Albright hereditary osteodystrophy (AHO) is caused by heterozygous inactivating mutations in GNAS. Patients with maternally-inherited mutations develop pseudohypoparathyroidism type 1A (PHP1A) with ...multi-hormone resistance and aberrant craniofacial and skeletal development among other abnormalities. Chiari malformation type 1 (CM1), a condition in which brain tissue extends into the spinal canal when the skull is too small, has been reported in isolated cases of PHP1A. It has been hypothesized to be associated with growth hormone (GH) deficiency. Given the adverse clinical sequelae that can occur if CM1 goes unrecognized, we investigated the previously undetermined prevalence of CM1, as well as any potential correlations with GH status, given the known increased prevalence of GH deficiency in PHP1A. We also investigated these metrics for low lying cerebellar tonsils (LLCT), defined as tonsillar descent less than 5 mm below the foramen magnum. In addition, we investigated possible correlations of CM1/LLCT with advanced hand/wrist bone ages and craniofacial abnormalities known to occur in PHP1A to determine whether premature chondrocyte differentiation and/or aberrant craniofacial development could be potential etiologies of CM1/LLCT through both human studies and investigations of our AHO mouse model.
We examined patients with PHP1A in our clinic and noticed CM1 more frequently than expected. Therefore, we set out to determine the true prevalence of CM1 and LLCT in a cohort of 54 mutation-confirmed PHP1A participants who had clinically-indicated brain imaging. We examined potential correlations with GH status, clinical features, biological sex, genotype, and hand/wrist bone age determinations. In addition, we investigated the craniofacial development in our mouse model of AHO (Gnas E1+/-m) by histologic analyses, dynamic histomorphometry, and micro-computerized tomographic imaging (MCT) in order to determine potential etiologies of CM1/LLCT in PHP1A.
In our cohort of PHP1A, the prevalence of CM1 is 10.8%, which is at least 10-fold higher than in the general population. If LLCT is included, the prevalence increases to 21.7%. We found no correlation with GH status, biological sex, genotype, or hand/wrist bone age. Through investigations of our Gnas E1+/-m mice, the correlate to PHP1A, we identified a smaller cranial vault and increased cranial dome angle with evidence of hyperostosis due to increased osteogenesis. We also demonstrated that there was premature closure of the spheno-occipital synchondrosis (SOS), a cartilaginous structure essential to the development of the cranial base. These findings lead to craniofacial abnormalities and could contribute to CM1 and LLCT development in PHP1A.
The prevalence of CM1 is at least 10-fold higher in PHP1A compared to the general population and 20-fold higher when including LLCT. This is independent of the GH deficiency that is found in approximately two-thirds of patients with PHP1A. In light of potential serious consequences of CM1, clinicians should have a low threshold for brain imaging. Investigations of our AHO mouse model revealed aberrant cranial formation including a smaller cranium, increased cranial dome angle, hyperostosis, and premature SOS closure rates, providing a potential etiology for the increased prevalence of CM1 and LLCT in PHP1A.
Parathyroid adenomas are a rare incidence in pediatric patients and typically occur secondary to primary hyperparathyroidism. Furthermore, the relation between neurofibromatosis 1 causing parathyroid ...adenoma is poorly understood. Here, we present the successful management of an 11-year old female adolescent diagnosed with primary hyperparathyroidism undergoing surgical excision of a parathyroid adenoma.
With the advent of asfotase alfa, the enzyme replacement therapy (ERT) approved for hypophosphatasia (HPP), health care providers need to navigate management of ERT during critical illness.
We ...present the case of a young girl, treated with ERT for severe perinatal HPP, who had cardiorespiratory arrest in the setting of influenza A. Her life-saving treatment involving extra corporeal membrane oxygenation (ECMO) required a two-week interruption of ERT leading to persistent hypercalcemia and hyperphosphatemia. A three year old female presented with respiratory distress and blood tinged secretions. She was influenza A positive with bilateral opacities on chest X-ray (CXR). Worsening respiratory distress and bradycardic arrest required intubation, CPR and venoarterial ECMO cannulation. She remained on ECMO for 10 days with anticoagulation restrictions requiring her thrice-weekly subcutaneous ERT to be held. Hypercalcemia (12.3 mg/dL) and hyperphosphatemia (7.6 mg/dL) developed two weeks after restarting ERT and resolved six weeks later.
We highlight that the obligatory cessation of ERT while on ECMO led to the loss of functional TNSALP with a profound decrease in bone mineralization leading to excess circulating calcium and phosphorus. In cases where it is necessary to interrupt ERT, we advise close monitoring of calcium and phosphorous levels.
OBJECTIVESWith the advent of asfotase alfa, the enzyme replacement therapy (ERT) approved for hypophosphatasia (HPP), health care providers need to navigate management of ERT during critical illness. ...CASE PRESENTATIONWe present the case of a young girl, treated with ERT for severe perinatal HPP, who had cardiorespiratory arrest in the setting of influenza A. Her life-saving treatment involving extra corporeal membrane oxygenation (ECMO) required a two-week interruption of ERT leading to persistent hypercalcemia and hyperphosphatemia. A three year old female presented with respiratory distress and blood tinged secretions. She was influenza A positive with bilateral opacities on chest X-ray (CXR). Worsening respiratory distress and bradycardic arrest required intubation, CPR and venoarterial ECMO cannulation. She remained on ECMO for 10 days with anticoagulation restrictions requiring her thrice-weekly subcutaneous ERT to be held. Hypercalcemia (12.3 mg/dL) and hyperphosphatemia (7.6 mg/dL) developed two weeks after restarting ERT and resolved six weeks later. CONCLUSIONSWe highlight that the obligatory cessation of ERT while on ECMO led to the loss of functional TNSALP with a profound decrease in bone mineralization leading to excess circulating calcium and phosphorus. In cases where it is necessary to interrupt ERT, we advise close monitoring of calcium and phosphorous levels.
Persistence of Mycobacterium tuberculosis (Mtb) is one of the challenges to successful treatment of tuberculosis (TB). In vitro models of non-replicating Mtb are used to test the efficacy of new ...molecules against Mtb persisters. The H37Ra strain is attenuated for growth in macrophages and mice. We validated H37Ra-infected immunocompetent mice for testing anti-TB molecules against slow/non-replicating Mtb in vivo. Swiss mice were infected intravenously with H37Ra and monitored for CFU burden and histopathology for a period of 12 weeks. The bacteria multiplied at a slow pace reaching a maximum load of ∼106 in 8–12 weeks depending on the infection dose, accompanied by time and dose-dependent histopathological changes in the lungs. Surprisingly, four-weeks of treatment with isoniazid-rifampicin-ethambutol-pyrazinamide combination caused only 0.4 log10 and 1 log10 reduction in CFUs in lungs and spleen respectively. The results show that ∼40 % of the H37Ra bacilli in lungs are persisters after 4 weeks of anti-TB therapy. Isoniazid/rifampicin monotherapy also showed similar results. A combination of bedaquiline and isoniazid reduced the CFU counts to <200 (limit of detection), compared to ∼5000 CFUs by isoniazid alone. The study demonstrates an in vivo model of Mtb persisters for testing new leads using a BSL-2 strain.
Prostate cancer, the second most prevalent malignancy among men, poses a significant threat to affected patients’ well-being due to its poor prognosis. Novel biomarkers are required to enhance ...clinical outcomes and tailor personalized treatments. Herein, we describe our research to explore the prognostic value of long non-coding RNAs (lncRNAs) deregulated by copy number variations (CNVs) in prostate cancer.
The study employed an integrative multi-omics data analysis of the prostate cancer transcriptomic, CNV and methylation datasets to identify prognosis-related subtypes. Subtype-specific expression profiles of protein-coding genes (PCGs) and lncRNAs were determined. We analysed CNV patterns of lncRNAs across the genome to identify subtype-specific lncRNAs with CNV changes. LncRNAs exhibiting significant amplification or deletion and a positive correlation were designated CNV-deregulated lncRNAs. A prognostic risk score model was subsequently developed using these CNV-driven lncRNAs.
Six molecular subtypes of prostate cancer were identified, demonstrating significant differences in prognosis (P = 0.034). The CNV profiles of subtype-specific lncRNAs were examined, revealing their correlation with CNV amplification or deletion. Six lncRNAs (CCAT2, LINC01593, LINC00276, GACAT2, LINC00457, LINC01343) were selected based on significant CNV amplifications or deletions using a rigorous univariate Cox proportional risk regression model. A robust risk score model was developed, stratifying patients into high-risk and low-risk categories. Notably, our prognostic model based on these six lncRNAs exhibited exceptional predictive capabilities for recurrence-free survival (RFS) in prostate cancer patients (P = 0.024).
Our study successfully identified a prognostic risk score model comprising six CNV-driven lncRNAs that could potentially be prognostic biomarkers for prostate cancer. These lncRNA signatures are closely associated with RFS, providing promising prospects for improved patient prognostication and personalized therapeutic strategies for novel prostate cancer treatment.
New chemical scaffolds with novel mechanism of action are urgently needed for the treatment of drug resistant tuberculosis. The oxidative phosphorylation pathway of Mycobacterium tuberculosis ...consists of multiple clinically validated drug targets. This pathway can function through any one of the two terminal oxidases-the proton pumping cytochrome bc1-aa3 supercomplex, or the less energy efficient but high affinity cytochrome bd oxidase. Inhibiting the bc1 complex alone has been found bacteriostatic and not bactericidal. On the other hand, inhibition of both these oxidases turns lethal to the pathogen. In the present study, we used a bc1 complex mutant of M. tuberculosis to screen (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives against the alternate oxidase, i.e., cytochrome bd oxidase. Two molecules, S-021-0601 and S-021-0607 were found to inhibit the mutant with MICs 8 and 16 μM respectively, compared to MICs of 128 and 256 μM against the wild type M. tuberculosis. In the wild type, one of the compounds showed synergism with Q203, an inhibitor of bc1 complex, in inhibiting growth under aerobic conditions. Both compounds showed synergism with Q203 in depleting bacterial ATP and inhibiting oxygen consumption. Both the compounds at 32 μM (one-fourth or one-eighth of their MICs for wild type) were bactericidal to wild type bacteria under hypoxic condition, causing ∼1.9 log10 reduction in viable counts which increased to ∼4-log10 when combined with Q203.
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•Quinazolines as cyt bd oxidase inhibitor.•Synergism with Q203.•Bactericidal.
Doppler Cahoon, Joyce; Wang, Wenjing; Zhu, Yiwen ...
Proceedings of the VLDB Endowment,
08/2022, Letnik:
15, Številka:
12
Journal Article
Recenzirano
Selecting the optimal cloud target to migrate SQL estates from on-premises to the cloud remains a challenge. Current solutions are not only time-consuming and error-prone, requiring significant user ...input, but also fail to provide appropriate recommendations. We present Doppler, a scalable recommendation engine that provides right-sized Azure SQL Platform-as-a-Service (PaaS) recommendations without requiring access to sensitive customer data and queries. Doppler introduces a novel price-performance methodology that allows customers to get a personalized rank of relevant cloud targets solely based on low-level resource statistics, such as latency and memory usage. Doppler supplements this rank with internal knowledge of Azure customer behavior to help guide new migration customers towards one optimal target. Experimental results over a 9-month period from prospective and existing customers indicate that Doppler can identify optimal targets and adapt to changes in customer workloads. It has also found cost-saving opportunities among over-provisioned cloud customers, without compromising on capacity or other requirements. Doppler has been integrated and released in the Azure Data Migration Assistant v5.5, which receives hundreds of assessment requests daily.
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