A Rare Case of Invasive Malignant Melanoma Metastasis in the Vulvar Mucosa 11 Years After Diagnosis and Treatment.

Mucosal melanoma is rare and the occurrence of an invasive malignant melanoma metastasis 11 years post-initial diagnosis is equally uncommon. This is a case of a 66-year-old woman with a history of bilateral vulvar invasive melanoma, who presented with an enlarging inguinal mass with associated tenderness upon palpation. After a right inguinal excisional lymph node biopsy, the pathological findings determined the final diagnosis as metastatic melanoma. To the best of our knowledge, this is the first report of vulvar mucosal melanoma metastasis greater than 10 years after initial diagnosis and treatment in the English language. This case discusses how treatment options for metastatic mucosal melanoma pose a challenge in such cases where follow-up for medical care is lacking. It also highlights the need for further preventative techniques and research directed towards screening techniques, staging guidelines, and treatment options for mucosal melanoma.

Ossifying Fibromyxoid Tumor of the Shoulder: A Case Report.

Ossifying fibromyxoid tumor (OFMT) is a rare, slow-growing, mesenchymal tumor with intermediate malignant potential, predominantly affecting middle-aged individuals. Histologically, it presents as a fibrous capsule or pseudocapsule, with a complete or incomplete lamellar bone shell surrounding oval/polygonal cells within a fibromyxoid matrix. Advances in immunohistochemistry have facilitated OFMT identification, with S100 protein expression and INI-1 loss being notable features. CD10 expression is also reported in a small minority of cases. Recent studies highlight a translocation of the PHF-1 gene, proposing a possible etiology for tumorigenesis. Treatment involves wide excision, with long-term follow-up for recurrence or metastasis. In this case, a 61-year-old White male presented to the outpatient surgical office with a painless mass on his right shoulder. The patient reported that the mass first appeared three to four years prior and that it had been growing slowly since the initial presentation. On examination, the patient had a well-circumscribed, 1.5 x 1.5 cm, soft, nontender, nonmobile subcutaneous mass on his right shoulder. The mass was initially suspected to be a subcutaneous cyst based on physical exam, but surgical excision and histopathology established the diagnosis of OFMT that extended to the margins of the specimen. The patient underwent a wider excision for margins and has had a benign postoperative course. The patient was referred to dermatology and oncology for continuation of care. This case demonstrates the necessity for a thorough work-up, appropriate excision, and histopathologic examination to rule in diagnoses of lower incidence with the potential for a worse prognosis. Appropriate and timely diagnoses can guide proper screening for cancer recurrence and management.

Cox7a1 controls skeletal muscle physiology and heart regeneration through complex IV dimerization.

The oxidative phosphorylation (OXPHOS) system is intricately organized, with respiratory complexes forming super-assembled quaternary structures whose assembly mechanisms and physiological roles remain under investigation. Cox7a2l, also known as Scaf1, facilitates complex III and complex IV (CIII-CIV) super-assembly, enhancing energetic efficiency in various species. We examined the role of Cox7a1, another Cox7a family member, in supercomplex assembly and muscle physiology. Zebrafish lacking Cox7a1 exhibited reduced CIV2 formation, metabolic alterations, and non-pathological muscle performance decline. Additionally, cox7a1-/- hearts displayed a pro-regenerative metabolic profile, impacting cardiac regenerative response. The distinct phenotypic effects of cox7a1-/- and cox7a2l-/- underscore the diverse metabolic and physiological consequences of impaired supercomplex formation, emphasizing the significance of Cox7a1 in muscle maturation within the OXPHOS system.

Are Activity Wrist-Worn Devices Accurate for Determining Heart Rate during Intense Exercise?

The market for wrist-worn devices is growing at previously unheard-of speeds. A consequence of their fast commercialization is a lack of adequate studies testing their accuracy on varied populations and pursuits. To provide an understanding of wearable sensors for sports medicine, the present study examined heart rate (HR) measurements of four popular wrist-worn devices, the (Fitbit Charge (FB), Apple Watch (AW), Tomtom runner Cardio (TT), and Samsung G2 (G2)), and compared them with gold standard measurements derived by continuous electrocardiogram examination (ECG). Eight athletes participated in a comparative study undergoing maximal stress testing on a cycle ergometer or a treadmill. We analyzed 1,286 simultaneous HR data pairs between the tested devices and the ECG. The four devices were reasonably accurate at the lowest activity level. However, at higher levels of exercise intensity the FB and G2 tended to underestimate HR values during intense physical effort, while the TT and AW devices were fairly reliable. Our results suggest that HR estimations should be considered cautiously at specific intensities. Indeed, an effective intervention is required to register accurate HR readings at high-intensity levels (above 150 bpm). It is important to consider that even though none of these devices are certified or sold as medical or safety devices, researchers must nonetheless evaluate wrist-worn wearable technology in order to fully understand how HR affects psychological and physical health, especially under conditions of more intense exercise.

A Case of Gallbladder Adenocarcinoma Presenting as Mirizzi Syndrome in a Non-Jaundiced Patient With Recent Weight Loss.

There are many different types of gallbladder diseases, mainly resulting from inflammation. The long-term presence of an insult to the gallbladder leads to chronic inflammation, which is a nidus for complications such as Mirizzi syndrome and gallbladder cancer, both of which can become mimics of one another. Preoperative diagnosis of either gallbladder cancer or Mirizzi syndrome is often difficult, leading to late diagnosis and complicating the patient's treatment course. We report a case of a 65-year-old male who presented with abdominal pain and significant weight loss, with no physical evidence of jaundice and normal liver function. This was initially diagnosed as acute cholecystitis and Mirizzi syndrome before being diagnosed as gallbladder adenocarcinoma on final histology.

Notch and Bmp signaling pathways act coordinately during the formation of the proepicardium.

BACKGROUND: The epicardium is the outer mesothelial layer of the heart. It encloses the myocardium and plays key roles in heart development and regeneration. It derives from the proepicardium (PE), cell clusters that appear in the dorsal pericardium (DP) close to the atrioventricular canal and the venous pole of the heart, and are released into the pericardial cavity. PE cells are advected around the beating heart until they attach to the myocardium. Bmp and Notch signaling influence PE formation, but it is unclear how both signaling pathways interact during this process in the zebrafish. RESULTS: Here, we show that the developing PE is influenced by Notch signaling derived from the endothelium. Overexpression of the intracellular receptor of notch in the endothelium enhances bmp expression, increases the number of pSmad1/5 positive cells in the DP and PE, and enhances PE formation. On the contrary, pharmacological inhibition of Notch1 impairs PE formation. bmp2b overexpression can rescue loss of PE formation in the presence of a Notch1 inhibitor, but Notch gain-of-function could not recover PE formation in the absence of Bmp signaling. CONCLUSIONS: Endothelial Notch signaling activates bmp expression in the heart tube, which in turn induces PE cluster formation from the DP layer.

Analysis of wt1a reporter line expression levels during proepicardium formation in the zebrafish.

The epicardium is the outer mesothelial layer of the heart. It covers the myocardium and plays important roles in both heart development and regeneration. It is derived from the proepicardium (PE), groups of cells that emerges at early developmental stages from the dorsal pericardial layer (DP) close to the atrio-ventricular canal and the venous pole of the heart-tube. In zebrafish, PE cells extrude apically into the pericardial cavity as a consequence of DP tissue constriction, a process that is dependent on Bmp pathway signaling. Expression of the transcription factor Wilms tumor-1, Wt1, which is a leader of important morphogenetic events such as apoptosis regulation or epithelial-mesenchymal cell transition, is also necessary during PE formation. In this study, we used the zebrafish model to compare intensity level of the wt1a reporter line epi:GFP in PE and its original tissue, the DP. We found that GFP is present at higher intensity level in the PE tissue, and differentially wt1 expression at pericardial tissues could be involved in the PE formation process. Our results reveal that bmp2b overexpression leads to enhanced GFP level both in DP and in PE tissues.

Adult sox10+ Cardiomyocytes Contribute to Myocardial Regeneration in the Zebrafish.

During heart regeneration in the zebrafish, fibrotic tissue is replaced by newly formed cardiomyocytes derived from preexisting ones. It is unclear whether the heart is composed of several cardiomyocyte populations bearing different capacity to replace lost myocardium. Here, using sox10 genetic fate mapping, we identify a subset of preexistent cardiomyocytes in the adult zebrafish heart with a distinct gene expression profile that expanded after cryoinjury. Genetic ablation of sox10+ cardiomyocytes impairs cardiac regeneration, revealing that these cells play a role in heart regeneration.

Wilms Tumor 1b Expression Defines a Pro-regenerative Macrophage Subtype and Is Required for Organ Regeneration in the Zebrafish.

Organ regeneration is preceded by the recruitment of innate immune cells, which play an active role during repair and regrowth. Here, we studied macrophage subtypes during organ regeneration in the zebrafish, an animal model with a high regenerative capacity. We identified a macrophage subpopulation expressing Wilms tumor 1b (wt1b), which accumulates within regenerating tissues. This wt1b+ macrophage population exhibited an overall pro-regenerative gene expression profile and different migratory behavior compared to the remainder of the macrophages. Functional studies showed that wt1b regulates macrophage migration and retention at the injury area. Furthermore, wt1b-null mutant zebrafish presented signs of impaired macrophage differentiation, delayed fin growth upon caudal fin amputation, and reduced cardiomyocyte proliferation following cardiac injury that correlated with altered macrophage recruitment to the regenerating areas. We describe a pro-regenerative macrophage subtype in the zebrafish and a role for wt1b in organ regeneration.

Actin dynamics and the Bmp pathway drive apical extrusion of proepicardial cells.

The epicardium, the outer mesothelial layer enclosing the myocardium, plays key roles in heart development and regeneration. During embryogenesis, the epicardium arises from the proepicardium (PE), a cell cluster that appears in the dorsal pericardium (DP) close to the venous pole of the heart. Little is known about how the PE emerges from the pericardial mesothelium. Using a zebrafish model and a combination of genetic tools, pharmacological agents and quantitative in vivo imaging, we reveal that a coordinated collective movement of DP cells drives PE formation. We found that Bmp signaling and the actomyosin cytoskeleton promote constriction of the DP, which enables PE cells to extrude apically. We provide evidence that cell extrusion, which has been described in the elimination of unfit cells from epithelia and the emergence of hematopoietic stem cells, is also a mechanism for PE cells to exit an organized mesothelium and fulfil their developmental fate to form a new tissue layer, the epicardium.

Impact of a phone app on nephrology referral.

BACKGROUND: Various factors can lead to inadequate nephrology referral decisions being taken by clinicians, but a major cause is unawareness of guidelines, recommendations and indications, or of appropriate timing. Today, tools such as smartphone applications (Apps) can make this knowledge more accessible to non-nephrologist clinicians. Our study aim is to determine the effectiveness of a purpose-built app in this respect. METHODS: In a retrospective study, nephrology referrals were compared before and after the introduction of the app in clinical practice. The initial study population consisted of first visits by patients referred to our department in 2015, before the introduction of the app. In 2016, the smartphone app NefroConsultor began to be implemented in our hospital. We compared the initial study population with the results obtained for patients referred in 2017, when the app was in use, taking into account clinical features considered, such as urinalysis, proteinuria or kidney ultrasound, to determine whether these patients met currently recommended criteria for referral. RESULTS: The total study population consisted of 628 patients, of whom 333 were examined before the introduction of the app (in 2015) and 295 when it was in use (in 2017). Among the first group, 132 (39.6%) met established KDIGO criteria for nephrology referral and were considered to be correctly referred. Among the second group, 200 (67.8%) met the criteria and were considered to be properly referred (P = 0.001). The increase in the rate of intervention success (before-after app) was 28.8% with a binomial effect size display (Cohen's d effect size) of 0.751. Before the introduction of the app, data for albuminuria were included in 62.5% of nephrology referrals; in 2017, the corresponding value was 87.5% (P = 0.001). In the same line, referrals including urinalysis rose from 68.5% to 85.8% (P = 0.001). Multivariate regression analysis, using referrals meeting KDIGO criteria as the dependent variable and adjusting for age, sex and referring department, showed that the 2017 group (after the introduction of NefroConsultor) was associated with an odds ratio of 3.57 (95% confidence interval 2.52-5.05) for correct referrals, compared with the 2015 group (P = 0.001). References to proteinuria as the reason for nephrology referral also increased from 23.7% to 34.2% (P = 0.004). CONCLUSIONS: Use of the app is associated with more frequent studies of albuminuria at the time of referral and a greater likelihood of proteinuria being cited as the reason for referral. The smartphone app considered can improve the accessibility of information concerning nephrology referrals and related studies.

"Over the Top" Augmentation for Partial Anterior Cruciate Ligament Tears Using Suspension Device for Tibial Fixation.

A technique for augmentation of the partial anterior cruciate ligament is presented. The patient is positioned supine with the knee flexed 90°. After addressing intra-articular injuries, the autologous semitendinosus tendon is harvested and measured in a doubled manner; after that, the tibial tunnel is performed in the outside-in direction, of the same diameter of the doubled graft. Both ends of the graft are sutured together, after inserting it through the loop of a suspension device, which is attached in its augmentation piece. A lateral femoral incision is made, to approach the joint through the "over the top" position. A looped thread is introduced inside the joint with the aid of a hook. This thread pulls the graft's sutures through the "over the top" position. A femoral tunnel is then drilled in the lateromedial and caudocranial direction. The suspension device is attached to the anterior tibial cortex and the graft is pulled in the caudocranial direction to the femoral tunnel, where an interference screw is used for fixation.

Transient fibrosis resolves via fibroblast inactivation in the regenerating zebrafish heart.

In the zebrafish (Danio rerio), regeneration and fibrosis after cardiac injury are not mutually exclusive responses. Upon cardiac cryoinjury, collagen and other extracellular matrix (ECM) proteins accumulate at the injury site. However, in contrast to the situation in mammals, fibrosis is transient in zebrafish and its regression is concomitant with regrowth of the myocardial wall. Little is known about the cells producing this fibrotic tissue or how it resolves. Using novel genetic tools to mark periostin b- and collagen 1alpha2 (col1a2)-expressing cells in combination with transcriptome analysis, we explored the sources of activated fibroblasts and traced their fate. We describe that during fibrosis regression, fibroblasts are not fully eliminated but become inactivated. Unexpectedly, limiting the fibrotic response by genetic ablation of col1a2-expressing cells impaired cardiomyocyte proliferation. We conclude that ECM-producing cells are key players in the regenerative process and suggest that antifibrotic therapies might be less efficient than strategies targeting fibroblast inactivation.

Tbx5a lineage tracing shows cardiomyocyte plasticity during zebrafish heart regeneration.

During development, mesodermal progenitors from the first heart field (FHF) form a primitive cardiac tube, to which progenitors from the second heart field (SHF) are added. The contribution of FHF and SHF progenitors to the adult zebrafish heart has not been studied to date. Here we find, using genetic tbx5a lineage tracing tools, that the ventricular myocardium in the adult zebrafish is mainly derived from tbx5a+ cells, with a small contribution from tbx5a- SHF progenitors. Notably, ablation of ventricular tbx5a+-derived cardiomyocytes in the embryo is compensated by expansion of SHF-derived cells. In the adult, tbx5a expression is restricted to the trabeculae and excluded from the outer cortical layer. tbx5a-lineage tracing revealed that trabecular cardiomyocytes can switch their fate and differentiate into cortical myocardium during adult heart regeneration. We conclude that a high degree of cardiomyocyte cell fate plasticity contributes to efficient regeneration.

Transosseous Posterior Meniscal Root Reinsertion Using Knotless Anchor for Tibial Fixation.

A technique for posterior meniscal root reinsertion is presented. With the arthroscope in the central transtendinous portal for a better view, a 5-mm transtibial tunnel is created with the aid of an anterior cruciate ligament guide open to 45°. A suture device, which consists of a long needle with an eyelet on its tip, is introduced through the tunnel with a suture thread inserted through the eyelet, while the meniscus is stabilized with a grasper inserted through the anterior portal. The meniscus is pierced with the device, and the suture thread is recovered with said grasper. A finger-tip pincer is inserted through the tunnel to recover the thread. The same procedure is followed to perform a second stitch. A lasso loop is made for both stitches, and the resultant tails are knotted to a knotless suture anchor, which is inserted in the anterior cortex of the tibia, 1 cm distal to the extra-articular end of the tibial tunnel.

CK19 expression in breast tumours and lymph node metastasis after neoadjuvant therapy.

AIMS: Neoadjuvant therapy is used in many patients with breast cancer before surgery, with the aim of reducing the tumour size, allowing conservative resections. Sentinel node biopsy is a conservative procedure for handling the axilla in breast cancer; however, the use of this technique after neoadjuvant treatment is under discussion. For sentinel node assay, methods based on the detection of cytokeratin 19 (CK19) mRNA, such as one-step nucleic acid amplification (OSNA), are available. However, if systemic therapy could alter protein expression, then CK19 would not be a good target for analysing these nodes. The aim of this study was to evaluate the immunohistochemical expression of CK19 within different cancer types, and to compare its expression in breast tumours and axillary nodes before and after treatment. METHODS AND RESULTS: CK19 immunostaining was studied in 162 tumour and node samples before and after treatment. Statistical studies using the McNemar test and chi-square test were performed. CK19 expression was found in 155 cases. We compared CK19 expression in tumour and node biopsies before and after treatment, and we found a lack of significant CK19 expression changes. CONCLUSIONS: Our study has confirmed the preservation of CK19 protein expression in breast cancer cells after neoadjuvant therapy. On the basis of these results, quantification-based methods such as the OSNA CK19 assay, could be an accurate tool with which to analyse the sentinel nodes, regardless of whether they had been obtained before or after treatment.

Alta correlación en la detección de anticuerpos y antígenos de virus del dengue en muestras de suero y plasma / High correlation in dengue antibodies and antigen detection using serum or plasma samples

Introducción. El diagnóstico adecuado de dengue por laboratorio es importante para la atención, así como para el control de brotes y epidemias. Hasta el momento, las pruebas ELISA para diagnóstico serológico de la infección se encuentran validadas en muestras de suero; sin embargo, en algunas ocasiones la cantidad o calidad de la muestra es inadecuada, o solo se tiene acceso a sangre anticoagulada tomada para el análisis de los parámetros hematológicos en el hemograma. Objetivo. Evaluar el desempeño de cuatro pruebas ELISA en muestras de suero y plasma de casos sospechosos de dengue. Materiales y métodos. Se procesaron 42 muestras -21 de suero y 21 de plasma- por las técnicas de ELISA de captura para IgM, ELISA de captura para IgG, ELISA indirecta para IgG y ELISA para la detección del antígeno viral NS1. Resultados. El porcentaje de muestras positivas encontrado fue IgM 33.3%, IgG Captura 33.3%, IgG Indirecta 90.5%, NS1 23.8%. El 42.9% de las muestras fueron positivas por RT-PCR (n=9). Todas las pruebas se comportaron igual tanto en sueros como plasmas (coeficiente Kappa 1.0). Conclusión. Los resultados obtenidos muestran una alta concordancia entre las mediciones realizadas en suero y en plasma, lo cual sugiere que la muestra de plasma puede utilizarse para el diagnóstico y la confirmación de los casos de dengue.

Introduction. Appropriate dengue laboratory diagnosis is an important tool to manage the disease, as well to control possible outbreaks. Currently, ELISA dengue serological tests are validated to use with serum, however sometimes samples quality or quantity is inappropriate or there is only availability of anti-coagulated blood samples which have been used in total blood tests -haemogram-. Objective. To assess the performance of four dengue ELISA tests in serum or plasma samples obtained from presumptive dengue cases. Methodology. Forty two samples, 21 of serum and plasma each, were processed to dengue Capture IgM ultramicro-ELISA, Capture IgG ELISA, Indirect IgG ELISA and NS1 antigen ELISA. Nine out of 21 patients were diagnosed as dengue cases following the diagnostic algorithm. Results. The percentage of positive samples found was Capture IgM 33.3%, Capture IgG 33.3%, Indirect IgG 90.5% and NS1 dengue antigen 23.8%. Comparing the results between all ELISA tests it can be said that they had similar performances both in serum and plasma, the Kappa coefficient obtained was 1.0. Conclusions. These results show a high concordance between the measurements carried out in serum and plasma, which leads to suggest the latter may be used as a tool in the diagnosis and confirmation of dengue cases.

Telomerase Is Essential for Zebrafish Heart Regeneration.

After myocardial infarction in humans, lost cardiomyocytes are replaced by an irreversible fibrotic scar. In contrast, zebrafish hearts efficiently regenerate after injury. Complete regeneration of the zebrafish heart is driven by the strong proliferation response of its cardiomyocytes to injury. Here we show that, after cardiac injury in zebrafish, telomerase becomes hyperactivated, and telomeres elongate transiently, preceding a peak of cardiomyocyte proliferation and full organ recovery. Using a telomerase-mutant zebrafish model, we found that telomerase loss drastically decreases cardiomyocyte proliferation and fibrotic tissue regression after cryoinjury and that cardiac function does not recover. The impaired cardiomyocyte proliferation response is accompanied by the absence of cardiomyocytes with long telomeres and an increased proportion of cardiomyocytes showing DNA damage and senescence characteristics. These findings demonstrate the importance of telomerase function in heart regeneration and highlight the potential of telomerase therapy as a means of stimulating cell proliferation upon myocardial infarction.