On the presence and immunoregulatory functions of extracellular microRNAs in the trematode Fasciola hepatica.

Liver flukes represent a paraphyletic group of endoparasitic flatworms that significantly affect man either indirectly due to economic damage on livestock or directly as pathogens. A range of studies have focussed on how these macroscopic organisms can evade the immune system and live inside a hostile environment such as the mammalian liver and bile ducts. Recently, microRNAs, a class of short noncoding gene regulators, have been proposed as likely candidates to play roles in this scenario. MicroRNAs (miRNAs) are key players in development and pathogenicity and are highly conserved between metazoans: identical miRNAs can be found in flatworms and mammalians. Interestingly, miRNAs are enriched in extracellular vesicles (EVs) which are secreted by most cells. EVs constitute an important mode of parasite/host interaction, and recent data illustrate that miRNAs play a vital part. We have demonstrated the presence of miRNAs in the EVs of the trematode species Dicrocoelium dendriticum and Fasciola hepatica (Fhe) and identified potential immune-regulatory miRNAs with targets in the host. After our initial identification of miRNAs expressed by F. hepatica, an assembled genome and additional miRNA data became available. This has enabled us to update the known complement of miRNAs in EVs and speculate on potential immune-regulatory functions that we review here.

The revised microRNA complement of Fasciola hepatica reveals a plethora of overlooked microRNAs and evidence for enrichment of immuno-regulatory microRNAs in extracellular vesicles.

MicroRNAs (miRNAs) are gene regulators that have recently been shown to down-regulate the immune response via extracellular vesicles in the mammalian host of helminthic parasites. Using the miRNA prediction pipeline miRCandRef, we expanded the current miRNA set of the liver fluke Fasciola hepatica (Platyhelminthes, Trematoda) from 16 to 54 miRNAs (42 conserved and 13 novel). Comparing the cellular expression levels with extracellular vesicles, we found all miRNAs expressed and enriched for miRNAs with immuno-regulatory function, tissue growth and cancer. Our findings support the hypothesis that miRNAs are the molecular mediators of the previously demonstrated immune modulatory function of extracellular vesicles.

[Often an orthopedic problem can manifest as chest pain. Cervical vertebrae syndrome mimics myocardial infarct]. / Oft steckt hinter den Brustschmerzen ein orthopädischer Befund. HWS-Syndrom mimt Herzinfarkt.

Up to 20% of all patients with pectoral symptoms have an underlying orthopedic problem. The most common orthopedic conditions that may mimic chest pain radiating into the left arm include slipped disc, cervicothoracic tension syndrome, blockage of intervertebral or rib joints, and intercostal neuralgia. Less common causes of such pain are arthrosis of the shoulder, spondylocystitis, osteoporotic fractures or tumors of the bone. Management is oriented to the underlying cause, and treatment extends from physiotherapeutic measures (rest, heat treatment) via medication (non-steroidal anti-inflammatory drugs, myotonolytic agents) to operative interventions.

[The Freehand System: an implantable neuroprosthesis for functional electrostimulation of the upper extremity]. / Das Freehand-System: Eine implantierbare Neuroprothese zur funktionellen Elektrostimulation der oberen Extremität.

We report on the first experience with the Freehand system in German-speaking countries, an implantable neuroprosthesis developed for the functional electrical stimulation of the upper extremity. Indications for its use are neurological deficits of the cervical spinal cord with active mobility of the shoulder and elbow flexion in tetraplegics, ideally in C5/6 tetraplegics. A further precondition for the implantation of this system is an intact reflex arc of the muscles that are to be stimulated, i.e. of the forearm and hand. Central defects such as hemiparesis, cerebral palsies or athetoid disorders or peripheral nerve palsies (e.g. brachial plexus lesions) are no good indications for the implantation of the Freehand system. We report on patient selection criteria, preoperative percutaneous electrical stimulation, the surgical procedure itself with optional active tendon transpositions, the intensive postoperative rehabilitation program until the patient is able to use the system independently and the life-long after-care.

Prominent ECG repolarization changes associated with intracoronary infusion of normal saline: comparisons with alternate coronary catheter flush solutions.

Normal saline (NS) is commonly used as a coronary catheter flush solution. We tested the hypothesis that intracoronary (i.c.) infusions of lactated Ringer's solution (LR) and LR with 5% dextrose (D5LR), both of which contain potassium and calcium, would be associated with less prominent surface ECG changes compared with i.c. infusions of NS. In 34 patients, 10 mL each of NS, LR, and D5LR at 37 degrees C were infused over 5 sec into the left main coronary artery. A 12-lead ECG was recorded before, continuously during, and after each infusion. Blinded ECG analysis revealed T-wave amplitude changes > 0.2 mV in 94%, 12%, and 3% of patients with the use of i.c. NS, D5LR, and LR, respectively (P < 0.0001, NS vs. D5LR or LR). QT prolongation > 40 msec occurred in 88%, 15%, and 18% of patients with i.c. NS, D5LR, and LR, respectively (P < 0.0001, NS vs. D5LR or LR). QT dispersion was increased by > 40 msec in 26% of patients during i.c. NS infusion compared to only 3% of patients with i.c. LR and D5LR infusions (P < 0.01). In conclusion, i.c. NS infusion is associated with more marked repolarization changes as compared with i.c. LR and D5LR infusions. Since such changes may lower arrhythmogenesis thresholds, the routine use of LR as a coronary catheter flush solution should be considered. Cathet. Cardiovasc. Intervent. 48:359-364, 1999.

Ascending myelopathy in the early stage of spinal cord injury.

A 30-year-old healthy woman was involved in a road traffic accident. She sustained a fracture dislocation of T11/12 with a complete Frankel A paraplegia below T11. She had no associated injuries. High Dose Methylprednisolone was administered according to the NASCIS III protocol (48 h) together with low molecular weight Heparin and gastroprotected medication. Complete transection of the spinal cord and an anterior haematoma from T11 to T12 were confirmed on X rays, CT's and MRI scans. Posterior surgical stabilisation was performed using Isola instrumentation, starting 8 h post injury. Her post surgical period was uneventful except for some episodes of low blood pressure (85/60 mmHg) from which she had no symptoms. On the 12th post operative day, while in the physiotherapy department, she complained of right scapular pain. This occurred every time she was sat up and was associated with paraesthesia of both upper limbs. Two days later she deteriorated neurologically and her level ascended initially to T8 and then to T3. MRI of the spine with and without gadolinium showed spinal cord oedema between C3 and T1. There was no evidence of haemorrhage or syringomyelia. The authors discussed this case making different hypotheses. They are mainly the following: (1) Gradually ascending ischaemia due to a vascular disorder; (2) Double spinal trauma; (3) Ischaemia related to repeated hypotensive episodes; (4) Low grade intramedullary tumour; and (5) Thrombus of the Radicularis Magna artery. The case has been recognised as being very rare and interesting. In the conclusions, the presenting author stresses the importance of adopting MRI-compatible instrumentation for the surgical stabilisation of the spine, and careful monitoring of blood pressure during the acute phase of spinal cord injury. Dr Aito agrees with Mr El Masry about the opportunity of forming a group of clinicians in order to discuss protocols to cope with this devastating complication.

Long-term survival of patients with coronary artery disease and left ventricular dysfunction: implications for the role of myocardial viability assessment in management decisions.

OBJECTIVES: Our purpose was to evaluate the long-term benefit of myocardial viability assessment for stratifying risk and selecting patients with low ejection fraction for coronary artery bypass grafting and to determine the relation between the severity of anginal symptoms, the amount of ischemic myocardium, and clinical outcome. METHODS: We studied 93 consecutive patients with severe coronary artery disease and low ejection fraction (median, 25%) who underwent positron emission tomography to delineate the extent of perfusion-metabolism mismatch (reflecting hibernating myocardium) for potential myocardial revascularization. Median follow-up was 4 years (range, 0 to 6.2 years). RESULTS: Fifty patients received medical therapy, and 43 patients underwent bypass grafting. In Cox survival models, heart failure class, prior myocardial infarction, and positron emission tomographic mismatch were the best predictors of survival. Patients with positron emission tomographic mismatch receiving bypass grafting had improved 4-year survival compared with those on medical therapy (75% versus 30%; P =.007) and a significant improvement in angina and heart failure symptoms. In patients without positron emission tomographic mismatch, bypass grafting tended to improve survival and symptoms only in those patients with severe angina (100% versus 60%; P =.085), whereas no survival advantage was apparent in patients with minimal or no anginal symptoms (63% versus 52%; P =.462). CONCLUSIONS: Patients with low ejection fraction and evidence of viable myocardium by positron emission tomography have improved survival and symptoms with coronary bypass grafting compared with medical therapy. In patients without evidence of viability, survival and symptom improvement with bypass grafting are apparent only among those patients with severe angina.

Functional hand development in tetraplegia.

The development of the 'functional hand' in tetraplegics has been historically facilitated through specialized hand positioning schemes. However, clinical experience at the University Hospital Heidelberg demonstrates no direct relationship between various hand positioning techniques and the probability of functional hand development. The aim of this study was to document the various methods of hand positioning and the resulting functional outcome. In a multi-center study, the paralysed thumb and finger positioning of 64 tetraplegics and the resultant functional outcome was evaluated with a specially developed survey form. Results indicated that the functional outcome of the tetraplegic hand was highly dependent on the level of the spinal cord injury and only to a minor degree dependent upon the different methods of hand positioning employed. The conclusion drawn is that remaining neurologic function after injury determines the final functional outcome of the tetraplegic hand.

Maximal ascending and descending slopes of the T wave in men and women.

To investigate possible sex differences in the dynamics of T wave generation, the maximum instantaneous slope of the ascending and descending limbs of the T wave (max dV/dt and min dV/dt, respectively), were calculated. These rate of repolarization parameters, as well as more traditional repolarization duration parameters (QT, JT, Q to T wave peak [QTm] and J to T wave peak [JTm]), were measured by computer using digitized electrocardiograms (ECGs) from the V5 lead in 562 normal subjects (443 men and 119 women; mean age 37 years), whose heart rates (HRs) were confined to one of three narrow ranges, namely 60 +/- 1, 70 +/- 1, or 80 +/- 1 beats/min. In both men and women, for each HR range absolute values of min dV/dt exceeded those of max dV/dt (P < .0001). However, absolute values of both max dV/dt and min dV/dt were consistently greater in men than in women for each HR range (P < .0001 at HR 60 +/- 1; P < .02 at HR 70 +/- 1, or 80 +/- 1). By using correlation analysis, max dV/dt and min dV/dt were shown to be independent of the repolarization duration variables (r < .30). Thus, whereas in both men and women the descending limb of the T wave is steeper than the ascending limb, the maximum slope of each limb of the T wave is steeper in men than in women. These findings add to a growing body of data indicating fundamental sex differences in the physiology of cardiac repolarization and propensity to torsade de pointes.

Retrospective comparative study of primary intracoronary stenting versus balloon angioplasty for acute myocardial infarction.

Balloon angioplasty has been shown to be an effective therapy for the treatment of acute myocardial infarction but is associated with a high restenosis rate, substantial early recoil, persistent thrombus and need for intracoronary thrombolysis, and a high rate of reclosure. Because many of the limitations of balloon angioplasty in the noninfarction setting are addressed by intracoronary stenting, we examined the results of primary stenting of 18 consecutive patients treated for acute myocardial infarction, and compared the results to those achieved with primary balloon angioplasty in 18 prior cases. Despite the presence of thrombus prior to angioplasty in 13 of the stented patients, no intracoronary thrombolytic therapy was required. Mean percent stenosis using quantitative coronary angiography was 17.7 +/- 10.2% after primary stenting compared with 43.7 +/- 20.3% after primary balloon angioplasty (P < .001). One stent patient who had all anticoagulant and antiplatelet therapy withdrawn early suffered subacute thrombosis. Patients were followed up to 3 yr. Complications were similar in two groups. We conclude that primary stenting for acute myocardial infarction results in superior angiographic appearance as well as resolution of thrombus without the need for routine thrombolysis, and is associated with a low complication rate and excellent short-term clinical patency.

Unrecognized paroxysmal supraventricular tachycardia. Potential for misdiagnosis as panic disorder.

BACKGROUND: The diagnostic criteria for panic disorder include symptoms commonly experienced by patients with paroxysmal supraventricular tachycardia (PSVT). Since electrocardiographic documentation of PSVT can be elusive, symptoms may be ascribed to other conditions. OBJECTIVE: To systematically evaluate the potential for PSVT to simulate panic disorder. METHODS: A retrospective survey of 107 consecutive patients with reentrant PSVT was conducted. Objective and subjective assessments of PSVT symptomatology were made, including the application of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), panic disorder criteria. RESULTS: The criteria for panic disorder according to DSM-IV were fulfilled by 67% of patients. Paroxysmal supraventricular tachycardia was unrecognized after initial medical evaluation in 59 patients (55%), including 13 (41%) of 32 patients with ventricular preexcitation by electrocardiogram, and remained unrecognized for a median of 3.3 years. Prior to eventual identification of PSVT, physicians (nonpsychiatrists) attributed symptoms to panic, anxiety, or stress in 32 (54%) of the 59 patients. When PSVT was unrecognized, women were more likely than men to have symptoms ascribed to psychiatric origins (65% vs 32%, respectively; P < .04). Paroxysmal supraventricular tachycardia was detected in only 6 (9%) of 64 patients undergoing Holter monitoring vs 8 (47%) of 17 patients who wore an event monitor (P < .001). During a 20-month median follow-up, electrophysiologically guided therapy (ablation in 81% of patients) resolved symptoms in 86% of patients; only 4% continued to meet DSM-IV panic disorder criteria without evidence of PSVT recurrence. CONCLUSIONS: The clinical characteristics of patients with PSVT referred for electrophysiologically guided therapy can mimic panic disorder. Diagnosis of PSVT is often delayed by inappropriate rhythm detection techniques (Holter instead of event monitoring) and failure to recognize ventricular preexcitation on the sinus electrocardiogram; symptoms due to unrecognized PSVT are often ascribed to psychiatric conditions.

Age-gender influence on the rate-corrected QT interval and the QT-heart rate relation in families with genotypically characterized long QT syndrome.

OBJECTIVES: We sought to analyze age-gender differences in the rate-corrected QT (QTc) interval in the presence of a QT-prolonging gene. BACKGROUND: Compared with men, women exhibit a longer QTc interval and an increased propensity toward torsade de pointes. In normal subjects, the QTc gender difference reflects QTc interval shortening in men during adolescence. METHODS: QTc intervals were analyzed according to age (< 16 or > or = 16 years) and gender in 460 genotyped blood relatives from families with long QT syndrome linked to chromosome 11p (KVLQT1; n = 199), 7q (HERG; n = 208) or 3p (SCN5A; n = 53). RESULTS: The mean QTc interval in genotype-negative blood relatives (n = 240) was shortest in men, but similar among women, boys and girls. For genotype-positive blood relatives, men exhibited the shortest mean QTc interval in chromosome 7q- and 11p-linked blood relatives (n = 194), but not in the smaller 3p-linked group (n = 26). Among pooled 7q- and 11p-linked blood relatives, multiple regression analysis identified both genotype (p < 0.001) and age-gender group (men vs. women/children; p < 0.001) as significant predictors of the QTc interval; and heart rate (p < 0.001), genotype (p < 0.001) and age-gender group (p = 0.01) as significant predictors of the absolute QT interval. A shorter mean QT interval in men was most evident for heart rates < 60 beats/min. CONCLUSIONS: In familial long QT syndrome linked to either chromosome 7q or 11p, men exhibit shorter mean QTc values than both women and children, for both genotype-positive and -negative blood relatives. Thus, adult gender differences in propensity toward torsade de pointes may reflect the relatively greater presence in men of a factor that blunts QT prolongation responses, especially at slow heart rates.

[Projections and fiber characteristics of sensory afferents of the anterior cruciate ligament in an animal experiment]. / Projektion und Faserqualität der sensiblen Afferenzen aus dem vorderen Kreuzband im Tierexperiment.

The sensory innervation of the rabbit anterior cruciate ligament was studied by retrograde tracing technique using wheat-germ-agglutinin-horseradish-peroxidase (WGA-HRP) and Fast Blue as neuronal tracers. Injection of the tracer into the ligament was followed by histo- and immunohistochemical investigation of labelled nerve cell bodies located in the dorsal root ganglia. In 4 animals we injected the tracer into the joint cavity to label general joint afferents. The segmental distribution of retrogradely labelled neurons following injection into the anterior cruciate ligament (L6, L7, S1) is significantly different from the distribution pattern after injection into the knee joint (L4-S2). Retrogradely labelled nerve cells innervating the anterior cruciate ligament were further investigated using immunohistochemical and morphometric analysis. The sensory innervation of the anterior cruciate ligament is therefore comprised of at least 2 different qualities of sensory afferent nerves: 1. Small neurones immunoreactive to the inflammatory peptide substance P most likely transmitting nociceptive information centrally (44%). 2. Large, presumably fast conducting A-fibre-afferents characterized by neurofilament proteins transmitting proprioceptive information from corpuscular mechanoreceptors (43%). The results of this study put further weight to the importance of the sensory role of the anterior cruciate ligament using neuroanatomical and immunohistochemical techniques.

Probucol-associated tachyarrhythmic events and QT prolongation: importance of gender.

From published articles and adverse reactions reports filed with the FDA (available through the Freedom of Information Act), we analyzed occurrences of tachyarrhythmias and the magnitude of QTc prolongation associated with probucol therapy. Of 16 cases of tachyarrhythmic events reported in association with probucol, 15 (94%) occurred in women (p < 0.01 vs expected value of 58%). Tachyarrhythmias were specifically described as TdP in 11 (63%) cases, all women; additional potential contributory QT-prolonging factors (besides probucol) were not identifiable in 2 of the 11 cases. We also analyzed QTc responses in 359 probucol-treated patients, all having baseline QTc < or = 0.44 sec1/2. At doses of 500 to 1000 mg/day, probucol-associated prolongation of QTc to values > or = 0.45 sec1/2 was observed in 22% of women versus 7% of men (p < 0.001) and to values > or = 0.47 sec1/2 in 8% of women versus 2% of men (p < 0.03). Multivariate analysis identified baseline QTc (p < 0.0001) and female gender (p < 0.03), but neither age nor dose, as significant independent predictors of QTc prolongation to > or = 0.45 sec1/2 with probucol. These findings have relevance to the clinical use of probucol, provide further evidence that women have a relatively greater predisposition to development of acquired long QT syndrome, and carry implications for the design of trials involving QT-prolonging drugs.

Reconstruction of the anterior cruciate ligament with a cyropreserved ACL allograft. A microangiographic and immunohistochemical study in rabbits.

The ACL in the rabbit is innervated by three types of nerve fibres. These subserve vasoconstriction, nociceptive and proprioceptive purposes. The aim of this paper was to investigate the revascularisation and reinnervation of cyropreserved ACL allografts in 22 New Zealand white rabbits. Cyropreserved grafts were used as they may excite less host immune response. Both microangiographic and immunohistochemical methods were used. We found that cryopreserved allografts exhibited little immune response, revascularisation was considerable by the 24th postoperative week and reinnervation was essentially complete by then. No mechanoreceptors were found in ACL allografts. In rabbits, the anatomical basis for the participation of ACL allografts in sensorimotor reflexes is not given before the twelfth week after transplantation.

Increased propensity of women to develop torsades de pointes during complete heart block.

INTRODUCTION: To determine whether an increased female gender susceptibility to torsades de pointes (TdP) may exist in a clinical model of bradycardia-induced long QT syndrome, we investigated reported cases of TdP associated with acquired complete heart block. METHODS AND RESULTS: Seventy-two cases reported in the medical literature dating from 1941 through 1993 were identified, all describing TdP or "transient ventricular tachycardia/fibrillation" (to include those cases reported prior to the use of TdP terminology) in the setting of acquired complete heart block unassociated with QT prolonging drugs. Expected female prevalence in complete heart block was estimated at 52%, based on projections derived from 206,016 hospital discharges in the National Inpatient Profile (Commission on Professional and Hospital Activities, Ann Arbor, MI), over the years 1985 through 1992. During complete heart block, mean heart rate was 37 beats/min in both sexes (combined n = 43), and absolute QT interval ranged from 0.52 to 0.88 seconds, with a mean of 0.68 seconds (n = 25). Female prevalence among patients with TdP during complete heart block was greater than expected: 72% for all studied cases (P < 0.001); 70% (P < 0.04) and 74% (P < 0.02) among those reported prior to (n = 35) and during or after (n = 37) 1980, respectively; 73% (P < 0.03) among those with documented normokalemia (n = 26); and 68% (P = 0.2) among those with a prolonged QT interval and known polymorphic VT (i.e., unequivocal TdP; n = 25). CONCLUSION: Despite inherent limitations of this retrospective study, the data are consistent in suggesting a greater than expected female prevalence among patients with TdP related to complete heart block. This finding lends support to a broadening concept of increased susceptibility of women to the development of TdP in various settings of QT prolongation.

[Exchange of endoprosthesis using a proximal femur resection prosthesis]. / Endoprothesenwechsel mittels proximaler Femurresektionsprothesen.

Total hip arthroplasty (THA) with the use of a Mega prosthesis was performed on 24 patients with significant loss of bone stock in revision THA. A clinical and radiological examination was carried out according to the Enneking evaluation scheme on average 7 years after THA. Pain, active hip motion and strength of hip muscles, walking ability, and activities of daily living rated excellent or good and compared well with the results following conventional THA. Limp and positive Trendelenburg sign were common to all except one after Mega prosthesis implantation and were independent on the type of refixation of the hip abductors. Dislocation of the prosthesis occurred in 16.6% of cases and depended on the type of cup implanted. Remarkable was a periprosthetic callus formation surrounding the stem of the femoral implant.

[Demonstration of the blood supply of human cruciate ligaments using the plastination method]. / Die Darstellung der Blutgefässversorgung des menschlichen Kreuzbandes mit der Plastinationsmethode.

The blood supply of the attachment regions of the anterior and posterior cruciate ligament is demonstrated in 14 cadaver knees by the plastination method. Our findings demonstrate the blood supply by vessels of the synovium. The direct attachment to the bone is free of vessels. Anastomoses between the synovium and the periosteum could be found. In conclusion the surgical coverage of ligament reconstruction and of ligament transplantation by synovium is recommended when ever possible to permit the ingrowth of revascularisation vessels.

Percutaneous balloon valvuloplasty compared with open surgical commissurotomy for mitral stenosis.

BACKGROUND: Percutaneous balloon mitral valvuloplasty has been proposed as an alternative to open surgical commissurotomy for the treatment of rheumatic mitral-valve stenosis. METHODS: We enrolled 60 patients with severe mitral stenosis and favorable valvular anatomy in a prospective, randomized trial comparing the two procedures. All patients underwent cardiac catheterization before the procedure and one week, six months, and three years thereafter. Hemodynamic data were analyzed by investigators who were blinded to the patients' treatment assignments. RESULTS: Mitral-valve areas improved initially in both groups, from a mean (+/- SD) of 0.9 +/- 0.3 cm2 to 2.1 +/- 0.6 cm2 in the balloon-valvuloplasty group (30 patients; P < 0.01) and from 0.9 +/- 0.3 cm2 to 2.0 +/- 0.6 cm2 in the surgical group (30 patients; P < 0.001). Although improvement was maintained in both groups, mitral-valve areas were greater in the patients in the balloon-valvuloplasty group at three years (2.4 +/- 0.6 cm2, vs. 1.8 +/- 0.4 cm2 in the surgery group, P < 0.001). Restenosis occurred in three patients in the balloon-valvuloplasty group and four in the surgery group. One patient in the balloon-valvuloplasty group died of an apparent stroke after 2.5 years; four patients in the balloon-valvuloplasty group had residual atrial septal defects, and three patients (two in the balloon-valvuloplasty group and one in the surgery group) were judged to have severe mitral regurgitation. Seventy-two percent of the patients who underwent balloon valvuloplasty and 57 percent of the surgically treated patients were in New York Heart Association functional class I (i.e., they had no cardiovascular symptoms) at three years. No patient was lost to follow-up. CONCLUSIONS: In the treatment of mitral stenosis, balloon valvuloplasty and open surgical commissurotomy have comparable initial results and low rates of restenosis, and both produce good functional capacity for at least three years. The potential complications associated with balloon valvuloplasty should be noted. The better hemodynamic results at three years, lower cost, and elimination of the need for thoracotomy suggest that balloon valvuloplasty should be considered for all patients with favorable mitral-valve anatomy.