A bibliometric review of peripartum cardiomyopathy compared to other cardiomyopathies using artificial intelligence and machine learning.

As developments in artificial intelligence and machine learning become more widespread in healthcare, their potential to transform clinical outcomes also increases. Peripartum cardiomyopathy is a rare and poorly-characterised condition that presents as heart failure in the last trimester prior to delivery or within 5-6 months postpartum. The lack of a definitive understanding of the molecular causes and clinical progress of this condition suggests that bibliometrics will be well-suited to creating new insights into this serious clinical problem. We examine similarities and differences between peripartum and its closely related familial dilated cardiomyopathy and idiopathic dilated cardiomyopathy. Using PubMed as the source of bibliometric data, we apply artificial intelligence-supported natural language processing to compare extracted data and genes association with these cardiomyopathies. Gene data were enhanced with additional metadata from third-party datasets and then analysed for their impact and specificity for peripartum cardiomyopathy. Artificial intelligence identified 14 genes that distinguished peripartum from both dilated and familial dilated cardiomyopathy. They are as follows: CTSD, RLN2, MMP23B*, SLC17A5, ST2*, PTHLH, CFH*, CFI, GPT, MR1, Rln1, SRI, STAT5A* and THBD. We then used the Human Protein Atlas website that uses affinity-purified rabbit polyclonal antibodies to identify genes that are expressed at the protein level (bold), or as RNA transcripts (*) in healthy human left ventricles. Additional analysis focussed on the full set of peripartum genes on linkage and specificity to cardiomyopathy yielded a different set of thirteen genes (bold font indicates those expressed in cardiomyocytes: PRL, RLN2, PLN, ST2, CTSD, F2, ACE, STAT3, TTN, SPP1, LGALS3, miR-146a, GNB3, SRI). This type of analysis can highlight new avenues for research, aimed at improving genomics-driven peripartum cardiomyopathy diagnosis as well as potential pathological and clinical sub-classification. We expect that this will allow for future improvements in identification, treatment and management of this condition. The first step in the application of these bibliometric-based artificial intelligence methods is to understand the current knowledge, and it is the aim of this paper to show how this might be achieved.

Phenytoin Reduces Activity of Cardiac Ryanodine Receptor 2; A Potential Mechanism for Its Cardioprotective Action.

Phenytoin is a hydantoin derivative that is used clinically for the treatment of epilepsy and has been reported to have antiarrhythmic actions on the heart. In a failing heart, the elevated diastolic Ca2+ leak from the sarcoplasmic reticulum can be normalized by the cardiac ryanodine receptor 2 (RyR2) inhibitor, dantrolene, without inhibiting Ca2+ release during systole or affecting Ca2+ release in normal healthy hearts. Unfortunately, dantrolene is hepatotoxic and unsuitable for chronic long-term administration. Because phenytoin and dantrolene belong to the hydantoin class of compounds, we test the hypothesis that dantrolene and phenytoin have similar inhibitory effects on RyR2 using a single-channel recording of RyR2 activity in artificial lipid bilayers. Phenytoin produced a reversible inhibition of RyR2 channels from sheep and human failing hearts. It followed a hyperbolic dose response with maximal inhibition of ∼50%, Hill coefficient ∼1, and IC50 ranging from 10 to 20 µM. It caused inhibition at diastolic cytoplasmic [Ca2+] but not at Ca2+ levels in the dyadic cleft during systole. Notably, phenytoin inhibits RyR2 from failing human heart but not from healthy heart, indicating that phenytoin may selectively target defective RyR2 channels in humans. We conclude that phenytoin could effectively inhibit RyR2-mediated release of Ca2+ in a manner paralleling that of dantrolene. Moreover, the IC50 of phenytoin in RyR2 is at least threefold lower than for other ion channels and clinically used serum levels, pointing to phenytoin as a more human-safe alternative to dantrolene for therapies against heart failure and cardiac arrythmias. SIGNIFICANCE STATEMENT: We show that phenytoin, a Na channel blocker used clinically for treatment of epilepsy, is a diastolic inhibitor of cardiac calcium release channels [cardiac ryanodine receptor 2 (RyR2)] at doses threefold lower than its current therapeutic levels. Phenytoin inhibits RyR2 from failing human heart and not from healthy heart, indicating that phenytoin may selectively target defective RyR2 channels in humans and pointing to phenytoin as a more human-safe alternative to dantrolene for therapies against heart failure and cardiac arrhythmias.

Correction to: The Sydney Heart Bank: improving translational research while eliminating or reducing the use of animal models of human heart disease.

In the original version of this article, the name of one of the authors is not correct. The correct name should be W. A. Linke, which is shown correctly in the authorgroup section above.

The Sydney Heart Bank: improving translational research while eliminating or reducing the use of animal models of human heart disease.

The Sydney Heart Bank (SHB) is one of the largest human heart tissue banks in existence. Its mission is to provide high-quality human heart tissue for research into the molecular basis of human heart failure by working collaboratively with experts in this field. We argue that, by comparing tissues from failing human hearts with age-matched non-failing healthy donor hearts, the results will be more relevant than research using animal models, particularly if their physiology is very different from humans. Tissue from heart surgery must generally be used soon after collection or it significantly deteriorates. Freezing is an option but it raises concerns that freezing causes substantial damage at the cellular and molecular level. The SHB contains failing samples from heart transplant patients and others who provided informed consent for the use of their tissue for research. All samples are cryopreserved in liquid nitrogen within 40 min of their removal from the patient, and in less than 5-10 min in the case of coronary arteries and left ventricle samples. To date, the SHB has collected tissue from about 450 failing hearts (>15,000 samples) from patients with a wide range of etiologies as well as increasing numbers of cardiomyectomy samples from patients with hypertrophic cardiomyopathy. The Bank also has hearts from over 120 healthy organ donors whose hearts, for a variety of reasons (mainly tissue-type incompatibility with waiting heart transplant recipients), could not be used for transplantation. Donor hearts were collected by the St Vincent's Hospital Heart and Lung transplantation team from local hospitals or within a 4-h jet flight from Sydney. They were flushed with chilled cardioplegic solution and transported to Sydney where they were quickly cryopreserved in small samples. Failing and/or donor samples have been used by more than 60 research teams around the world, and have resulted in more than 100 research papers. The tissues most commonly requested are from donor left ventricles, but right ventricles, atria, interventricular system, and coronary arteries vessels have also been reported. All tissues are stored for long-term use in liquid N or vapor (170-180 °C), and are shipped under nitrogen vapor to avoid degradation of sensitive molecules such as RNAs and giant proteins. We present evidence that the availability of these human heart samples has contributed to a reduction in the use of animal models of human heart failure.

Ryanodine receptor modification and regulation by intracellular Ca2+ and Mg2+ in healthy and failing human hearts.

RATIONALE: Heart failure is a multimodal disorder, of which disrupted Ca2+ homeostasis is a hallmark. Central to Ca2+ homeostasis is the major cardiac Ca2+ release channel - the ryanodine receptor (RyR2) - whose activity is influenced by associated proteins, covalent modification and by Ca2+ and Mg2+. That RyR2 is remodelled and its function disturbed in heart failure is well recognized, but poorly understood. OBJECTIVE: To assess Ca2+ and Mg2+ regulation of RyR2 from left ventricles of healthy, cystic fibrosis and failing hearts, and to correlate these functional changes with RyR2 modifications and remodelling. METHODS AND RESULTS: The function of RyR2 from left ventricular samples was assessed using lipid bilayer single-channel measurements, whilst RyR2 modification and protein:protein interactions were determined using Western Blots and co-immunoprecipitation. In all failing hearts there was an increase in RyR2 activity at end-diastolic cytoplasmic Ca2+ (100nM), a decreased cytoplasmic [Ca2+] required for half maximal activation (Ka) and a decrease in inhibition by cytoplasmic Mg2+. This was accompanied by significant hyperphosphorylation of RyR2 S2808 and S2814, reduced free thiol content and a reduced interaction with FKBP12.0 and FKBP12.6. Either dephosphorylation of RyR2 using PP1 or thiol reduction using DTT eliminated any significant difference in the activity of RyR2 from healthy and failing hearts. We also report a subgroup of RyR2 in failing hearts that were not responsive to regulation by intracellular Ca2+ or Mg2+. CONCLUSION: Despite different aetiologies, disrupted RyR2 Ca2+ sensitivity and biochemical modification of the channel are common constituents of failing heart RyR2 and may underlie the pathological disturbances in intracellular Ca2+ signalling.

Quantification of thyroxine and 3,5,3'-triiodo-thyronine in human and animal hearts by a novel liquid chromatography-tandem mass spectrometry method.

Assaying tissue T3 and T4 would provide important information in experimental and clinical investigations. A novel method to determine tissue T3 and T4 by HPLC coupled to mass spectrometry is described. The major difference vs. previously described methods lies in the addition of a derivatization step, that is, to convert T3 and T4 into the corresponding butyl esters. The yield of esterification was Ì´ 100% for T3 and 80% for T4. The assay was linear (r>0.99) in the range of 0.2-50 ng/ml, accuracy was in the order of 70-75%, and the minimum tissue amount needed was in the order of 50 mg, that is, about one order of magnitude lower than observed with the same equipment (AB Sciex API 4000 triple quadrupole mass spectrometer) if derivatization was omitted. The method allowed detection of T3 and T4 in human left ventricle biopsies yielding concentrations of 1.51±0.16 and 5.94±0.63 pmol/g, respectively. In rats treated with different dosages of exogenous T3 or T4, good correlations (r>0.90) between plasma and myocardial T3 and T4 concentrations were observed, although in specific subsets different plasma T4 concentrations were not associated with different tissue content in T4. We conclude that this method could provide a novel insight into the relationship between plasma and tissue thyroid hormone levels.

Cluster of differentiation antibody microarrays on plasma immersion ion implanted polycarbonate.

Plasma immersion ion implantation (PIII) modifies the surface properties of polymers, enabling them to covalently immobilize proteins without using linker chemistry. We describe the use of PIII treated polycarbonate (PC) slides as a novel platform for producing microarrays of cluster of differentiation (CD) antibodies. We compare their performance to identical antibody microarrays printed on nitrocellulose-coated glass slides that are currently the industry standard. Populations of leukocytes are applied to the CD microarrays and unbound cells are removed revealing patterns of differentially immobilized cells that are detected in a simple label-free approach by scanning the slides with visible light. Intra-slide and inter-slide reproducibility, densities of bound cells, and limits of detection were determined. Compared to the nitrocellulose-coated glass slides, PIII treated PC slides have a lower background noise, better sensitivity, and comparable or better reproducibility. They require three-fold lower antibody concentrations to yield equivalent signal strength, resulting in significant reductions in production cost. The improved transparency of PIII treated PC in the near-UV and visible wavelengths combined with superior immobilization of biomolecules makes them an attractive platform for a wide range of microarray applications.

A comparison of covalent immobilization and physical adsorption of a cellulase enzyme mixture.

This paper reports the first use of a linker-free covalent approach for immobilizing an enzyme mixture. Adsorption from a mixture is difficult to control due to varying kinetics of adsorption, variations in the degree of unfolding and competitive binding effects. We show that surface activation by plasma immersion ion implantation (PIII) produces a mildly hydrophilic surface that covalently couples to protein molecules and avoids these issues, allowing the attachment of a uniform monolayer from a cellulase enzyme mixture. Atomic force microscopy (AFM) showed that the surface layer of the physically adsorbed cellulase layer on the mildly hydrophobic surface (without PIII) consisted of aggregated enzymes that changed conformation with incubation time. The evolution observed is consistent with the existence of transient complexes previously postulated to explain the long time constants for competitive displacement effects in adsorption from enzyme mixtures. AFM indicated that the covalently coupled bound layer to the PIII-treated surface consisted of a stable monolayer without enzyme aggregates, and became a double layer at longer incubation times. Light scattering analysis showed no indication of aggregates in the solution at room temperature, which indicates that the surface without PIII-treatment induced enzyme aggregation. A model for the attachment process of a protein mixture that includes the adsorption kinetics for both surfaces is presented.

[Pronator quadratus preservation for distal radius fractures with locking palmar plate osteosynthesis. Surgical technique]. / Préservation du muscle carré pronateur dans les ostéosynthèses des fractures de l'extrémité distale du radius par plaque palmaire verrouillée. Technique chirurgicale.

INTRODUCTION: A surgical technique is described to preserve the pronator quadratus muscle when fixing distal radius fractures with volar locking palmar plates. TECHNIQUE: Using a classic volar Henry approach to the wrist, the fibrous distal attachments of the pronator quadratus muscle are released. The locking palmar plate is passed under the pronator quadratus muscle and its correct placement is checked by fluoroscopy. Locking screws are inserted through mini-incisions in pronator quadratus. DISCUSSION: The pronator quadratus muscle plays an important role in wrist function, both in forearm pronation and as a stabilizer of the distal radioulnar joint. Mechanical impingement between the volar plate and the flexor tendons can cause adherences, ruptures and tenosynovitis. These should be reduced if pronator quadratus were intact. CONCLUSION: Preservation of the pronator quadratus muscle is possible for the majority of the fractures of the distal radius treated with locking volar plate osteosynthesis.

An actin-myosin functional assay for analysis of smooth muscle (anti-microfilament) autoantibodies in human plasma.

The detection of serum autoantibodies to smooth muscle (SMA) on rodent gastric mucosa by indirect immunofluorescence (IIF) has long been an immunodiagnostic marker for autoimmune hepatitis type 1 (AIH-1). The reactive antigenic moieties are cytoskeletal proteins which include polymeric F-actin as judged by the staining of microfilaments of tissue by IIF. However, their specificity for actin in AIH-1 can be and usually is uncertain. Using an in vitro functional assay, we compared the effects of Fab fragments of immunoglobulin (IgG) prepared from SMA-positive plasma from two patients with the effects of Fabs from 10 healthy subjects. Fabs are incorporated into an assay where actin (the putative antigen) activates skeletal muscle heavy meromyosin (HMM) ATPase activity. The data from these functional assays provide new insights into the significance of anti-microfilament assays in the diagnosis, and perhaps also pathogenesis, of AIH-1.

Intra-articular compressive stress of the elbow joint in extension: an experimental study using Fuji films.

The use of Fuji films is simple but their manipulation and result interpretation seem to be difficult in the framework of medical research. The reliability and reproducibility of Fuji films have been proved by many previous studies. This study was undertaken to know precisely the articular zones of the elbow and to determine the compressive stress these areas undergo during different activities, in order to assess the importance of different articular contact areas. These data indicate the need for better-adapted elbow prosthesis and can be eventually used to design more durable prosthesis for the elbow. The compressive stress on the radial head was less than 25% in extension. The stress on the radial head varied from the neutral position (23% of the stress), to full pronation (11% of the stress) and to full supination (6% of the stress). The Humero-ulnar compartment had the maximum impact. Coronoid process seemed to be a fundamental element of the elbow joint in extension (60% of total compressive stress). The Medial humero-ulnar compartment was less stressed than the lateral compartment. The radial head does not seem to play a major role in the stability of the elbow in extension if the ulnar collateral ligament exists. The ulnar collateral ligament is essential to the elbow joint stability. The lifespan of a non-constrained prosthesis would depend on the existence of the couple: radial head/ulnar collateral ligament; the absence of radial head could compromise the humero-ulnar stability. This work paved the way for the designing of new non-constrained elbow prosthesis with the reconstruction of the radial head.

Plasma immersion ion implantation treatment of polyethylene for enhanced binding of active horseradish peroxidase.

Robust attachment of active proteins to synthetic surfaces underpins the development of biosensors and protein arrays. This paper presents the results of experiments in which energetic ions, extracted from an inductively coupled nitrogen plasma, are used to modify the surface of ultrahigh molecular weight polyethylene (UHMWPE). The ability of the surface to bind active horseradish peroxidase (HRP) is significantly enhanced by the plasma treatment. The amide signal in infrared spectroscopy indicates an increased quantity of surface-attached protein on the modified surface. The activity of the bound HRP remains high compared with that of protein attached to the untreated surface, after repeated washing in buffer solution. Although Tween 20 was an effective blocking agent for the unmodified polyethylene surface, binding of HRP to the modified surface is not inhibited by its presence. We propose that the treatment produces new binding sites on the surface and that the function of the HRP is retained because the treated surface is substantially more hydrophilic.

[Repair of a triceps tendon rupture using autogenous semi-tendinous and gracilis tendons. A case report and retrospective chart review]. / Réparation d'une rupture complète du triceps brachial par greffe tendineuse au DIDT. A propos d'un cas et revue de la littérature.

The authors report the rare case of an athlete having a complete rupture of the distal triceps tendon associated with severe chronic degenerative pathology of the triceps tendon induced by forced weight-lifting exercises and repetitive corticosteroid injections. Reconstruction of the ruptured triceps was possible using autogenous semi-tendinous and gracilis tendons. The good functional outcome obtained with this technique and the analysis of the retrospective chart review suggest that when direct reattachment is impossible (tendon retraction or loss of tendon in post-traumatic or degenerative injury) or not sufficient (weakness after total elbow arthroplasty surgery), the use of an autogenous semi-tendinous and gracilis tendons permits a good functional outcome.

Anatomic bases of vascularized elbow joint harvesting to achieve vascularized allograft.

In order to later make precise the operative technique of free vascularized elbow allograft transfer, the anatomic conditions necessary for the success of such an operation are reviewed. The exact topography of the nutrient foramina of the humerus, radius, and ulna has been specified on 102 dry bones. The osseous resection at the recipient will have to be carried out on these aspects: nutrient foramina of the three bones of the elbow (at 9 cm from medial epicondyle for the humerus; at 8 cm for the two bones of forearm) in order to preserve diaphysary vascularization of the recipient. A study of arterial and venous vascularization carried out on 18 anatomic specimens showed that the osseous ends were irrigated by a periosteal arterial network and were drained in the centromedullary cavities. Systematization of the arteriovenous blood supply of the distal end of the humerus and proximal ends of the two forearm bones is proposed after dissection of 18 anatomic specimens. Arterial periosteal territories are defined. The importance of each peri articular arteriole is estimated according to the surface of its respective section. A radial, constant, and musculoperiosteal collateral artery from the brachial artery is described. It accounts for 12% (+/- 3%) of the total contribution. The recurrent radial artery is the most significant: 31% (+/- 9%) of the total contribution. The profunda brachii artery is negligible: 4% (+/- 2%) of the total contribution. As well for vascular as mechanical reasons, osteosynthesis will have to be carried out using screwed plates, the optimal location of which is specified according to the arterial periosteal cartography. Ulnar and radial nerves and, to a lesser extent, the median nerve can be harvested "en bloc" preserving their vascular supply in order to make vascularized grafts of them. Free vascularized elbow allograft transfer is technically possible, if one respects these anatomic bases.

[Results of 46 digital replantations. With a minimal follow-up of one year]. / Résultats de 46 replantations digitales. A un an de recul minimum.

Forty six digital replantations were analysed with a minimum follow-up of one year. The mechanism of the injury and the level of the amputation were systematically analysed to asses the objective (mobility, sensitivity, prehension), and the subjective results (pain, vasomotor dysfunction, satisfaction). The replantations were typically in the long fingers in young men (index and middle fingers at the level of the middle phalanx) by work or industrial accident (complete section or digital crushing). Seventeen replantations (37%) were secondarily amputated. Arterial thrombosis was the main cause of amputation in 94% of the cases and had occurred in 50% of the cases by the forty eight postoperative hour. An early revascularization procedure was attempted in ten cases (21%). Among these ten revascularizations procedures, we noted eight failures (80%). During the first six postoperative weeks, the complications of the replantations were skeletal displacements, tendon ruptures and joint subluxations. After six weeks, the complications were joint stiffness (26%), sensory deficits (19.5%), severe cold intolerance (13%), vasomotor dysfunction (10%) with stiffness of the proximal interphalangeal joints in 60% of the cases. We noted other complications such as neuroma of distal stump, cutaneous retraction and deformation of the fingers. Finally, only nine digital replantations (19.5%) evolved favourably with complete restoration of sensorimotor function without any complication. The best results were obtained from amputations of the middle finger with the mechanism of section being a circular saw (40%).

[The anterior interosseous flap in wrist and hand surgery: a series of fifteen cases]. / Le lambeau interosseux antérieur dans la chirurgie du poignet et de la main: à propos de 15 cas.

INTRODUCTION: Fifteen anterior interosseous flaps were used to reconstruct wrist and hand defects in fifteen patients (thirteen men and two women) with a mean of 38 years (27-42 years). PATIENTS AND METHODS: Seven anterior interosseous osteoperiosteal flaps and eight anterior interosseous osteocutaneous flaps were used. Seven island flaps and eight free flaps based on the anterior interosseous artery were raised. The indications were scaphoid non-union (4 cases), first metacarpal non-union (2 cases), proximal phalanx non-union (1 case), Kienböck's disease (2 cases), osteocutaneous phalangeal defects (3 cases), osseous capitatum defect (1 case) and intracarpal arthrodesis (2 cases). RESULTS: Postoperatively, one fracture of the distal end of the radius was noted because of a large osteoperiosteal corticotomy. Osseous reconstruction was usually consolidated at three months. One failure was noticed (Kienböck's disease). No significant deformity was noticed in the donor site. CONCLUSION: The anterior interosseous flap seems to be a useful alternative to reconstruct small or moderate defects in wrist and hand surgery.