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

J Clin Invest. 2020 02 03;130(2):754-767

Authors: de Winter JM, Molenaar JP, Yuen M, van der Pijl R, Shen S, Conijn S, van de Locht M, Willigenburg M, Bogaards SJ, van Kleef ES, Lassche S, Persson M, Rassier DE, Sztal TE, Ruparelia AA, Oorschot V, Ramm G, Hall TE, Xiong Z, Johnson CN, Li F, Kiss B, Lozano-Vidal N, Boon RA, Marabita M, Nogara L, Blaauw B, Rodenburg RJ, Küsters B, Doorduin J, Beggs AH, Granzier H, Campbell K, Ma W, Irving T, Malfatti E, Romero NB, Bryson-Richardson RJ, van Engelen BG, Voermans NC, Ottenheijm CA

Abstract
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.

PMID: 31671076 [PubMed - indexed for MEDLINE]

Hemophagocytic syndrome, a diagnostic challenge in Gastroenterology.

Rev Esp Enferm Dig. 2019 10;111(10):816

Authors: Jiménez Rosales R, Martín-Rodríguez MDM, Redondo-Cerezo E

Abstract
Hemophagocytic lymphohistiocytosis is a syndrome of severe immune activation with macrophage and T- cell infiltration resulting in multi organ damage. We report the case of a patient successfully treated for a haemophagocytic syndrome triggered by a metastatic neoplasm of the rectum. A 57 years old man is initially presented with fever without focus. Despite of wide spectrum antibiotics he developed a multi-organ dysfunction. A bone marrow aspirate showed histiocytes that had phagocytosed hematic cells. Hemophagocytic syndrome was suspected and specific treatment was administered. The patient's condition improved remarkably and he was discharged. Nevertheles, finally, the patient died due to a bad response to chemotherapy. Malignancies are a well known triggering of hemophagocytic lymphohistiocytosis being hematological the most commun malignancy associated. However, solid tumors are anecdotic and, to our knowledge, this case is the first one documented due only to rectal carcinoma.

PMID: 31545066 [PubMed - indexed for MEDLINE]

Striated preferentially expressed protein kinase (SPEG)-deficient skeletal muscles display fewer satellite cells with reduced proliferation and delayed differentiation.

Am J Pathol. 2020 Sep 10;:

Authors: Li Q, Lin J, Rosen SM, Zhang T, Kazerounian S, Luo S, Agrawal PB

Abstract
Centronuclear myopathies (CNMs) are a subtype of congenital myopathies characterized by skeletal muscle weakness and an increase in the number of central myonuclei. SPEG (striated preferentially expressed protein kinase) has been identified as the sixth gene associated with CNM, and it has been shown that striated muscle-specific Speg-knockout (KO) mice have defective triad formation, abnormal excitation-contraction coupling and calcium mishandling. The impact of SPEG deficiency on the survival and function of myogenic cells remains to be deciphered. In this study, we examined the overall population, proliferation, and differentiation of myogenic cells obtained from striated-muscle specific Speg-KO mice and compared them with wild-type (WT) controls. SPEG-deficient skeletal muscles contained fewer myogenic cells, which on further study demonstrated reduced proliferation and delayed differentiation compared to those from WT. Regenerative response to skeletal muscle injury in Speg-KO was compared to that of WT, leading to the identification of similar abnormalities including fewer satellite cells, fewer dividing cells, and an increase in apoptotic cells in KO mice. Overall, these results reveal specific abnormalities in myogenic cell number and behavior associated with SPEG deficiency. Similar SC defects have been reported in mouse models of MTM1- and DNM2-associated CNM, suggestive of shared underlying pathways.

PMID: 32919980 [PubMed - as supplied by publisher]

Diversification of reprogramming trajectories revealed by parallel single-cell transcriptome and chromatin accessibility sequencing.

Sci Adv. 2020 Sep;6(37):

Authors: Xing QR, El Farran CA, Gautam P, Chuah YS, Warrier T, Toh CXD, Kang NY, Sugii S, Chang YT, Xu J, Collins JJ, Daley GQ, Li H, Zhang LF, Loh YH

Abstract
Cellular reprogramming suffers from low efficiency especially for the human cells. To deconstruct the heterogeneity and unravel the mechanisms for successful reprogramming, we adopted single-cell RNA sequencing (scRNA-Seq) and single-cell assay for transposase-accessible chromatin (scATAC-Seq) to profile reprogramming cells across various time points. Our analysis revealed that reprogramming cells proceed in an asynchronous trajectory and diversify into heterogeneous subpopulations. We identified fluorescent probes and surface markers to enrich for the early reprogrammed human cells. Furthermore, combinatory usage of the surface markers enabled the fine segregation of the early-intermediate cells with diverse reprogramming propensities. scATAC-Seq analysis further uncovered the genomic partitions and transcription factors responsible for the regulatory phasing of reprogramming process. Binary choice between a FOSL1 and a TEAD4-centric regulatory network determines the outcome of a successful reprogramming. Together, our study illuminates the multitude of diverse routes transversed by individual reprogramming cells and presents an integrative roadmap for identifying the mechanistic part list of the reprogramming machinery.

PMID: 32917699 [PubMed - as supplied by publisher]

8 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2020/09/12

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

8 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2020/09/12

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Providing high-quality care remotely to patients with rare bone diseases during COVID-19 pandemic.

Orphanet J Rare Dis. 2020 08 31;15(1):228

Authors: Brizola E, Adami G, Baroncelli GI, Bedeschi MF, Berardi P, Boero S, Brandi ML, Casareto L, Castagnola E, Fraschini P, Gatti D, Giannini S, Gonfiantini MV, Landoni V, Magrelli A, Mantovani G, Michelis MB, Nasto LA, Panzeri L, Pianigiani E, Scopinaro A, Trespidi L, Vianello A, Zampino G, Sangiorgi L

Abstract
During the COVID-19 outbreak, the European Reference Network on Rare Bone Diseases (ERN BOND) coordination team and Italian rare bone diseases healthcare professionals created the "COVID-19 Helpline for Rare Bone Diseases" in an attempt to provide high-quality information and expertise on rare bone diseases remotely to patients and healthcare professionals. The present position statement describes the key characteristics of the Helpline initiative, along with the main aspects and topics that recurrently emerged as central for rare bone diseases patients and professionals. The main topics highlighted are general recommendations, pulmonary complications, drug treatment, trauma, pregnancy, children and elderly people, and patient associations role. The successful experience of the "COVID-19 Helpline for Rare Bone Diseases" launched in Italy could serve as a primer of gold-standard remote care for rare bone diseases for the other European countries and globally. Furthermore, similar COVID-19 helplines could be considered and applied for other rare diseases in order to implement remote patients' care.

PMID: 32867855 [PubMed - indexed for MEDLINE]

Re: Rate and Determinants of Completing Neoadjuvant Chemotherapy in Medicare Beneficiaries with Bladder Cancer: A SEER-Medicare Analysis.

J Urol. 2020 08;204(2):363

Authors: Griebling TL

PMID: 32401576 [PubMed - indexed for MEDLINE]

A focus on rare and undiagnosed skin diseases.

Exp Dermatol. 2019 10;28(10):1103-1105

Authors: Bauer JW, Schmuth M, Bodemer C

PMID: 31663654 [PubMed - indexed for MEDLINE]

Impact Of The Priority Review Voucher Program On Drug Development For Rare Pediatric Diseases.

Health Aff (Millwood). 2019 02;38(2):313-319

Authors: Hwang TJ, Bourgeois FT, Franklin JM, Kesselheim AS

Abstract
Only an estimated 5 percent of rare pediatric diseases have a treatment, although collectively they affect more than ten million children in the US. To stimulate drug development for rare pediatric diseases, Congress expanded the priority review voucher (PRV) program in 2012. A pediatric PRV, which can be sold to another manufacturer, requires the FDA to provide priority six-month review rather than the standard ten-month review to another drug of the company's choosing. We compared rare pediatric disease drugs eligible for a PRV and rare adult disease drugs (which are not eligible for a PRV). We found that compared to drugs for rare adult diseases, drugs for rare pediatric diseases progressed more quickly through all phases of clinical testing and were more likely to be first-in-class. The voucher program was not associated with a change in the rate of new pediatric drugs starting or completing clinical testing, but there was a significant increase in the rate of progress from Phase I to Phase II clinical trials after the program was implemented. New policies may be needed to expand the pipeline of therapies for rare pediatric diseases.

PMID: 30715972 [PubMed - indexed for MEDLINE]

Lomitapide for treatment of homozygous familial hypercholesterolemia: The Québec experience.

Atherosclerosis. 2020 Aug 05;310:54-63

Authors: Aljenedil S, Alothman L, Bélanger AM, Brown L, Lahijanian Z, Bergeron J, Couture P, Baass A, Ruel I, Brisson D, Khoury E, Gaudet D, Genest J

Abstract
BACKGROUND AND AIMS: Homozygous familial hypercholesterolemia (HoFH) is an orphan disease, most often caused by bi-allelic mutations of the LDLR gene. Patients with HoFH have elevated LDL-C levels >13 mmol/L, tendinous xanthomata and severe, premature atherosclerotic cardiovascular disease (ASCVD). Untreated, most HoFH patients die of ASCVD in youth. New therapeutic modalities include lomitapide, an inhibitor of microsomal triglyceride transfer protein that lowers hepatic LDL-C production. We have recently identified 79 Canadian patients with HoFH. Here, we describe our experience with lomitapide in the province of Quebec, a geographic area known to have a high prevalence of HoFH.
METHODS: This is a retrospective case series of 12 HoFH patients followed at three lipidology centers in the province of Quebec.
RESULTS: Mean age of the patients was 44 ± 18 years; age at time of HoFH diagnosis ranged from 2 to 59 years. All patients were on a statin and ezetimibe 10 mg/day and five patients were treated with LDL apheresis. Treatment with lomitapide reduced LDL-C levels by 38% (intention-to-treat). Intolerable gastrointestinal side effects were observed in 3/12 patients and were the main reason for treatment discontinuation. Three patients tolerated lomitapide at doses ranging between 5 and 30 mg/day without major side effects. Downwards drug titration was necessary in the 6 remaining patients because of gastrointestinal side effects (n = 5) and elevated liver enzymes (n = 1), and 2 of them finally discontinued treatment.
CONCLUSIONS: Lomitapide may be used to further decrease LDL-C in HoFH patients; gastrointestinal side effects and hepatic toxicity may limit adherence.

PMID: 32906018 [PubMed - as supplied by publisher]

COMDORA-SBN recommendations for patients with rare kidney diseases in relation to the Covid-19 pandemic.

J Bras Nefrol. 2020 Aug 26;42(2 suppl 1):36-40

Authors: Colares VS, Miranda SM, Andrade LGM, Palma LMP, Castro MCR, Silva CAB, Penido MGMG, Sobral R, Vaisbich MH

Abstract
During the Covid-19 pandemic, the issue is how to maintain adequate care for people with other diseases. In this document, the SBN Rare Diseases Committee (COMDORA) gives some guidelines on the care of patients with rare kidney diseases. These patients should follow the recommendations for the general population, bearing in mind that, as they have chronic kidney disease, they are included in the risk group for more serious outcomes if they develop Covid-19. Non-essential decision-making procedures should be postponed. In stable cases under appropriate treatment, we must choose to contact our patients remotely, using teleconsultations and home exam collections (if possible). In the presence of a symptom or sign of decompensation of the underlying disease, or infection with Sars-cov-2, advise the patient to seek medical assistance. The patient should not be waiting to get worse. Changes to the prescription should only be made on a scientific basis. Dosage suspension or change is not recommended, even in cases in which the patient needs to go to a center to receive his medication; in this case, the infusion center must follow the recommendations of the Ministry of Health. If the patient develops Covid-19 and uses any drugs, check the need for dose adjustment of the routine medications. Avoid the use of antimetabolics and anti-CD20 in patients with Covid-19, as they reduce viral clearance and predispose to bacterial infections. Contact between the patient and the medical team is essential; changes are recommended only with specialized medical guidance.

PMID: 32877497 [PubMed - indexed for MEDLINE]

Pneumomediastinum in COVID-19 patients: a case series of a rare complication.

Eur J Cardiothorac Surg. 2020 09 01;58(3):646-647

Authors: Volpi S, Ali JM, Suleman A, Ahmed RN

Abstract
Pneumomediastinum is a rare clinical finding, but one which can be the source of significant concern for clinicians. By presenting 3 such cases, we highlight that pneumomediastinum can complicate the course of a severe coronavirus disease 2019 infection but emphasize that conservative management is the first-line method of treatment, with gradual resorption of the air from the tissues. It is important to be alert to the development of pneumothorax, which will require drainage.

PMID: 32754730 [PubMed - indexed for MEDLINE]

Rare case of venous tumour thrombus from acinic cell carcinoma of the parotid gland.

Ann R Coll Surg Engl. 2020 Sep;102(7):e161-e166

Authors: Yap D, Dragan A, Weller A, Tatla T

Abstract
Head and neck tumour thrombus is a rare pathology and at present there are no reported cases of tumour thrombus secondary to acinic cell carcinoma of the parotid gland. We report a case of an 81-year-old man with an acinic cell carcinoma of the left parotid and an intravenous tumour thrombus extending from the retromandibular vein into the internal jugular vein. This case also highlights the importance of radiological imaging in the management of tumour thrombus.

PMID: 32347741 [PubMed - indexed for MEDLINE]

Overshoot of FVIII activity in patients with acquired hemophilia A who achieve complete remission.

Int J Hematol. 2020 Apr;111(4):544-549

Authors: Ogawa Y, Yanagisawa K, Naito C, Uchiumi H, Ishizaki T, Shimizu H, Gohda F, Ieko M, Ichinose A, Handa H

Abstract
Acquired hemophilia A (AHA) is a rare, life-threatening bleeding disorder caused by autoantibodies against coagulation factor VIII (FVIII). Immunosuppressive therapy for AHA aims to arrest bleeding by eliminating FVIII inhibitors. Factor VIII activity overshoot after complete remission (CR) has been reported anecdotally, but details remain unclear. We retrospectively analyzed data from 17 patients with AHA who achieved CR under immunosuppressive therapy between 2009 and 2019 at Gunma University Hospital. FVIII activity overshoot was defined as ≥ 150%. All 17 patients had low FVIII activity (median 2.1%; range < 1.0-8.9%) due to FVIII inhibition (median 14.7 BU/mL; range 2.0-234.0) and all achieved CR within a median of 39 (range 19-173) days. Overshoot occurred in 11 (64.7%) patients and maximal FVIII activity reached > 200% in six of them. The median duration from CR to overshoot was 13 (range 0-154) days. The FVIII overshoot was transient (72.7%) or persistent (27.3%). Venous thromboembolism developed as a complication of overshoot in one patient due to iliac vein compression by a massive hematoma. Overshoot of FVIII activity after CR occurs more frequently than previously expected in patients with AHA.

PMID: 31939075 [PubMed - indexed for MEDLINE]

Yolk sac tumour of ovary with fever and overt hypothyroidism: rare clinical presentation.

BMJ Case Rep. 2020 Jan 09;13(1):

Authors: Kansara M, Yadav G, Gothwal M, Singh P

Abstract
Yolk sac tumours of the ovary are rare and highly malignant germ cell tumours, which comprise of only 10%-15% of all malignant germ cell tumours. They have various clinical presentations most common being subacute pelvic pain and feeling of lump but sometimes high-grade fever can be one of the rare presentations. Here, we present a case report of a 26-year-old nulliparous woman with 36 weeks gravid uterus size advanced stage yolk sac tumour of one ovary with fever as main clinical presentation and overt hypothyroidism. We did staging laparotomy with total abdominal hysterectomy with bilateral salpingo-oophorectomy and omentectomy with multiple peritoneal biopsies. Postoperatively, we had started adjuvant chemotherapy. Since yolk sac tumours are highly aggressive tumours as they rapidly increase in size, their early diagnosis and appropriate surgical management is required particularly in young women where fertility sparing surgery is possible in early stage with good prognosis.

PMID: 31924708 [PubMed - indexed for MEDLINE]

Incidental urothelial rest within the vermiform appendix of a paediatric male patient: an extremely rare entity.

BMJ Case Rep. 2020 Jan 08;13(1):

Authors: Schild MH, Leckey BD, Coulas A, McCall S

PMID: 31919071 [PubMed - indexed for MEDLINE]

Insights Into the Pathogenesis of Sweet's Syndrome.

Front Immunol. 2019;10:414

Authors: Heath MS, Ortega-Loayza AG

Abstract
Sweet's syndrome, also known as Acute Febrile Neutrophilic Dermatosis, is a rare inflammatory condition. It is considered to be the prototype disease of neutrophilic dermatoses, and presents with acute onset dermal neutrophilic lesions, leukocytosis, and pyrexia. Several variants have been described both clinically and histopathologically. Classifications include classic Sweet's syndrome, malignancy associated, and drug induced. The cellular and molecular mechanisms involved in Sweet's syndrome have been difficult to elucidate due to the large variety of conditions leading to a common clinical presentation. The exact pathogenesis of Sweet's syndrome is unclear; however, new discoveries have shed light on the role of inflammatory signaling, disease induction, and relationship with malignancy. These findings include an improved understanding of inflammasome activation, malignant transformation into dermal infiltrating neutrophils, and genetic contributions. Continued investigations into effective treatments and targeted therapy will benefit patients and improve our molecular understanding of inflammatory diseases, including Sweet's syndrome.

PMID: 30930894 [PubMed - indexed for MEDLINE]

[Optical coherence tomography angiography in the diagnosis of retinal microangiopathy in atypical hemolytic-uremic syndrome (a case report)].

Vestn Oftalmol. 2020;136(4. Vyp. 2):226-234

Authors: Smirnova TV, Kozlovskaya NL, Sheludchenko VM, Budzinskaya MV

Abstract
The article describes a clinical case of acute macular neuroretinopathy and «chronic» paracentral acute middle maculopathy in a patient with atypical hemolytic-uremic syndrome - an orphan disease characterized by systemic thrombosis in the vessels of the microcirculatory bed due to chronic uncontrolled activation of the alternative complement pathway. Optical coherence tomography angiography data confirm the ischemic nature of the disease with localization in the deep vascular plexus of the retina in acute macular neuroretinopathy and in the superficial vascular plexus of the retina in «chronic» paracentral acute middle maculopathy. The use of modern diagnostic methods, including optical coherence tomography angiography, can help improve detection of the pathology and expand its understanding in severe microangiopathic syndromes, which include atypical hemolytic-uremic syndrome.

PMID: 32880144 [PubMed - indexed for MEDLINE]

Fasting-mimicking diet plus chemotherapy in breast cancer treatment.

Nat Commun. 2020 08 26;11(1):4274

Authors: Vernieri C, Ligorio F, Zattarin E, Rivoltini L, de Braud F

PMID: 32848145 [PubMed - indexed for MEDLINE]