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"Levine, Michael A."
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The leader in you : how to win friends, influence people, and succeed in a changing world
In \"The leader in you\", coauthors Stuart R. Levine and Michael A. Crom apply the famed organization's time-tested human relations principles to demonstrate how anyone, regardless of his or her job, can harness creativity and enthusiasm to work more productively. With insights from leading figures in the corporate, entertainment, sports, academic, and political arenas, and encompassing interviews and advice from such eminent authorities as Ford Motor Company's Lee lacocca and former prime minister Margaret Thatcher, this comprehensive step-by-step guide includes strategies to help you succeed in all aspects of your life.
Book
ENPP1 variants in patients with GACI and PXE expand the clinical and genetic heterogeneity of heritable disorders of ectopic calcification
Pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI) are clinically distinct genetic entities of ectopic calcification associated with differentially reduced circulating levels of inorganic pyrophosphate (PPi), a potent endogenous inhibitor of calcification. Variants in ENPP1 , the gene mutated in GACI, have not been associated with classic PXE. Here we report the clinical, laboratory, and molecular evaluations of ten GACI and two PXE patients from five and two unrelated families registered in GACI Global and PXE International databases, respectively. All patients were found to carry biallelic variants in ENPP1 . Among ten ENPP1 variants, one homozygous variant demonstrated uniparental disomy inheritance. Functional assessment of five previously unreported ENPP1 variants suggested pathogenicity. The two PXE patients, currently 57 and 27 years of age, had diagnostic features of PXE and had not manifested the GACI phenotype. The similarly reduced PPi plasma concentrations in the PXE and GACI patients in our study correlate poorly with their disease severity. This study demonstrates that in addition to GACI, ENPP1 variants can cause classic PXE, expanding the clinical and genetic heterogeneity of heritable ectopic calcification disorders. Furthermore, the results challenge the current prevailing concept that plasma PPi is the only factor governing the severity of ectopic calcification.
Journal Article
اكتشف القائد الذي بداخلك : (فن القيادة في العمل) : كيف تكسب الأصدقاء وتؤثر في الناس وتنجح وسط عالم متغير
كتاب (اكتشف القائد الذى بداخلك) هو كتاب يكشف لك عن القواعد السحرية للتعامل مع الناس فقد يكون التعامل مع الناس هو أكبر مشكلة تواجهك خاصة فى مجال العمل وينطبق ذلك أيضا على المنزل مع الزوجة ولقد وضع \"ديل كارنيجي\" مبادئ العديد من المبادئ في فنون التعامل مع الآخرين مناسبة وملائمة للضغوط الشديدة والحركة السريعة في عالم اليوم بنيت هذه المبادئ والقواعد على حقائق أساسية للطبيعة البشرية يقول كارنيجى القواعد التي وضعناها ليست مجرد أفكار نظرية أو تخمينات إنها ذات تأثير يماثل أثر السحر ويقول أيضا عن المبادئ التي قضى حياته يعلمها الملايين إنها مبادئ رائعة وإنه شاهد على تطبيقاتها حرفيا وأن هذا التطبيق أحدث ثورة في حياة كثير من الناس طبق هذه الدروس والأساليب وأجعلها جزءا من حياتك طبقها مع أصدقائك وعائلتك وزملائك ولاحظ الفارق بعد ذلك احفظ هذه الكلمات عن ظهر قلب واكتشف القائد الكامن بداخلك.
Book
Diagnosis and Management of Osteopetrosis: Consensus Guidelines From the Osteopetrosis Working Group
BackgroundOsteopetrosis encompasses a group of rare metabolic bone diseases characterized by impaired osteoclast activity or development, resulting in high bone mineral density. Existing guidelines focus on treatment of the severe infantile forms with hematopoietic cell transplantation (HCT) but do not address the management of patients with less severe forms for whom HCT is not the standard of care. Therefore, our objective was to develop expert consensus guidelines for the management of these patients.MethodsA modified Delphi method was used to build consensus among participants of the Osteopetrosis Working Group, with responses to an anonymous online survey used to identify areas of agreement and conflict and develop a follow-up survey. The strength of recommendations and quality of evidence was graded using the Grading of Recommendations Assessment, Development and Evaluation system.ResultsConsensus was found in the areas of diagnosis, monitoring, and treatment. We recommend relying on characteristic radiographic findings to make the diagnosis and found that genetic testing adds important information by identifying mutations associated with unique disease complications. We recommend ongoing monitoring for changes in mineral metabolism and other complications, including cranial nerve impingement, anemia, leukopenia, and dental disease. We suggest that calcitriol should not be used in high doses and instead recommend symptom-based supportive therapy for disease complications because noninfantile osteopetrosis has no effective treatment.ConclusionsScarcity of published studies on osteopetrosis reduce the ability to develop evidence-based guidelines for the management of these patients. Expert opinion-based guidelines for this rare condition are nevertheless important to enable improved care.This article presents the Osteopetrosis Working Group expert consensus guidelines for the diagnosis, monitoring, and medical treatment of patients with osteopetrosis .
Journal Article
High-throughput Molecular Analysis of Pseudohypoparathyroidism 1b Patients Reveals Novel Genetic and Epigenetic Defects
Abstract
Context
Patients with pseudohypoparathyroidism type 1b (PHP1b) show disordered imprinting of the maternal GNAS allele or paternal uniparental disomy (UPD). Genetic deletions in STX16 or in upstream exons of GNAS are present in many familial but not sporadic cases.
Objective
Characterization of epigenetic and genetic defects in patients with PHP1b.
Design and Patients
DNA from 84 subjects, including 26 subjects with sporadic PHP1b, 27 affected subjects and 17 unaffected and/or obligate gene carriers from 12 PHP1b families, 11 healthy individuals, and 3 subjects with PHP1a was subjected to quantitative pyrosequencing of GNAS differentially methylated regions (DMRs), microarray analysis, and microsatellite haplotype analysis.
Setting
Academic medical center.
Main Outcome Measurements
Molecular pathology of PHP1b.
Results
Healthy subjects, unaffected family members and obligate carriers of paternal PHP1b alleles, and subjects with PHP1a showed normal methylation of all DMRs. All PHP1b subjects showed loss of methylation (LOM) at the exon A/B DMR. Affected members of 9 PHP1b kindreds showed LOM only at the exon A/B DMR, which was associated with a 3-kb deletion of STX16 exons 4 through 6 in 7 families and a novel deletion of STX16 and adjacent NEPEPL1 in 1 family. A novel NESP deletion was found in 1 of 2 other families with more extensive methylation defects. One sporadic PHP1b had UPD of 20q, 2 had 3-kb STX16 deletions, and 5 had apparent epigenetic mosaicism.
Conclusions
We found diverse patterns of defective methylation and identified novel or previously known mutations in 9 of 12 PHP1b families.
Journal Article
Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI)
Purpose
Generalized arterial calcification of infancy (GACI), characterized by vascular calcifications that are often fatal shortly after birth, is usually caused by deficiency of ENPP1. A small fraction of GACI cases result from deficiency of ABCC6, a membrane transporter. The natural history of GACI survivors has not been established in a prospective fashion.
Methods
We performed deep phenotyping of 20 GACI survivors.
Results
Sixteen of 20 subjects presented with arterial calcifications, but only 5 had residual involvement at the time of evaluation. Individuals with ENPP1 deficiency either had hypophosphatemic rickets or were predicted to develop it by 14 years of age; 14/16 had elevated intact FGF23 levels (iFGF23). Blood phosphate levels correlated inversely with iFGF23. For ENPP1-deficient individuals, the lifetime risk of cervical spine fusion was 25%, that of hearing loss was 75%, and the main morbidity in adults was related to enthesis calcification. Four ENPP1-deficient individuals manifested classic skin or retinal findings of PXE. We estimated the minimal incidence of ENPP1 deficiency at ~1 in 200,000 pregnancies.
Conclusion
GACI appears to be more common than previously thought, with an expanding spectrum of overlapping phenotypes. The relationships among decreased ENPP1, increased iFGF23, and rickets could inform future therapies.
Journal Article
Cherubism: best clinical practice
Cherubism is a skeletal dysplasia characterized by bilateral and symmetric fibro-osseous lesions limited to the mandible and maxilla. In most patients, cherubism is due to dominant mutations in the
SH3BP2
gene on chromosome 4p16.3. Affected children appear normal at birth. Swelling of the jaws usually appears between 2 and 7 years of age, after which, lesions proliferate and increase in size until puberty. The lesions subsequently begin to regress, fill with bone and remodel until age 30, when they are frequently not detectable.
Fibro-osseous lesions, including those in cherubism have been classified as quiescent, non-aggressive and aggressive on the basis of clinical behavior and radiographic findings. Quiescent cherubic lesions are usually seen in older patients and do not demonstrate progressive growth. Non-aggressive lesions are most frequently present in teenagers. Lesions in the aggressive form of cherubism occur in young children and are large, rapidly growing and may cause tooth displacement, root resorption, thinning and perforation of cortical bone.
Because cherubism is usually self-limiting, operative treatment may not be necessary. Longitudinal observation and follow-up is the initial management in most cases. Surgical intervention with curettage, contouring or resection may be indicated for functional or aesthetic reasons. Surgical procedures are usually performed when the disease becomes quiescent. Aggressive lesions that cause severe functional problems such as airway obstruction justify early surgical intervention.
Journal Article
Directional memory arises from long-lived cytoskeletal asymmetries in polarized chemotactic cells
Chemotaxis, the directional migration of cells in a chemical gradient, is robust to fluctuations associated with low chemical concentrations and dynamically changing gradients as well as high saturating chemical concentrations. Although a number of reports have identified cellular behavior consistent with a directional memory that could account for behavior in these complex environments, the quantitative and molecular details of such a memory process remain unknown. Using microfluidics to confine cellular motion to a 1D channel and control chemoattractant exposure, we observed directional memory in chemotactic neutrophil-like cells. We modeled this directional memory as a long-lived intracellular asymmetry that decays slower than observed membrane phospholipid signaling. Measurements of intracellular dynamics revealed that moesin at the cell rear is a long-lived element that when inhibited, results in a reduction of memory. Inhibition of ROCK (Rho-associated protein kinase), downstream of RhoA (Ras homolog gene family, member A), stabilized moesin and directional memory while depolymerization of microtubules (MTs) disoriented moesin deposition and also reduced directional memory. Our study reveals that long-lived polarized cytoskeletal structures, specifically moesin, actomyosin, and MTs, provide a directional memory in neutrophil-like cells even as they respond on short time scales to external chemical cues.
Journal Article