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1.
Pediatr Res ; 2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34601494

RESUMO

BACKGROUND: Apnea of prematurity cannot be reliably measured with current monitoring techniques. Instead, indirect parameters such as oxygen desaturation or bradycardia are captured. We propose a Kalman filter-based detection of respiration activity and hence apnea using multichannel esophageal signals in neonatal intensive care unit patients. METHODS: We performed a single-center observational study with moderately preterm infants. Commercially available nasogastric feeding tubes containing multiple electrodes were used to capture signals with customized software. Multichannel esophageal raw signals were manually annotated, processed using extended Kalman filter, and compared with standard monitoring data including chest impedance to measure respiration activity. RESULTS: Out of a total of 405.4 h captured signals in 13 infants, 100 episodes of drop in oxygen saturation or heart rate were examined. Median (interquartile range) difference in respiratory rate was 0.04 (-2.45 to 1.48)/min between esophageal measurements annotated manually and with Kalman filter and -3.51 (-7.05 to -1.33)/min when compared to standard monitoring, suggesting an underestimation of respiratory rate when using the latter. CONCLUSIONS: Kalman filter-based estimation of respiratory activity using multichannel esophageal signals is safe and feasible and results in respiratory rate closer to visual annotation than that derived from chest impedance of standard monitoring.

2.
J Assoc Physicians India ; 69(4): 11-12, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34470187

RESUMO

OBJECTIVE: Guidelines recommend prescription of statins in all high-risk patients with hypertension irrespective of their cholesterol levels. We performed a prescription audit in India to determine the application of recommendations. METHODS: A registry-based audit of patients with primary diagnosis of hypertension (n=3073) was performed. Details of co-morbidities and medications were obtained. Patients with known vascular disease were excluded. Patients were classified into subgroups based on risk factors and type of therapy. A multivariate model of risk was developed using clinical data and patients were classified into low, moderate and high risk. Statin prescriptions were divided into low, medium and high intensity based on US guidelines. Descriptive statistics are reported. RESULTS: Mean age of patients was 59±13 years, 47 % were women and 26 % were less than 50 years age. Diabetes was noted in 31.1 %, current smoking in 1.3 %, obesity in 14.7 % and hypothyroidism in 7.9 %. Statins were prescribed in 41.2 % (95% CI 39.4-42.9%), more in men compared to women (47.7% vs 33.7%, p<0.001). Most of the patients received moderate intensity statins (83.9%). In age-groups >40, 40-59, 60-79 and 80+ years, statins were prescribed in 18.7%, 36.5%, 49.5% and 49.4% respectively (ptrend <0.001). Statins were prescribed in 52.0% diabetics, 60.9% obese, 52.5% smokers and 34.8% hypothyroid. In the multivariate model statins use in low, medium and high risk patients was 28.4%, 46.6% and 55.1% respectively (ptrend <0.001). CONCLUSION: In an Indian secondary care practice only half of patients with moderate to high risk uncomplicated hypertension receive statins.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Hipertensão , Adulto , Idoso , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Prescrições , Fatores de Risco
3.
Pediatr Neurol ; 123: 50-66, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34399110

RESUMO

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting multiple body systems with wide variability in presentation. In 2013, Pediatric Neurology published articles outlining updated diagnostic criteria and recommendations for surveillance and management of disease manifestations. Advances in knowledge and approvals of new therapies necessitated a revision of those criteria and recommendations. METHODS: Chairs and working group cochairs from the 2012 International TSC Consensus Group were invited to meet face-to-face over two days at the 2018 World TSC Conference on July 25 and 26 in Dallas, TX, USA. Before the meeting, working group cochairs worked with group members via e-mail and telephone to (1) review TSC literature since the 2013 publication, (2) confirm or amend prior recommendations, and (3) provide new recommendations as required. RESULTS: Only two changes were made to clinical diagnostic criteria reported in 2013: "multiple cortical tubers and/or radial migration lines" replaced the more general term "cortical dysplasias," and sclerotic bone lesions were reinstated as a minor criterion. Genetic diagnostic criteria were reaffirmed, including highlighting recent findings that some individuals with TSC are genetically mosaic for variants in TSC1 or TSC2. Changes to surveillance and management criteria largely reflected increased emphasis on early screening for electroencephalographic abnormalities, enhanced surveillance and management of TSC-associated neuropsychiatric disorders, and new medication approvals. CONCLUSIONS: Updated TSC diagnostic criteria and surveillance and management recommendations presented here should provide an improved framework for optimal care of those living with TSC and their families.

4.
Lancet Respir Med ; 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34461049

RESUMO

Lymphangioleiomyomatosis (LAM) is a slowly progressive, low-grade, metastasising neoplasm of women, characterised by infiltration of the lung parenchyma with abnormal smooth muscle-like cells, resulting in cystic lung destruction. The invading cell in LAM arises from an unknown source and harbours mutations in tuberous sclerosis complex (TSC) genes that result in constitutive activation of the mechanistic target of rapamycin (mTOR) pathway, dysregulated cellular proliferation, and a programme of frustrated lymphangiogenesis, culminating in disordered lung remodelling and respiratory failure. Over the past two decades, all facets of LAM basic and clinical science have seen important advances, including improved understanding of molecular mechanisms, novel diagnostic and prognostic biomarkers, effective treatment strategies, and comprehensive clinical practice guidelines. Further research is needed to better understand the natural history of LAM; develop more powerful diagnostic, prognostic, and predictive biomarkers; optimise the use of inhibitors of mTOR complex 1 in the treatment of LAM; and explore novel approaches to the development of remission-inducing therapies.

5.
Front Immunol ; 12: 645717, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815402

RESUMO

Idiopathic Pulmonary Fibrosis (IPF) is a severe fibrotic lung disease characterized by excessive collagen deposition and progressive decline in lung function. Th2 T cell-derived cytokines including IL-4 and IL-13 have been shown to contribute to inflammation and fibrotic remodeling in multiple tissues. Interleukin-31 (IL-31) is a newly identified cytokine that is predominantly produced by CD4 Th2 T cells, but its signaling receptor IL-31RA is primarily expressed by non-hematopoietic cells. However, the potential role of the IL-31-IL31RA axis in pulmonary inflammation and fibrosis has remained largely unknown. To determine the role of IL-31RA deficiency in pulmonary fibrosis, wildtype, and IL-31RA knockout mice were treated with bleomycin and measured changes in collagen deposition and lung function. Notably, the loss of IL-31 signaling attenuated collagen deposition and lung function decline during bleomycin-induced pulmonary fibrosis. The total lung transcriptome analysis showed a significant reduction in fibrosis-associated gene transcripts including extracellular matrix and epithelial cell-associated gene networks. Furthermore, the lungs of human IPF showed an elevated expression of IL-31 when compared to healthy subjects. In support, the percentage of IL-31 producing CD4+ T cells was greater in the lungs and PBMCs from IPF patients compared to healthy controls. Our findings suggest a pathogenic role for IL-31/IL-31RA signaling during bleomycin-induced pulmonary fibrosis. Thus, therapeutic targeting the IL-31-IL-31RA axis may prevent collagen deposition, improve lung function, and have therapeutic potential in pulmonary fibrosis.


Assuntos
Fibrose Pulmonar Idiopática/tratamento farmacológico , Receptores de Interleucina/fisiologia , Animais , Bleomicina/toxicidade , Colágeno/metabolismo , Feminino , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/imunologia , Fibrose Pulmonar Idiopática/fisiopatologia , Interleucinas/fisiologia , Pulmão/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Interleucina/antagonistas & inibidores
6.
Quant Imaging Med Surg ; 11(4): 1619-1627, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33816196

RESUMO

Vascular access procedures are crucial for the management of various critically ill pediatric and adult patients. Venous access is commonly performed in the form routine as well as tunneled peripherally inserted central catheters (PICC). These venous accesses are commonly used in emergency, surgical as well as ICU settings, for various infusions, total parenteral nutrition, long term intravenous antibiotics, frequent blood draws, etc. PICC insertion is guided using ultrasound and fluoroscopic guidance, which decreases the risk of complications that are otherwise seen with central venous accesses like triple lumen catheters, etc. PICC insertion and care is very simple and can be performed by specially trained PICC nurses and that helps in decreasing the overall cost of healthcare. This review article is written with educational intent for the readers to discuss indications, contraindications, procedure techniques, imaging, care of routine as well as tunneled PICC.

7.
J Affect Disord ; 286: 204-212, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33740637

RESUMO

INTRODUCTION: Attenuated adult hippocampal neurogenesis may manifest in affective symptomatology and/or resistance to antidepressant treatment. While early-life adversity and the short variant ('s') of the serotonin transporter gene's long polymorphic region (5-HTTLPR) are suggested as interacting risk factors for affective disorders, no studies have examined whether their superposed risk effectuates neurogenic changes into adulthood. Similarly, it is not established whether reduced hippocampal volume in adolescence, variously identified as a marker and antecedent of affective disorders, anticipates diminished adult neurogenesis. We investigate these potential developmental precursors of neurogenic alterations using a bonnet macaque model. METHODS: Twenty-five male infant bonnet macaques were randomized to stressed [variable foraging demand (VFD)] or normative [low foraging demand (LFD)] rearing protocols and genotyped for 5-HTTLPR polymorphisms. Adolescent MRI brain scans (mean age 4.2y) were available for 14 subjects. Adult-born neurons were detected post-mortem (mean age 8.6y) via immunohistochemistry targeting the microtubule protein doublecortin (DCX). Models were adjusted for age and weight. RESULTS: A putative vulnerability group (VG) of VFD-reared 's'-carriers (all 's/l') exhibited reduced neurogenesis compared to non-VG subjects. Neurogenesis levels were positively predicted by ipsilateral hippocampal volume normalized for total brain volume, but not by contralateral or raw hippocampal volume. LIMITATIONS: No 's'-carriers were identified in LFD-reared subjects, precluding a 2×2 factorial analysis. CONCLUSION: The 's' allele (with adverse rearing) and low adolescent hippocampal volume portend a neurogenic deficit in adult macaques, suggesting persistent alterations in hippocampal plasticity may contribute to these developmental factors' affective risk in humans.


Assuntos
Experiências Adversas da Infância , Proteínas da Membrana Plasmática de Transporte de Serotonina , Adolescente , Adulto , Animais , Criança , Pré-Escolar , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Humanos , Macaca/metabolismo , Masculino , Neurogênese/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Estresse Psicológico/genética
8.
PLoS One ; 16(2): e0246604, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33577606

RESUMO

BACKGROUND: The prevalence of psychological symptoms and the co-occurrence of substance abuse disorders in adult patients with Langerhans cell histiocytosis (LCH) has not been previously explored. We aimed to use validated scales to evaluate depression and anxiety symptoms experienced by adult LCH patients. METHODS: In this cross-sectional study, all consecutive adult LCH patients seen at our national reference center between January 2012 and January 2013 were asked to complete the following instruments: the Hospital Anxiety and Depression scale (HADS); Barratt Impulsiveness Scale, Version 10 (BIS-10); and Cannabis Use Disorders Identification Test (CUDIT). Self-reported scores on these scales were used to determine the point prevalence of clinically significant psychological symptoms and substance use disorders in LCH patients. Patient profiles in terms of psychological features were assessed by principal component analysis including the HADS and BIS-10 instruments values, followed by hierarchical clustering. Fisher exact tests and Wilcoxon tests were used to examine the associations between disease-related parameters and high levels of anxiety and impulsivity. RESULTS: Seventy-one adult LCH patients, mainly with pulmonary LCH (PLCH), completed the evaluations. Clinically significant anxiety and depression symptoms were reported by 22 (31%) and 4 (6%) subjects, respectively. Impulsivity was detected in 14% (10/71) of the patients. Seventeen percent (12/71) of the patients used cannabis on a regular basis, with 50% of these individuals (6/12) exhibiting scores consistent with cannabis use disorder. Three derived clusters of patients were identified in the principal component analysis; these patient clusters differed in successful weaning from tobacco at the time of evaluation (p = 0.03). In univariate analyses, isolated PLCH and the use of psychotropic treatments were statistically associated with clinically significant anxiety symptoms. CONCLUSIONS: High levels of anxiety and impulsivity are common in adult patients with LCH. The consequences of these symptoms for the management of LCH patients warrant further evaluation.


Assuntos
Ansiedade/psicologia , Depressão/psicologia , Histiocitose de Células de Langerhans/psicologia , Adulto , Ansiedade/epidemiologia , Comorbidade , Estudos Transversais , Depressão/epidemiologia , Feminino , França/epidemiologia , Histiocitose de Células de Langerhans/epidemiologia , Humanos , Masculino , Fumar Maconha/psicologia , Pessoa de Meia-Idade , Análise de Componente Principal
11.
Ann Am Thorac Soc ; 18(5): 815-819, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33171065

RESUMO

Rationale: Lymphangioleiomyomatosis (LAM) is a female-predominant lung disease caused by mutations in the tuberous sclerosis complex (TSC) genes TSC1 and TSC2.Objectives: To examine the association between TSC mutation subtypes and the prevalence of LAM in women with TSC.Methods: Adult women seen at the Cincinnati Children's Hospital Medical Center's TSC clinic were stratified into the following three groups: those with TSC1 mutation, those with TSC2 mutation, and those with no mutation identified (NMI). Individual TSC manifestations were ascertained by blinded review of chest computed tomographic scans (LAM, multifocal micronodular pneumocyte hyperplasia, and sclerotic bone lesions) and chart review (all other manifestations). The association between mutation status and TSC manifestations was assessed by the Wilcoxon rank-sum test.Results: Our cohort consisted of 55 TSC women, including 30/55 (55%) with TSC2, 12/55 (22%) with TSC1, and 13/55 (23%) with NMI. Twenty-three women (42%) had characteristic cysts consistent with LAM, of whom 16 had TSC2 mutations and seven had NMI. The prevalence of LAM was higher in women with TSC2 mutations compared with women with TSC1 mutations (16/29 [55%] vs. 0/12; P = 0.003). Similarly, renal angiomyolipomas were more common in women with TSC2 mutations compared with women with TSC1 mutations (29/30 [97%] vs. 6/12 [50%]; P = 0.01). There was no association between TSC mutation subtype and the presence of multifocal micronodular pneumocyte hyperplasia, sclerotic bone lesions, and skin or brain involvement. Serum VEGF-D (vascular endothelial growth factor-D) concentrations (median [95% confidence interval]) tended to be higher in patients harboring TSC2 mutations compared with patients with TSC1 mutations (725 pg/ml [612-1,317] vs. 331 pg/ml [284-406]; P = 0.03) and in patients with LAM compared with patients without LAM (725 pg/ml [563-1,609] vs. 429 pg/ml [357-773]; P = 0.02).Conclusions: LAM and angiomyolipomas are more common in women with TSC harboring TSC2 mutations compared with women with TSC1 mutations. Serum VEGF-D is a useful biomarker to suggest the presence of LAM in women with TSC.

12.
Clin Imaging ; 72: 122-135, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33232899

RESUMO

Obesity is a disease that has achieved the level that can be considered an epidemic. According to the National Center for Health Statistics data, the prevalence of obesity has increased from 30.5% in 1999-2000 to 42.4% in 2017-2018. During the same period, severe obesity has increased from 4.7% to 9.2%. With the growing prevalence of obesity, related conditions such as coronary artery disease, diabetes, and strokes have also become more prevalent. In the past few years, the need for bariatric surgeries such as laparoscopic Roux-en-Y gastric bypass, sleeve gastrectomy, and laparoscopic adjustable gastric banding has increased considerably. With an increasing number of bariatric surgeries, multiple postoperative complications have become common. In this review, we have attempted to describe normal postsurgical anatomical findings after bariatric surgeries and pictorial review of a few common postoperative complications.


Assuntos
Cirurgia Bariátrica , Derivação Gástrica , Gastroplastia , Laparoscopia , Obesidade Mórbida , Cirurgia Bariátrica/efeitos adversos , Gastrectomia , Derivação Gástrica/efeitos adversos , Humanos , Obesidade Mórbida/cirurgia , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/epidemiologia , Resultado do Tratamento
13.
Chest ; 159(2): 683-698, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33075377

RESUMO

BACKGROUND: Pulmonary disease is a potentially serious yet underdiagnosed complication of Sjögren's syndrome, the second most common autoimmune rheumatic disease. Approximately 16% of patients with Sjögren's demonstrate pulmonary involvement with higher mortality and lower quality of life. RESEARCH QUESTION: Clinical practice guidelines for pulmonary manifestations of Sjögren's were developed by the Sjögren's Foundation after identifying a critical need for early diagnosis and improved quality and consistency of care. STUDY DESIGN AND METHODS: A rigorous and transparent methodology was followed according to American College of Rheumatology guidelines. The Pulmonary Topic Review Group (TRG) developed clinical questions in the PICO (Patient, Intervention, Comparison, Outcome) format and selected literature search parameters. Each article was reviewed by a minimum of two TRG members for eligibility and assessment of quality of evidence and strength of recommendation. Guidelines were then drafted based on available evidence, expert opinion, and clinical importance. Draft recommendations with a clinical rationale and data extraction tables were submitted to a Consensus Expert Panel for consideration and approval, with at least 75% agreement required for individual recommendations to be included in the final version. RESULTS: The literature search revealed 1,192 articles, of which 150 qualified for consideration in guideline development. Of the original 85 PICO questions posed by the TRG, 52 recommendations were generated. These were then reviewed by the Consensus Expert Panel and 52 recommendations were finalized, with a mean agreement of 97.71% (range, 79%-100%). The recommendations span topics of evaluating Sjögren's patients for pulmonary manifestations and assessing, managing, and treating upper and lower airway disease, interstitial lung disease, and lymphoproliferative disease. INTERPRETATION: Clinical practice guidelines for pulmonary manifestations in Sjögren's will improve early identification, evaluation, and uniformity of care by primary care physicians, rheumatologists, and pulmonologists. Additionally, opportunities for future research are identified.

14.
Eur Respir J ; 57(6)2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33303533

RESUMO

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare multisystem disease with variable clinical manifestations and differing rates of progression that make management decisions and giving prognostic advice difficult. We used machine learning to identify clusters of associated features which could be used to stratify patients and predict outcomes in individuals. PATIENTS AND METHODS: Using unsupervised machine learning we generated patient clusters using data from 173 women with LAM from the UK and 186 replication subjects from the US National Heart, Lung, and Blood Institute (NHLBI) LAM registry. Prospective outcomes were associated with cluster results. RESULTS: Two- and three-cluster models were developed. A three-cluster model separated a large group of subjects presenting with dyspnoea or pneumothorax from a second cluster with a high prevalence of angiomyolipoma symptoms (p=0.0001) and tuberous sclerosis complex (TSC) (p=0.041). Patients in the third cluster were older, never presented with dyspnoea or pneumothorax (p=0.0001) and had better lung function. Similar clusters were reproduced in the NHLBI cohort. Assigning patients to clusters predicted prospective outcomes: in a two-cluster model the future risk of pneumothorax was 3.3 (95% CI 1.7-5.6)-fold greater in cluster 1 than cluster 2 (p=0.0002). Using the three-cluster model, the need for intervention for angiomyolipoma was lower in clusters 2 and 3 than cluster 1 (p<0.00001). In the NHLBI cohort, the incidence of death or lung transplant was much lower in clusters 2 and 3 (p=0.0045). CONCLUSIONS: Machine learning has identified clinically relevant clusters associated with complications and outcome. Assigning individuals to clusters could improve decision making and prognostic information for patients.

15.
Clin Imaging ; 69: 126-132, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32717540

RESUMO

Idiopathic granulomatous mastitis (IGM), or granulomatous lobular mastitis is a rare, benign, inflammatory condition of the breast, without an identifiable underlying etiology. The clinical and imaging diagnosis of this entity is challenging with the presentation frequently mimicking inflammatory breast carcinoma (IBC). Mammography and breast ultrasound (US) have an important role in its detection, however, biopsy is imperative for histopathological confirmation. We present three cases of biopsy proven IGM, highlighting the variability of the clinical and imaging features,brieflyreview the relevant literature and discuss the challenges associated with its diagnosis and management.


Assuntos
Mastite Granulomatosa , Mastite , Biópsia , Feminino , Mastite Granulomatosa/diagnóstico por imagem , Humanos , Mamografia , Mastite/diagnóstico por imagem , Ultrassonografia Mamária
16.
Ann Transl Med ; 8(17): 1094, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33145313

RESUMO

Radiological studies have an important role in the diagnosis and follow up of many infectious diseases. With current pandemic of Coronavirus disease 2019 (COVID-19) though the molecular analysis with reverse transcriptase polymerase chain reaction (RT-PCR) remains the cornerstone of diagnosis, the critical role of chest imaging including CT scan and baseline X-ray became apparent early in the course due to concern for less than optimal sensitivity of PCR testing. Delay in molecular diagnosis due to a shortage of testing kits and laboratory personnel also makes imaging an important modality in early diagnosis for appropriate triage and isolation decisions. CT scan technology is widely available in developed parts of the world but in developing countries, CT scanner is not widely available especially in rural settings. CT imaging usually requires patient movement to the radiology department and the scanner is not easy to disinfect. Point of care ultrasound (POCUS) has been used for many years in the assessment of critically ill patients in emergency departments and intensive care units. It is rapidly gaining popularity across many specialties and part of many general medicine training programs across the United States. It can be learned rapidly and with experienced hands, POCUS can help identify disease patterns in the lung parenchyma, and during the current pandemic has been gaining special attention. In this article, we review the most prominent imaging findings on chest X-ray and CT scan in patients with COVID-19. We also focus on the background and evolution of POCUS with studies showing the promising role of this diagnostic modality in COVID-19 infection. In addition, we describe step by step guidance on the use and disinfection of the portable ultrasound machine.

17.
World J Radiol ; 12(9): 195-203, 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-33033574

RESUMO

As healthcare professionals continue to combat the coronavirus disease 2019 (COVID-19) infection worldwide, there is an increasing interest in the role of imaging and the relevance of various modalities. Since imaging not only helps assess the disease at the time of diagnosis but also aids evaluation of response to management, it is critical to examine the role of different modalities currently in use, such as baseline X-rays and computed tomography scans carefully. In this article, we will draw attention to the critical findings for the radiologist. Further, we will look at point of care ultrasound, an increasingly a popular tool in diagnostic medicine, as a component of COVID-19 management.

18.
Bioorg Med Chem ; 28(24): 115819, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33120078

RESUMO

The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing's sarcoma models.

20.
Radiol Case Rep ; 15(9): 1523-1527, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32670453

RESUMO

Osteochondrosis is a developmental condition affecting the endochondral ossification. It is commonly idiopathic however can be due to vascular anomalies, dietary conditions, hormonal irregularity, or overuse trauma. Osteochondrosis occurring in the inferior pole of the scapula is an extremely rare condition and is referred to as roca disease. A higher degree of suspicion is required especially in a young patient with atraumatic shoulder pain and additional unconventional MRI sequences focusing on the inferior pole of scapula can be taken to rule out such conditions. We report a case of Roca disease in a 16-year male who presented with right shoulder pain. This is the third case report of roca disease in the English literature according to our knowledge and the first case report to demonstrate extensive MRI imaging features with a normal radiograph. Imaging, particularly MRI, plays a pivotal role in the diagnosis of this extremely rare entity. Also, the inferior pole of the scapula is usually not included in routine shoulder MRI imaging thus close scrutiny with additional MRI sequences should be done to diagnose such a rare entity.

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