all rats were given 5 mg DMBA by oral intubation, and 2 days later the test diets were resumed until termination of the experiment. Analysis of tumor incidence, and multiplicity data for 5 diet groups indicated that rats fed 23.5% CO (II) exhibited enhanced mammary tumor yields when compared to animals on the remaining 4 diets in the order II greater than I, III, V greater than IV. Since the level of fat (23.5% w/w) was similar in all 5 diets, and body weight gain was in the order IV greater than II greater than I, the results of this study indicate that differences in tumor yields were related to fatty acid composition of diets. In support of this conclusion, fatty acid profiles of RBC and tumor phosphoglycerides reflected dietary fatty acid composition. In groups I and II, even though tumor levels of LA were similar, the levels of GLA, DHLA (20:3 n-6) and a-LN were higher in I compared to II, suggesting that these differences may be associated with lower yields of DMBA-induced mammary tumors in group I. Incorporation of marine type n-3 PUFA (EPA, DPA and DHA) in tumor PL was greater in Group IV compared to plant type n-3 PUFA (a-LN) in Groups I, III, and V. Since tumor yields were the lowest in Group IV, these results suggest that incorporation of marine type n-3 PUFA into cell membranes does not favor development of DMBA-induced mammary tumors.

Dendritic changes in the spinal dorsal horn following transection of a peripheral nerve.

In an attempt to examine the morphologic changes which take place in the spinal dorsal horn as a consequence of peripheral nerve injury, the superficial radial nerve was cut and prevented from regenerating in adult cats. In laminae I-V of the 7th cervical segment of spinal dorsal horn at 2 weeks, 1 and 2 months following transection, small and medium-sized dendritic shafts developed membrane-bounded cavities. These cavities varied in number and size in each dendrite and were sometimes connected to the agranular reticulum. Large cavities often hollowed out a dendrite, leaving little remaining cytoplasm between the cavity membrane and the plasma membrane. Small and large cavities were frequently found open to the intercellular space. Synaptic glomeruli showed a loss of small dendrites with empty scalloped depressions in the central axonal endings of these structures left exposed to enlarged intercellular spaces. In addition, clusters of many enlarged oval or irregular intercellular spaces were found in the neuropil where many cavitated dendrites were observed. At least some of these intercellular spaces were thought to be derived from the loss of dendrites. From these observations we conclude that small and medium-sized dendrites involute through cavitation and eventually disappear from the spinal dorsal horn when primary input is disturbed by transection of peripheral sensory nerves.

An electron microscopic analysis of the trans-synaptic effects of peripheral nerve injury subsequent to tooth pulp extirpations on neurons in laminae I and II of the medullary dorsal horn.

To examine the effects of peripheral nerve injury on second-order neurons in laminae I and II of the medullary dorsal horn, tooth pulps of all mandibular teeth in adult cats on one side were extirpated. This procedure severed and removed the receptors and terminal branches of the primary trigeminal neurons which innervate the tooth pulps of these teeth. The empty pulp chambers were then filled with dental cement to prevent regeneration. At 30 and 60 days postoperatively, membrane-lined cavities had formed inside many of the small-caliber dendrites of second-order neurons in laminae I and II. Cavity formation occurred mainly in dendritic shafts less than 2 micron in diameter and involved dendrites with synaptic vesicles as well as those without synaptic vesicles. The cavities extensively hollowed out these dendrites, often occupying more than half the cross-sectional diameter of the shafts and extending for appreciable distances in the long axis of the shaft. The process of cavitation ultimately resulted in the destruction of the affected dendrites. Many cavities became patent to the intercellular space with the cavity membrane establishing continuity with the dendritic membrane. Many cavities often formed in a single dendrite, and such severely cavitated dendrites became reduced to a trabeculated shell which ultimately fragmented into several small pieces. The presence of synaptic connections from a number of different kinds of axonal endings, including scalloped and dome-shaped endings, was not sufficient to prevent cavitation. The actual severing of synaptic connections on the cavitated dendrite appeared to be a relatively late event in the process since small pieces of dendritic debris could still be found clinging to their axodendritic synapses. Evidence that dendrites were being lost from the neuropil was most readily apparent in many of the disrupted glomeruli in lamina II in which many of the scalloped depressions in the central axonal endings that normally contained small dendrites were empty. Many central axonal endings remained in synaptic contact with only a single dendrite which often showed signs of cavitation. Such central endings showed only subtle remaining traces of their normal scalloped contours. This study demonstrates that injury to the distal branches of primary trigeminal neurons which innervate tooth pulps resulted in trans-synaptic degenerative changes in the dendritic arbors of second-order neurons which destroyed fine-caliber higher order dendrites.

An anatomical demonstration of projections to the medullary dorsal horn (trigeminal nucleus caudalis) from rostral trigeminal nuclei and the contralateral caudal medulla.

This study demonstrates that the medullary dorsal horn (MDH), the most caudal subdivision of the spinal trigeminal nucleus, receives input from neurons located in the trigeminal main sensory nucleus, the more rostral subdivisions of the spinal trigeminal nucleus, and the contralateral MDH. Using the retrograde transport of horseradish peroxidase (HRP), we show here that the MDH receives ipsilateral projections from rostral trigeminal nuclei but not from adjacent areas of the retricular formation. The rostral pole of spinal trigeminal nucleus oralis (nucleus oralis, pars beta) contains the highest density of MDH projection neurons. In addition, the MDH on one side receives projections from contralateral MDH neurons located in layers I, III, IV, V, VII and VIII but not from neurons in layers II and VI. We conclude that: (1) specific subdivisions of rostral trigeminal nuclei send projections to the MDH that could modulate the activity of MDH neurons; (2) projections from trigeminal nuclei to layers V and VI of the MDH, but not from adjacent areas of the reticular formation, provide further evidence that these deeper layers are related functionally to the MDH and trigeminal sensory processes; and (3) several populations of MDH neurons send axons across the midline into the contralateral MDH and may mediate contralateral inhibitory effects.

Enkephalin immunoreactive stalked cells and lamina IIb islet cells in cat substantia gelatinosa.

Neurons in lamina II of the lumbar spinal cords of colchicine-pretreated cats were stained immunocytochemically for enkephalin. Two morphological types were found. The most common type had the light microscopic characteristics of stalked cell. The other type was found in the deep part of the lamina and had the light and electron microscopic characteristics of the lamina IIb islet cell.

Morphology and synaptic connections of ultrafine primary axons in lamina I of the spinal dorsal horn: candidates for the terminal axonal arbors of primary neurons with unmyelinated (C) axons.

Neurons in Rexed's lamina I have the bulk of their dendritic arbors confined within this lamina. This study examines the morphology and synaptic connections of primary axons which generate axonal endings in lamina I of the spinal dorsal horn and are in position to deliver their inputs directly to lamina I neurons. Primary axons were made visible for light and electron microscopical study by applying horseradish peroxidase (HRP) to the severed central stumps of cervical and lumbar dorsal roots and allowing sufficient time for the orthograde movement of the HRP into the terminal axonal arbors. Golgi preparations provided supplementary light microscopical views of these axons. Lamina I receives the terminal arborization of two very different kinds of primary axons. One of these generates many ultrafine endings along unbranched, long rostrocaudally oriented, strand-like collaterals which arise from thin parent branches in Lissauer's tract. In view of these thin parent branches, most ultrafine primary axons are considered to be unmyelinated (C) primary axons. The second kind of primary axon generates large caliber endings on branched collaterals. These arise from relatively thick parent branches in Lissauer's tract which, on the basis of their size, are considered to be myelinated (A delta) primary axons. The scalloped endings of both primary axons lie in the interior of glomeruli where they form axodendritic synapses on small dendritic shafts and spines. It is at these synapses that these two kinds of primary axons are thought to transfer nociceptive and thermal inputs directly to the dendritic arbors of lamina I neurons. Transmitter release at these axodendritic synapses in response to primary inputs can be modified, probably diminished or inhibited, by synaptic events within the glomeruli from at least three sources. Synaptic vesicle-containing dendrites form dendroaxonic synapses on primary endings and two kinds of axons form axoaxonic synapses either on primary endings or on the intervaricose segments of the primary axons.

An HRP study of the central projections of primary trigeminal neurons which innervate tooth pulps in the cat.

Trigeminal ganglia and brain stem of adult cats were studied following HRP injections into tooth pulps or after exposure of the cut end of the inferior alveolar nerve to HRP. Ipsilateral ganglion cells within a wide range of sizes were labeled in both experimental situations, whereas no labeled cells were observed in the contralateral ganglion in any animal. Labeled central branches of tooth pulp and inferior alveolar neurons were observed in all subdivisions of the ipsilateral trigeminal sensory complex. Terminal labeling in the tooth pulp experiments was confined to the dorsomedial parts of the main sensory nucleus and subnuclei oralis and interpolaris. Caudal to the obex terminal labeling was restricted to the medial halves of laminae I, IIa and V of the medullary dorsal horn. In the inferior alveolar nerve experiments dense terminal labeling was observed in the dorsal parts of the main sensory nucleus and subnuclei oralis and interpolaris. Caudal to the obex terminal labeling was located throughout laminae I to V in contrast to the tooth pulp experiments. Neither of the two experimental situations offers any evidence for a bilateral or contralateral brain stem projection of primary trigeminal neurons.

Ultrastructure of descending serotoninergic axonal endings in layers I and II of the dorsal horn.

Serotoninergic axonal endings in layers I and II of the medullary and spinal dorsal horn of the cat were ultrastructurally characterized following uptake of [3H]serotonin. The two most common types were dome-shaped endings which could be distinguished by the size and shape of their agranular synaptic vesicles. The two types of endings were found throughout layers I and II, but were most numerous in layer I. The labeled endings formed both symmetrical and asymmetrical synapses on dendritic shafts and spines, and occasionally a symmetrical synapse on a neuronal soma. Using the technique of anterograde transport of [3H]amino acid, two morphologically identical types of endings were demonstrated as originating from neurons in the caudal raphe nuclei and adjacent reticular formation.

Ultrastructural analysis of medial brain stem afferents to the superficial dorsal horn.

Axonal projections of medial brain stem areas rich in serotonin-containing neurons were identified in layers I and II of cat medullary dorsal horn using EM autoradiography. Following [3H]amino acid injections into the brain stem, labeled axonal endings were found throughout layers I and II but were most numerous in layer I. Three different morphological types of endings could be distinguished. Each type resembled serotonergic axonal endings identified in previous experiments. The labeled endings formed both symmetrical and asymmetrical synapses on dendritic shafts and spines and occasionally on a neuronal soma suggesting that the major site of action of the descending serotonergic afferents is on the neurons in layers I and II.