Arthroscopic capsular release is more effective in pain relief than conservative treatment in patients with frozen shoulder.

BACKGROUND: Frozen shoulder is a common medical condition, but the ideal therapeutic method is yet to be determined. Our aim was to analyze the pain-relieving effect of different treatment options used for the management of this disease. METHODS: Medical records of 59 patients (22 male, 37 female, average age: 55.5 years ±9.9) with early stage primary frozen shoulder were evaluated, their demographic data, physical examination, concomitant diseases and treatment specific data were registered. Life quality and the level of pain were assessed using the Oxford Shoulder Score (OSS) and Numeric Rating Scale (NRS). Different treatment modalities and their effect on pain relief were recorded. Any existing correlation between life quality, pain and demographic data, concomitant diseases or the therapeutic method used was investigated. RESULTS: The level of pain measured on NRS improved from 7.9 ± 1.6 to 1.9 ± 2.2. The most effective therapeutic method in terms of pain relief was surgery, followed by physiotherapy and intraarticular steroid injection (NRS score after treatment: 2 - p < 0.0001; 3.3 - p < 0.0001; 4.9 - p < 0.0001, respectively). Non-steroidal anti-inflammatory drugs (NSAIDs) did not reduce pain significantly. OSS improved from 24 to 43.6 and was not affected by the investigated variables, time to recovery was not influenced by the demographic data, the type of treatment or concomitant diseases. CONCLUSIONS: Arthroscopic capsular release, physiotherapy and intraarticular steroid injection outperformed physical therapy and NSAID treatment in terms of pain relief. Despite of slight but persistent post-therapeutic pain found in half of the cases, treatment was considered satisfactory by the patients. Nor patient specific neither therapy specific data had a significant effect on the course of the disease.

Truncated titin is structurally integrated into the human dilated cardiomyopathic sarcomere.

Heterozygous (HET) truncating variant mutations in the TTN gene (TTNtvs), encoding the giant titin protein, are the most common genetic cause of dilated cardiomyopathy (DCM). However, the molecular mechanisms by which TTNtv mutations induce DCM are controversial. Here, we studied 127 clinically identified DCM human cardiac samples with next-generation sequencing (NGS), high-resolution gel electrophoresis, Western blot analysis, and super-resolution microscopy in order to dissect the structural and functional consequences of TTNtv mutations. The occurrence of TTNtv was found to be 15% in the DCM cohort. Truncated titin proteins matching, by molecular weight, the gene sequence predictions were detected in the majority of the TTNtv+ samples. Full-length titin was reduced in TTNtv+ compared with TTNtv- samples. Proteomics analysis of washed myofibrils and stimulated emission depletion (STED) super-resolution microscopy of myocardial sarcomeres labeled with sequence-specific anti-titin antibodies revealed that truncated titin was structurally integrated into the sarcomere. Sarcomere length-dependent anti-titin epitope position, shape, and intensity analyses pointed at possible structural defects in the I/A junction and the M-band of TTNtv+ sarcomeres, which probably contribute, possibly via faulty mechanosensor function, to the development of manifest DCM.

Business Risk Mitigation in the Development Process of New Monoclonal Antibody Drug Conjugates for Cancer Treatment.

Recent developments aim to extend the cytotoxic effect and therapeutic window of mAbs by constructing antibody-drug conjugates (ADCs), in which the targeting moiety is the mAb that is linked to a highly toxic drug. According to a report from mid of last year, the global ADCs market accounted for USD 1387 million in 2016 and was worth USD 7.82 billion in 2022. It is estimated to increase in value to USD 13.15 billion by 2030. One of the critical points is the linkage of any substituent to the functional group of the mAb. Increasing the efficacy against cancer cells' highly cytotoxic molecules (warheads) are connected biologically. The connections are completed by different types of linkers, or there are efforts to add biopolymer-based nanoparticles, including chemotherapeutic agents. Recently, a combination of ADC technology and nanomedicine opened a new pathway. To fulfill the scientific knowledge for this complex development, our aim is to write an overview article that provides a basic introduction to ADC which describes the current and future opportunities in therapeutic areas and markets. Through this approach, we show which development directions are relevant both in terms of therapeutic area and market potential. Opportunities to reduce business risks are presented as new development principles.

Seasonal changes in photoperiod and temperature lead to changes in cuticular hydrocarbon profiles and affect mating success in Drosophila suzukii.

Seasonal plasticity in insects is often triggered by temperature and photoperiod changes. When climatic conditions become sub-optimal, insects might undergo reproductive diapause, a form of seasonal plasticity delaying the development of reproductive organs and activities. During the reproductive diapause, the cuticular hydrocarbon (CHC) profile, which covers the insect body surface, might also change to protect insects from desiccation and cold temperature. However, CHCs are often important cues and signals for mate recognition and changes in CHC composition might affect mate recognition. In the present study, we investigated the CHC profile composition and the mating success of Drosophila suzukii in 1- and 5-day-old males and females of summer and winter morphs. CHC compositions differed with age and morphs. However, no significant differences were found between the sexes of the same age and morph. The results of the behavioral assays show that summer morph pairs start to mate earlier in their life, have a shorter mating duration, and have more offspring compared to winter morph pairs. We hypothesize that CHC profiles of winter morphs are adapted to survive winter conditions, potentially at the cost of reduced mate recognition cues.

[Reducing the risk of radiation-induced cardiotoxicity in patients with left breast tumor]. / A sugárkezelés okozta cardiotoxicitas kockázatának csökkentése bal oldali emlotumoros betegek kezelése során.

INTRODUCTION: Breast cancer is one of the most common malignancies affecting women. Treatment with drugs and radiotherapy increases the incidence of late cardiovascular disease. It is therefore particularly important to protect the heart from radiation exposure. METHOD: We prepared an irradiation plan for 45 patients with left breast cancer using deep breathing and normal breathing techniques. The plans were compared and analyzed. The irradiation plans were created in the Philips Pinnacle v. 16 planning system. RESULTS: At the same target volume coverage, the use of the deep breathing technique leads to a reduction of the dose burden to the heart and to the left descending coronary branch, thus reducing the incidence of late cardiovascular complications. DISCUSSION: The results obtained show that the use of the deep breathing technique during adjuvant radiotherapy of left-sided breast cancer patients has a beneficial effect on the radiation exposure of the heart. Our results are in good agreement with similar data from national centres. We were not only able to maintain planning target volume coverage, but also to achieve an improvement of 1%. There is a significant difference in dose to the heart and coronary artery. By using the deep breathing technique, we were able to reduce the average cardiac dose by almost half (deep breathing: 2.87 Gy, normal breathing: 5.4 Gy). The coronary exposure was reduced from 19.5 Gy to 10.98 Gy. CONCLUSION: The accuracy of treatment can be further improved by using a respiratory gating system with a surface-guided radiotherapy system. The successful use of deep breathing technique requires professionalism of the treatment staff and good patient cooperation. It is less equipment intensive than a respiration-guided system. The deep breathing technique is no longer considered state-of-the-art in the era of breath-holding, but the experience gained in our department is worth describing because of its relevance to oncocardiology. Orv Hetil. 2023; 164(11): 420-425.

[Introduction of high-precision stereotactic body radiotherapy of lung tumors at Markusovszky Hospital]. / Tüdodaganatok nagy pontosságú stereotaxiás kezelésének bevezetése a Markusovszky Kórházban.

INTRODUCTION: A new, modern computed tomograph simulator was installed in the Oncology Department of the Markusovsky University Teaching Hospital from September 2021. The computed tomography simulator not only makes the work of specialists easier with its automatic contouring tool, but is also able to produce four-dimensional computed tomography scans. This facility is essential for radiotherapy of lung and breast cancer patients. OBJECTIVE: In this paper, we briefly review lung tumors and their treatment options, focusing on radiotherapy requiring high precision. We summarize patient selection criteria, the quality assurance processes for planning and treatment, and the experience gained in treating patients. METHOD: 5 patients were selected for our study. Their disease met the following criteria: 1 nodule, tumor diameter not exceeding 5 cm, patient was inoperable or negated surgery. The planning computed tomography scan was performed with Siemens Somatom go.Sim. At each respiratory phase, the tumor conturs were drawn and then aggregated as an integrated volume and an irradiation plan was prepared on this image. The treatments were performed on a Varian TrueBeam accelerator. RESULTS: Before each treatment, an adjusting CT scan was taken. The higher dose (4 × 12 Gy) treatment caused a reduction in tumor size on the last adjustment scan. DISCUSSION: Stereotaxic treatment, which is already available in Szombathely, may be a good alternative in the treatment of patients with inoperable lung cancer. The method is not burdensome for patients: fewer sessions, short treatment time. CONCLUSION: In the future, we would like to improve the accelerator with a breath capture system, which will allow even more precise treatment. Orv Hetil. 2022; 163(52): 2079-2087.

Citrullinated fibrinogen forms densely packed clots with decreased permeability.

BACKGROUND: Fibrin, the main scaffold of thrombi, is susceptible to citrullination by PAD (peptidyl arginine deiminase) 4, secreted from neutrophils during the formation of neutrophil extracellular traps. Citrullinated fibrinogen (citFg) has been detected in human plasma as well as in murine venous thrombi, and it decreases the lysability and mechanical resistance of fibrin clots. OBJECTIVE: To investigate the effect of fibrinogen citrullination on the structure of fibrin clots. METHODS: Fibrinogen was citrullinated with PAD4 and clotted with thrombin. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) were used to measure fiber thickness, fiber height/width ratio, and fiber persistence length in clots containing citFg. Fiber density was measured with laser scanning microscopy (LSM) and permeability measurements were carried out to estimate the porosity of the clots. The intra-fiber structure of fibrin was analyzed with small-angle X-ray scattering (SAXS). RESULTS: SEM images revealed a decrease in the median fiber diameter that correlated with the fraction of citFg in the clot, while the fiber width/length ratio remained unchanged according to AFM. With SAXS we observed that citrullination resulted in the formation of denser clots in line with increased fiber density shown by LSM. The permeability constant of citrullinated fibrin decreased more than 3-fold indicating significantly decreased porosity. SAXS also showed largely preserved periodicity in the longitudinal assembly of fibrin monomers. CONCLUSION: The current observations of thin fibers combined with dense packing and low porosity in the presence of citFg can provide a structural framework for the mechanical fragility and lytic resistance of citrullinated fibrin.

Large-magnitude (VEI ≥ 7) 'wet' explosive silicic eruption preserved a Lower Miocene habitat at the Ipolytarnóc Fossil Site, North Hungary.

During Earth's history, geosphere-biosphere interactions were often determined by momentary, catastrophic changes such as large explosive volcanic eruptions. The Miocene ignimbrite flare-up in the Pannonian Basin, which is located along a complex convergent plate boundary between Europe and Africa, provides a superb example of this interaction. In North Hungary, the famous Ipolytarnóc Fossil Site, often referred to as "ancient Pompeii", records a snapshot of rich Early Miocene life buried under thick ignimbrite cover. Here, we use a multi-technique approach to constrain the successive phases of a catastrophic silicic eruption (VEI ≥ 7) dated at 17.2 Ma. An event-scale reconstruction shows that the initial PDC phase was phreatomagmatic, affecting ≥ 1500 km2 and causing the destruction of an interfingering terrestrial-intertidal environment at Ipolytarnóc. This was followed by pumice fall, and finally the emplacement of up to 40 m-thick ignimbrite that completely buried the site. However, unlike the seemingly similar AD 79 Vesuvius eruption that buried Pompeii by hot pyroclastic density currents, the presence of fallen but uncharred tree trunks, branches, and intact leaves in the basal pyroclastic deposits at Ipolytarnóc as well as rock paleomagnetic properties indicate a low-temperature pyroclastic event, that superbly preserved the coastal habitat, including unique fossil tracks.

Shortening the thick filament by partial deletion of titin's C-zone alters cardiac function by reducing the operating sarcomere length range.

Titin's C-zone is an inextensible segment in titin, comprised of 11 super-repeats and located in the cMyBP-C-containing region of the thick filament. Previously we showed that deletion of titin's super-repeats C1 and C2 (TtnΔC1-2 model) results in shorter thick filaments and contractile dysfunction of the left ventricular (LV) chamber but that unexpectedly LV diastolic stiffness is normal. Here we studied the contraction-relaxation kinetics from the time-varying elastance of the LV and intact cardiomyocyte, cellular work loops of intact cardiomyocytes, Ca2+ transients, cross-bridge kinetics, and myofilament Ca2+ sensitivity. Intact cardiomyocytes of TtnΔC1-2 mice exhibit systolic dysfunction and impaired relaxation. The time-varying elastance at both LV and single-cell levels showed that activation kinetics are normal in TtnΔC1-2 mice, but that relaxation is slower. The slowed relaxation is, in part, attributable to an increased myofilament Ca2+ sensitivity and slower early Ca2+ reuptake. Cross-bridge dynamics showed that cross-bridge kinetics are normal but that the number of force-generating cross-bridges is reduced. In vivo sarcomere length (SL) measurements revealed that in TtnΔC1-2 mice the operating SL range of the LV is shifted towards shorter lengths. This normalizes the apparent cell and LV diastolic stiffness but further reduces systolic force as systole occurs further down on the ascending limb of the force-SL relation. We propose that the reduced working SLs reflect titin's role in regulating diastolic stiffness by altering the number of sarcomeres in series. Overall, our study reveals that thick filament length regulation by titin's C-zone is critical for normal cardiac function.

Nebulin and Lmod2 are critical for specifying thin-filament length in skeletal muscle.

Regulating the thin-filament length in muscle is crucial for controlling the number of myosin motors that generate power. The giant protein nebulin forms a long slender filament that associates along the length of the thin filament in skeletal muscle with functions that remain largely obscure. Here nebulin's role in thin-filament length regulation was investigated by targeting entire super-repeats in the Neb gene; nebulin was either shortened or lengthened by 115 nm. Its effect on thin-filament length was studied using high-resolution structural and functional techniques. Results revealed that thin-filament length is strictly regulated by the length of nebulin in fast muscles. Nebulin's control is less tight in slow muscle types where a distal nebulin-free thin-filament segment exists, the length of which was found to be regulated by leiomodin-2 (Lmod2). We propose that strict length control by nebulin promotes high-speed shortening and that dual-regulation by nebulin/Lmod2 enhances contraction efficiency.

Triggering typical nemaline myopathy with compound heterozygous nebulin mutations reveals myofilament structural changes as pathomechanism.

Nebulin is a giant protein that winds around the actin filaments in the skeletal muscle sarcomere. Compound-heterozygous mutations in the nebulin gene (NEB) cause typical nemaline myopathy (NM), a muscle disorder characterized by muscle weakness with limited treatment options. We created a mouse model with a missense mutation p.Ser6366Ile and a deletion of NEB exon 55, the Compound-Het model that resembles typical NM. We show that Compound-Het mice are growth-retarded and have muscle weakness. Muscles have a reduced myofibrillar fractional-area and sarcomeres are disorganized, contain rod bodies, and have longer thin filaments. In contrast to nebulin-based severe NM where haplo-insufficiency is the disease driver, Compound-Het mice express normal amounts of nebulin. X-ray diffraction revealed that the actin filament is twisted with a larger radius, that tropomyosin and troponin behavior is altered, and that the myofilament spacing is increased. The unique disease mechanism of nebulin-based typical NM reveals novel therapeutic targets.

[Prevalence of blood transfusion after primary total hip arthroplasty]. / A vértranszfúzió gyakorisága primer csípoprotézis-beültetés után.

Introduction: Total hip arthroplasty is one of the most common surgical procedures that requires blood transfusion, with the possible risk of significant complications. Aim: A retrospective study was performed to analyze the predictors of blood transfusion after primary total hip arthroplasty. Method: We collected the data of 210 consecutive patients undergoing total hip arthroplasty. Patient's data, preoperative hemoglobin and hematocrit level, the type of the prosthesis, the use of a suction drain, tranexamic acid or anticoagulants and the type and amount of blood transfusion were recorded. Results: A total of 41% of our patients required transfusion, 8.6% receiving allogenic blood. Significant predictors of allogenic blood transfusion were preoperative hemoglobin and hematocrit levels, the type of prosthesis, the use of suction drainage and the use of tranexamic acid. Patients with pre-donated autologous blood did not require allogenic blood transfusion. Conclusion: Based on our study, total hip arthroplasty necessitates allogenic blood transfusion in 8.6%. Major predictors associated with the need for transfusion are preoperative hemoglobin and hematocrit levels, the type of prosthesis, the use of suction drainage and the use of tranexamic acid. Pre-donated autologous blood helps to reduce allogenic transfusion rate. Orv Hetil. 2020; 161(8): 290-294.

KBTBD13 is an actin-binding protein that modulates muscle kinetics.

The mechanisms that modulate the kinetics of muscle relaxation are critically important for muscle function. A prime example of the impact of impaired relaxation kinetics is nemaline myopathy caused by mutations in KBTBD13 (NEM6). In addition to weakness, NEM6 patients have slow muscle relaxation, compromising contractility and daily life activities. The role of KBTBD13 in muscle is unknown, and the pathomechanism underlying NEM6 is undetermined. A combination of transcranial magnetic stimulation-induced muscle relaxation, muscle fiber- and sarcomere-contractility assays, low-angle x-ray diffraction, and superresolution microscopy revealed that the impaired muscle-relaxation kinetics in NEM6 patients are caused by structural changes in the thin filament, a sarcomeric microstructure. Using homology modeling and binding and contractility assays with recombinant KBTBD13, Kbtbd13-knockout and Kbtbd13R408C-knockin mouse models, and a GFP-labeled Kbtbd13-transgenic zebrafish model, we discovered that KBTBD13 binds to actin - a major constituent of the thin filament - and that mutations in KBTBD13 cause structural changes impairing muscle-relaxation kinetics. We propose that this actin-based impaired relaxation is central to NEM6 pathology.

Fine mapping titin's C-zone: Matching cardiac myosin-binding protein C stripes with titin's super-repeats.

Titin is largely comprised of serially-linked immunoglobulin (Ig) and fibronectin type-III (Fn3) domains. Many of these domains are arranged in an 11 domain super-repeat pattern that is repeated 11 times, forming the so-named titin C-zone in the A-band region of the sarcomere. Each super-repeat is thought to provide binding sites for thick filament proteins, such as cMyBP-C (cardiac myosin-binding protein C). However, it remains to be established which of titin's 11 C-zone super-repeats anchor cMyBP-C as titin contains 11 super-repeats and cMyBP-C is found in 9 stripes only. To study the layout of titin's C-zone in relation to MyBP-C, immunolabeling studies were performed on mouse skinned myocardium with antibodies to titin and cMyBP-C, using both immuno-electron microscopy and super-resolution optical microscopy. Results indicate that cMyBP-C locates near the interface between titin's C-zone super-repeats. Studies on a mouse model in which two of titin's C-zone repeats have been genetically deleted support that the first Ig domain of a super-repeat is important for anchoring cMyBP-C but also Fn3 domains located at the end of the preceding repeat. Furthermore, not all super-repeat interfaces are equal as the interface between super-repeat 1 and 2 (close to titin's D-zone) does not contain cMyBP-C. Finally, titin's C-zone does not extend all the way to the bare zone but instead terminates at the level of the second myosin crown. This study enhances insights in the molecular layout of the C-zone of titin, its relation to cMyBP-C, and its possible roles in cardiomyopathies.

[Evaluation of cardiovascular diseases in connection with the issuing or renewal of driving licenses following the European Union law harmonization]. / Cardiovascularis betegségek megítélése a gépjármuvezetoi engedélyek kiadásának vagy meghosszabbításának szempontjából az európai uniós jogharmonizációt követoen.

The European Union (EU) law harmonization expects from each EU country to apply the same principles and same standards of the medical evaluation of driving licenses. All EU member states have to apply common evaluations of the driving licenses - based on the EU Regulation 2016/1006 - at the latest from January of this year. Hungary launched this new regulation on the 12th of January 2018. The most important source document of the current national regulation is the expert consensus document "New Standards for Driving and Cardiovascular Diseases" published in 2013. This is the professional evaulation of the cardiovascular diseases which can influence driving, and its importance is highlighted because even the Hungarian law listed this document as a resource. In this summary, in accordance with the current law, we provide a practical guide for the day-to-day work of assessing the permission of driving licence in connection with the different kinds of cardiovascular diseases. Orv Hetil. 2019; 160(10): 370-377.

Downsizing the molecular spring of the giant protein titin reveals that skeletal muscle titin determines passive stiffness and drives longitudinal hypertrophy.

Titin, the largest protein known, forms an elastic myofilament in the striated muscle sarcomere. To establish titin's contribution to skeletal muscle passive stiffness, relative to that of the extracellular matrix, a mouse model was created in which titin's molecular spring region was shortened by deleting 47 exons, the TtnΔ112-158 model. RNA sequencing and super-resolution microscopy predicts a much stiffer titin molecule. Mechanical studies with this novel mouse model support that titin is the main determinant of skeletal muscle passive stiffness. Unexpectedly, the in vivo sarcomere length working range was shifted to shorter lengths in TtnΔ112-158 mice, due to a ~ 30% increase in the number of sarcomeres in series (longitudinal hypertrophy). The expected effect of this shift on active force generation was minimized through a shortening of thin filaments that was discovered in TtnΔ112-158 mice. Thus, skeletal muscle titin is the dominant determinant of physiological passive stiffness and drives longitudinal hypertrophy. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

Nebulin stiffens the thin filament and augments cross-bridge interaction in skeletal muscle.

Nebulin is a giant sarcomeric protein that spans along the actin filament in skeletal muscle, from the Z-disk to near the thin filament pointed end. Mutations in nebulin cause muscle weakness in nemaline myopathy patients, suggesting that nebulin plays important roles in force generation, yet little is known about nebulin's influence on thin filament structure and function. Here, we used small-angle X-ray diffraction and compared intact muscle deficient in nebulin (using a conditional nebulin-knockout, Neb cKO) with control (Ctrl) muscle. When muscles were activated, the spacing of the actin subunit repeat (27 Å) increased in both genotypes; when converted to thin filament stiffness, the obtained value was 30 pN/nm in Ctrl muscle and 10 pN/nm in Neb cKO muscle; that is, the thin filament was approximately threefold stiffer when nebulin was present. In contrast, the thick filament stiffness was not different between the genotypes. A significantly shorter left-handed (59 Å) thin filament helical pitch was found in passive and contracting Neb cKO muscles, as well as impaired tropomyosin and troponin movement. Additionally, a reduced myosin mass transfer toward the thin filament in contracting Neb cKO muscle was found, suggesting reduced cross-bridge interaction. We conclude that nebulin is critically important for physiological force levels, as it greatly stiffens the skeletal muscle thin filament and contributes to thin filament activation and cross-bridge recruitment.