The role of GDF5 in regulating enthesopathy development in the Hyp mouse model of XLH.

X-linked hypophosphatemia (XLH) is caused by mutations in PHEX, leading to rickets and osteomalacia. Adults affected with XLH develop a mineralization of the bone-tendon attachment site (enthesis), called enthesopathy, which causes significant pain and impaired movement. Entheses in mice with XLH (Hyp) have enhanced Bone Morphogenetic Protein (BMP) and Indian hedgehog (IHH) signaling. Treatment of Hyp mice with the BMP signaling blocker palovarotene attenuated BMP/IHH signaling in Hyp entheses, thus indicating that BMP signaling plays a pathogenic role in enthesopathy development and that IHH signaling is activated by BMP signaling in entheses. It was previously shown that mRNA expression of Gdf5 is enhanced in Hyp entheses at P14. Thus, to determine a role for GDF5 in enthesopathy development, Gdf5 was deleted globally in Hyp mice and conditionally in Scx + cells of Hyp mice. In both murine models, BMP/IHH signaling was similarly decreased in Hyp entheses, leading to decreased enthesopathy. BMP/IHH signaling remained unaffected in WT entheses with decreased Gdf5 expression. Moreover, deletion of Gdf5 in Hyp entheses starting at P30, after enthesopathy has developed, partially reversed enthesopathy. Taken together, these results demonstrate that while GDF5 is not essential for modulating BMP/IHH signaling in WT entheses, inappropriate GDF5 activity in Scx + cells contributes to XLH enthesopathy development. As such, inhibition of GDF5 signaling may be beneficial for the treatment of XLH enthesopathy.

X-linked hypophosphatemia (XLH) is a rare bone disorder that leads to short stature and poorly mineralized bones. As adults, patients with XLH often develop a mineralization of the bone-tendon attachment site, called enthesopathy, that results in significant pain. We previously showed that Achilles bone-tendon attachment sites (entheses) in mice with XLH (Hyp) have an enthesopathy characterized by increased Bone Morphogenetic Protein (BMP) signaling. In the current studies, we show that treating Hyp mice with the BMP signaling inhibitor palovarotene prevents enthesopathy, demonstrating that the increased BMP signaling in Hyp entheses leads to enthesopathy development. We also reported that expression of Gdf5, which activates BMP signaling, is enhanced in Hyp entheses. Therefore, to determine if the enhanced Gdf5 expression leads to the increased BMP signaling seen Hyp entheses, Gdf5 was deleted from Hyp mice and also deleted specifically in the entheses of Hyp mice. In both mouse models, enthesopathy development was attenuated, demonstrating that the increased Gdf5 expression in Hyp entheses plays a role in enthesopathy development. These data indicate that blocking GDF5 and BMP signaling may prevent enthesopathy in patients with XLH.

Giant Sinoatrial Nodal Artery Aneurysm with Fistula into the Right Atrium Treated by Partial Resection and Plication: A Case Report.

Coronary artery aneurysms (CAAs) occur when an artery dilates 1.5 times the reference vessel. They occur most commonly because of atherosclerosis. CAAs are a rare phenomenon, and it is even rarer to find a giant CAA, which is roughly defined as a size 400% above the reference vessel. Giant CAAs are commonly found in the right coronary artery. The sinoatrial nodal artery (SNA) is among the least common sites for CAA involvement. Sometimes, communication exists between the aneurysm and a chamber of the heart or a great vessel. The consequences of the fistula depend on its size. Because of the rarity of the condition, guidelines are not well developed. However, small CAAs can be managed conservatively, whereas giant CAAs require resection, ligation, and bypass grafting. CAAs have a predilection for males and the elderly. We describe a 40-year-old South Asian woman presenting with mild dyspnea on exertion of 1 year's duration. Echocardiography showed a 60×60 mm cystic sac, subsequently confirmed by computerized tomography, which showed 3 large aneurysms (70×61 mm) and 3 small aneurysms in the SNA. Coronary angiography illustrated that the SNA branched off the left main coronary artery, and the aneurysm communicated with the right coronary artery. The aneurysm was partially resected and plicated.

A systematic review on the available treatment modalities for Bacillus Calmette-Guérin-unresponsive carcinoma in situ and tumors in patients who are ineligible for or decline radical cystectomy.

Introduction: Globally, urothelial bladder carcinoma is a disease which carries a poor prognosis. There are various treatment modalities for urothelial bladder carcinoma with intravesical Bacillus Calmette-Guérin immunotherapy being the most efficacious intravesical therapy and the treatment of choice for patients with carcinoma in situ. A number of chemotherapeutic drugs are also available for the management of Ta/T1 tumors such as mitomycin C and epirubicin. However, relapse and progression is quite common. The optimal management of patients with Bacillus Calmette-Guérin-unresponsive disease remains to be a challenge. The purpose of this study was to conduct a systematic review on the treatment modalities available for the management of Bacillus Calmette-Guérin-unresponsive carcinoma in situ and urothelial bladder carcinoma in patients who are ineligible or decline radical cystectomy. Methods: Two authors independently searched three databases on the treatment modalities available for the management of Bacillus Calmette-Guérin-unresponsive carcinoma in situ and Bacillus Calmette-Guérin-unresponsive urothelial bladder carcinoma. Results: The systematic search resulted in 15 studies. We recommend the use of intravesical CG0070 adenovirus or hyperthermic intravesical chemotherapy mitomycin C in patients with carcinoma in situ only disease. In patients with carcinoma in situ ± Ta/T1 disease, we recommend the use of intravesical radiofrequency-induced chemohyperthermia or electromotive drug administration of mitomycin C. In patients who have Ta/T1 disease, we recommend the use of either hyperthermic intravesical chemotherapy epirubicin or electromotive drug administration mitomycin C followed by chemohyperthermia mitomycin C. If any of these second line therapies fail, an alternative regimen would be a combination of gemcitabine, cabazitaxel, and cisplatin. Conclusion: This recommendation is subject to the available resources and clinical expertise available in different hospitals. More studies using study designs such as randomized controlled trials comparing multiple drugs with larger sample sizes and regular follow-up intervals should be performed to accurately assess the different medications and aid in designing guidelines to guide the management of Bacillus Calmette-Guérin-unresponsive non-muscle invasive intravesical bladder cancer.

Ectopic Mediastinal and Lumbar Thyroid Tissue.

The thyroid gland is found in the neck and corresponds to the 2-4 tracheal cartilages. It is rarely found in other sites and is termed ectopic thyroid tissue (ETT) once found. In this report, we present a case of a 19-year-old female who was diagnosed with ETT in the lumbar region and posterior mediastinal region after total thyroidectomy for a large dominant thyroid nodule. ETT has a unique presentation and physicians should be vigilant to diagnose it correctly and promptly to decrease morbidity associated with the disease.

Toxic Epidermal Necrolysis Secondary to Metronidazole.

Hypersensitivity reactions occur when a host exhibits an inappropriate or exaggerated response to allergens. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are examples of such exaggerated responses to various drugs or illnesses. Both conditions affect the skin and mucosal surfaces of the oral cavity, urethra, and conjunctiva to varying degrees. TEN involves more than 30% of the total body surface area as opposed to SJS with less than 10% involvement. Skin biopsy is considered the gold standard for diagnosis; however, obtaining appropriate clinical context at presentation with the history of a potential offending drug can help diagnose the condition in situations where skin biopsy is not feasible. Metronidazole has been rarely reported as the offending agent for TEN/SJS with only two previously reported cases in the literature. We present the third case of TEN secondary to metronidazole and discuss the potential mechanism of action of metronidazole along with its common side effects. Our case adds to the existing literature of this rare clinical presentation and highlights the importance of the judicious use of metronidazole in clinical practice.

Spectrum of Morphologic Features of Lupus Nephritis According to Nephrology/Renal Pathology Society (ISN/RPS) Classification.

Introduction Lupus nephritis is one of the most important secondary glomerulopathy and a significant cause of chronic renal failure. Early diagnosis is key to improved prognosis. The International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification stratifies renal biopsy evaluation in different classes that correlates with clinical renal outcome. In the current study, we aimed to evaluate the proportion of patients in each class of lupus nephritis in our population. Methods We evaluated renal biopsies of 128 patients that fulfilled the clinical and serologic criteria of lupus nephritis. The histologic classification was done according to the ISN/RPS classification, and immunofluorescence studies were performed. Active and chronic lesions were assessed on renal biopsy, and association of different histopatholgic parameters with lupus classes was done. Results The mean age was 28.85±12.24 years. Most of the patients were from age group ≤25 years (48.4%). Active lesions were seen in 66 (51.6%) patients, with endocapillary hypercellularity being the most common active lesion type, i.e. 81.8%. Chronic lesions were noted in 42 (32.8%) patients, with glomerular sclerosis being the most common chronic lesion type, i.e. 69%. Majority of the patients belonged to class IV (46.9%). Females were more likely to present at advanced lupus stage compared to males, and older patients (>50 years) had a higher chance to present at a late stage (class IV and higher). Active lesions were significantly found more frequently in classes III and IV, while chronic lesions were more likely to present in classes III to V. Conclusion We found that a significant proportion of patients of lupus nephritis in our population presents at an advanced stage as more than 60% patients were of class IV or higher. This signifies lack of appropriate clinical surveillance of patients and assessment of renal functions early in disease course. This also necessitates revision of our locoregional protocols to manage lupus nephritis patients and a need to perform a renal biopsy early in disease course.

Listing of Indian Folk Games for Potential Therapeutic Benefits in Children with Neurodevelopmental Disability.

Background: India has a diverse cultural heritage, with a wealth of indigenous folk games that are culturally ingrained. Due to the ease of acquisition, low costs, and widespread acceptability, this form of games can be incorporated to facilitate and improve physical fitness among children with neurodevelopmental disabilities. Hence this study focuses on the analysis of the therapeutic benefits of traditional Indian folk games. Objective: To explore the therapeutic benefits of traditional Indian folk games. Methodology: Ten traditional Indian folk games were selected through purposive sampling and videotaped on skilled players. Each game was analyzed by two observers based on an operationalized conceptual model by using a six-point Likert scale. Results: Functional domains of the game have been identified and listed by using the operationalized conceptual model. Conclusion: Folk games encompass a variety of functions and can potentially be used for therapeutic purposes in children with neurodevelopmental disabilities.