Recent Publications by CFE Educators

The last decade has yielded many significant advances in hematopoietic transplantation techniques, immunomodulatory prophylaxis, and diagnostic and treatment approaches to acute and chronic graft-versus-host disease (GVHD). Unfortunately, GVHD remains the cardinal complication in allogeneic hematopoietic stem cell transplantation, with significant associated rates of morbidity and mortality. In this review, we highlight the numerous strides that have been made in making hematopoietic transplantation more successful and provide an update on the clinical and histopathological features of both acute and chronic GVHD in the pediatric population. It is critical for dermatologists to be aware of the characteristic features of cutaneous acute and chronic GVHD and to remain up to date on the evolving spectrum of these conditions. We discuss 5 cases with clinico-pathologic correlation to illustrate the key concepts and principles underlying the diagnosis and management of both acute and chronic GVHD.

The purpose of this study is to examine the characteristics and costs of postoperative fever diagnostic evaluations after total joint arthroplasty. All patients who underwent hip and knee arthroplasty (n = 1100) at a single institution for a 2-year period were included. Fever (temperature > or = 38.5 degrees C) occurred in 15% of patients. The rate of positive tests was as follows: chest radiograph (2%), blood culture (6%), urine culture (22%), and urinalysis (23.7%). Fever occurring after postoperative day 3 (odds ratio [OR] 23.3; P .001) and multiple days febrile (OR, 8.6; P = .003) are independent predictors of a positive workup, and patients with a maximum temperature of 39.0 degrees C or higher (25.4% vs 6.9%; P = .001) had a significantly higher rate of positive fever evaluations. The total direct cost associated with fever evaluations was $73 878, and cost per change in clinical management was $8209. Fever is a common occurrence after hip and knee arthroplasty, and many elements of an infectious evaluation are costly and clinically unnecessary.

The mTOR signaling complex integrates signals from growth factors and nutrient availability to control cell growth and proliferation, in part through effects on the protein-synthetic machinery. Protein synthesis rates fluctuate throughout the cell cycle but diminish significantly during the G(2)/M transition. The fate of the mTOR complex and its role in coordinating cell growth and proliferation signals with protein synthesis during mitosis remain unknown. Here we demonstrate that the mTOR complex 1 (mTORC1) pathway, which stimulates protein synthesis, is actually hyperactive during mitosis despite decreased protein synthesis and reduced activity of mTORC1 upstream activators. We describe previously unknown G(2)/M-specific phosphorylation of a component of mTORC1, the protein raptor, and demonstrate that mitotic raptor phosphorylation alters mTORC1 function during mitosis. Phosphopeptide mapping and mutational analysis demonstrate that mitotic phosphorylation of raptor facilitates cell cycle transit through G(2)/M. Phosphorylation-deficient mutants of raptor cause cells to delay in G(2)/M, whereas depletion of raptor causes cells to accumulate in G(1). We identify cyclin-dependent kinase 1 (cdk1 [cdc2]) and glycogen synthase kinase 3 (GSK3) pathways as two probable mitosis-regulated protein kinase pathways involved in mitosis-specific raptor phosphorylation and altered mTORC1 activity. In addition, mitotic raptor promotes translation by internal ribosome entry sites (IRES) on mRNA during mitosis and is demonstrated to be associated with rapamycin resistance. These data suggest that this pathway may play a role in increased IRES-dependent mRNA translation during mitosis and in rapamycin insensitivity.

BACKGROUND

Individuals with exaggerated exercise blood pressure (BP) tend to develop future hypertension. It is controversial whether they have higher risk of death from cardiovascular disease (CVD).

METHODS AND RESULTS

A total of 6578 asymptomatic Lipid Research Clinics Prevalence Study participants (45% women; mean age, 46 years; 74% with untreated baseline BP 140/90 mm Hg [nonhypertensive]) performing submaximal Bruce treadmill tests were followed for 20 years (385 CVD deaths occurred). Systolic and diastolic BP at rest, Bruce stage 2, and maximal BP during exercise were significantly associated with CVD death. When we compared multivariate hazard ratios and 95% confidence intervals per 10/5-mm Hg BP increments, the association was strongest for rest BP (systolic, 1.21 [1.14 to 1.27]; diastolic, 1.20 [1.14 to 1.26]), then Bruce stage 2 BP (systolic, 1.09 [1.04 to 1.14]; diastolic, 1.09 [1.05 to 1.13]), then maximal exercise BP (systolic, 1.06 [1.01 to 1.10]; diastolic, 1.04 [1.01 to 1.08]). Overall, exercise BP was not significant after adjustment for rest BP. However, hypertension status modified the risk associated with exercise BP (P(interaction)=0.03). Among nonhypertensives, whether they had normal BP (120/80 mm Hg) or prehypertension, Bruce stage 2 BP >180/90 versus or =180/90 mm Hg carried increased risk independent of rest BP and risk factors (adjusted hazard ratio for systolic, 1.96 [1.40 to 2.74], P0.001; diastolic, 1.48 [1.06 to 2.06], P=0.02) and added predictive value (net reclassification improvement, systolic, 12.0% [-0.1% to 24.2%]; diastolic, 9.9% [-0.3% to 20.0%]; relative integrated discrimination improvement, 14.3% and 12.0%, respectively).

CONCLUSIONS

In asymptomatic individuals, elevated exercise BP carried higher risk of CVD death but became nonsignificant after accounting for rest BP. However, Bruce stage 2 BP >180/90 mm Hg identified nonhypertensive individuals at higher risk of CVD death.

Saethre-Chotzen syndrome (acrocephalosyndactyly type III) is a craniosynostosis syndrome inherited in an autosomal dominant manner. Although similar to the other craniosynostosis syndromes in its clinical presentation, this syndrome is caused by a mutation in the TWIST1 gene. The TWIST1 gene product is a transcription factor containing a basic helix-loop-helix (bHLH) domain important in the development of the head and limbs. Clinical features of this syndrome include unilateral or bilateral coronal synostosis, ptosis, low-set ears, hearing loss, hypertelorism, maxillary hypoplasia, deviated nasal septum, broad great toes, clinodactyly, and syndactyly. We report a young girl with clinical features of Saethre-Chotzen syndrome who has a previously undescribed sequence variant in the TWIST1 gene, corresponding to p.R191M. The location of the altered amino acid in the Twist-box of TWIST1, the high conservation of this amino acid between different species, and the phenotype of the child all support a pathogenic role for this novel TWIST1 sequence alteration.

The authors report a new case of Beare-Stevenson syndrome (BSS) characterized by cutis gyrata, craniosynostosis, acanthosis nigricans, ear defects, a prominent umbilical stump, and midface hypoplasia. The patient had dental findings of natal teeth and hypodontia of the primary and permanent teeth. This is the second patient with BSS syndrome to be reported with hypodontia and natal teeth; the first patient was described by Beare in 1969. The authors review the current literature to investigate the relationship between dental anomalies and fibroblast growth factor receptor-related mutations in BSS and other craniosynostosis syndromes such as Apert, Crouzon, and Pfeiffer.