Mice deficient in the mitochondrial branched-chain aminotransferase (BCATm) respond with delayed tumour growth to a challenge with EL-4 lymphoma.

BACKGROUND: The mitochondrial branched-chain aminotransferase (BCATm) is a recently discovered cancer marker with a poorly defined role in tumour progression. METHODS: To understand how a loss of function of BCATm affects cancer, the global knockout mouse BCATmKO was challenged with EL-4 lymphoma under different diet compositions with varying amounts of branched-chain amino acids (BCAAs). Next, the growth and metabolism of EL-4 cells were studied in the presence of different leucine concentrations in the growth medium. RESULTS: BCATmKO mice experienced delayed tumour growth when fed standard rodent chow or a normal BCAA diet. Tumour suppression correlated with 37.6- and 18.9-fold increases in plasma and tumour BCAAs, 37.5% and 30.4% decreases in tumour glutamine and alanine, and a 3.5-fold increase in the phosphorylation of tumour AMPK in BCATmKO mice on standard rodent chow. Similar results were obtained with a normal but not with a choice BCAA diet. CONCLUSIONS: Global deletion of BCATm caused a dramatic build-up of BCAAs, which could not be utilised for energy or amino acid synthesis, ultimately delaying the growth of lymphoma tumours. Furthermore, physiological, but not high, leucine concentrations promoted the growth of EL-4 cells. BCATm and BCAA metabolism were identified as attractive targets for anti-lymphoma therapy.

Rickettsia parkeri infections diagnosed by eschar biopsy, Virginia, USA.

BACKGROUND: Infection with Rickettsia parkeri is an emerging tick-borne illness, often accompanied by fever and an eschar at the site of tick attachment. We present three cases of R. parkeri in Virginia residents. CASE PRESENTATIONS: Case 1 presented initially afebrile, failed to seroconvert to rickettsial antigens, and was diagnosed by DNA testing of the eschar. Case 2 presented febrile with eschar, no serologies were performed, and was diagnosed by DNA testing of the eschar. Case 3 presented febrile with eschar, serologies were negative for rickettsial antigens, and was diagnosed by DNA testing of the eschar. CONCLUSION: DNA testing of eschars represents an under-utilized diagnostic test and may aid in cases where the diagnosis is not made clinically.

Effect of 22q11.2 deletion on bleeding and transfusion utilization in children with congenital heart disease undergoing cardiac surgery.

BACKGROUND: Postsurgical bleeding causes significant morbidity and mortality in children undergoing surgery for congenital heart defects (CHD). 22q11.2 deletion syndrome (DS) is the second most common genetic risk factor for CHD. The deleted segment of chromosome 22q11.2 encompasses the gene encoding glycoprotein (GP) Ibß, which is required for expression of the GPIb-V-IX complex on the platelet surface, where it functions as the receptor for von Willebrand factor (VWF). Binding of GPIb-V-IX to VWF is important for platelets to initiate hemostasis. It is not known whether hemizygosity for the gene encoding GPIbß increases the risk for bleeding following cardiac surgery for patients with 22q11.2 DS. METHODS: We performed a case-control study of 91 pediatric patients who underwent cardiac surgery with cardiopulmonary bypass from 2004 to 2012 at Children's Hospital of Wisconsin. RESULTS: Patients with 22q11.2 DS had larger platelets and lower platelet counts, bled more excessively, and received more transfusion support with packed red blood cells in the early postoperative period relative to control patients. CONCLUSION: Presurgical genetic testing for 22q11.2 DS may help to identify a subset of pediatric cardiac surgery patients who are at increased risk for excessive bleeding and who may require more transfusion support in the postoperative period.

Immunoreceptor tyrosine-based inhibitory motif (ITIM)-mediated inhibitory signaling is regulated by sequential phosphorylation mediated by distinct nonreceptor tyrosine kinases: a case study involving PECAM-1.

The activation state of many blood and vascular cells is tightly controlled by a delicate balance between receptors that contain immunoreceptor tyrosine-based activation motifs (ITAMs) and those that contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Precisely how the timing of cellular activation by ITAM-coupled receptors is regulated by ITIM-containing receptors is, however, poorly understood. Using platelet endothelial cell adhesion molecule 1 (PECAM-1) as a prototypical ITIM-bearing receptor, we demonstrate that initiation of inhibitory signaling occurs via a novel, sequential process in which Src family kinases phosphorylate the C-terminal ITIM, thereby enabling phosphorylation of the N-terminal ITIM of PECAM-1 by other Src homology 2 domain-containing nonreceptor tyrosine kinases (NRTKs). NRTKs capable of mediating the second phosphorylation event include C-terminal Src kinase (Csk) and Bruton's tyrosine kinase (Btk). Btk and Csk function downstream of phosphatidylinositol 3-kinase (PI3K) activation during ITAM-dependent platelet activation. In ITAM-activated platelets that were treated with a PI3K inhibitor, PECAM-1 was phosphorylated but did not bind the tandem SH2 domain-containing tyrosine phosphatase SHP-2, indicating that it was not phosphorylated on its N-terminal ITIM. Csk bound to and phosphorylated PECAM-1 more efficiently than did Btk and required its SH2 domain to perform these functions. Additionally, the phosphorylation of the N-terminal ITIM of Siglec-9 by Csk is enhanced by the prior phosphorylation of its C-terminal ITIM, providing evidence that the ITIMs of other dual ITIM-containing receptors are also sequentially phosphorylated. On the basis of these findings, we propose that sequential ITIM phosphorylation provides a general mechanism for precise temporal control over the recruitment and activation of tandem SH2 domain-containing tyrosine phosphatases that dampen ITAM-dependent signals.

The evaluation of children and adolescents with headache.

Headache can be caused by primary entities (as in migraine or tension-type headache) or the pain may result from secondary causes, such as brain tumors, idiopathic intracranial hypertension, chronic meningitis, hydrocephalus, drug intoxications, paranasal sinus disease, or acute febrile illnesses (eg, influenza). To determine the nature of a child's headache, the evaluation begins with a thorough medical history, followed by methodic physical examination with measurement of vital signs and complete neurologic examination. The diagnosis of primary headache disorders such as migraine and tension-type rests principally on clinical criteria as set forth by the International Headache Society (http://www.i-h-s.org/). Clues to the presence and identification of secondary causes of headache are uncovered through this systematic process of history and physical examination. The performance of ancillary diagnostic testing rests upon information or concerns revealed during the history and physical examination.

Belly models as teaching tools: what is their utility?

Marble/ball models are often used to represent newborn stomach capacity; however, their accuracy has not been determined. The objective of this review was to analyze data on newborn stomach capacity and determine whether marble/ball models serve as accurate representations. A literature search yielded limited data, most emanating from the early 1900s. Data suggest that anatomic capacity of the newborn stomach varies with the birth weight of the infant. Physiologic capacity bears no relation to anatomic capacity of the newborn stomach but is a measure of the ability of the mother to produce milk and the newborn to ingest milk. Given the wide range of feeding volumes on days 1 and 3 and the reported 8-fold increase in average feeding volume during the same time period, it is best to acknowledge that feeding volumes like anatomic stomach capacity vary widely and do not lend well to visual representation by marble/ball models.

Pediatric Integrative Medicine in Residency Program: Relationship between Lifestyle Behaviors and Burnout and Wellbeing Measures in First-Year Residents.

It is widely recognized that burnout is prevalent in medical culture and begins early in training. Studies show pediatricians and pediatric trainees experience burnout rates comparable to other specialties. Newly developed Accreditation Council for Graduate Medical Education (ACGME) core competencies in professionalism and personal development recognize the unacceptably high resident burnout rates and present an important opportunity for programs to improve residents experience throughout training. These competencies encourage healthy lifestyle practices and cultivation of self-awareness, self-regulation, empathy, mindfulness, and compassion—a paradigm shift from traditional medical training underpinned by a culture of unrealistic endurance and self-sacrifice. To date, few successful and sustainable programs in resident burnout prevention and wellness promotion have been described. The University of Arizona Center for Integrative Medicine Pediatric Integrative Medicine in Residency (PIMR) curriculum, developed in 2011, was designed in part to help pediatric programs meet new resident wellbeing requirements. The purpose of this paper is to detail levels of lifestyle behaviors, burnout, and wellbeing for the PIMR program’s first-year residents (N = 203), and to examine the impact of lifestyle behaviors on burnout and wellbeing. The potential of the PIMR to provide interventions addressing gaps in lifestyle behaviors with recognized association to burnout is discussed.

Pediatric Integrative Medicine in Residency (PIMR): Description of a New Online Educational Curriculum.

Use of integrative medicine (IM) is prevalent in children, yet availability of training opportunities is limited. The Pediatric Integrative Medicine in Residency (PIMR) program was designed to address this training gap. The PIMR program is a 100-hour online educational curriculum, modeled on the successful Integrative Medicine in Residency program in family medicine. Preliminary data on site characteristics, resident experience with and interest in IM, and residents' self-assessments of perceived knowledge and skills in IM are presented. The embedded multimodal evaluation is described. Less than one-third of residents had IM coursework in medical school or personal experience with IM. Yet most (66%) were interested in learning IM, and 71% were interested in applying IM after graduation. Less than half of the residents endorsed pre-existing IM knowledge/skills. Average score on IM medical knowledge exam was 51%. Sites endorsed 1-8 of 11 site characteristics, with most (80%) indicating they had an IM practitioner onsite and IM trained faculty. Preliminary results indicate that the PIMR online curriculum targets identified knowledge gaps. Residents had minimal prior IM exposure, yet expressed strong interest in IM education. PIMR training site surveys identified both strengths and areas needing further development to support successful PIMR program implementation.

Breastfeeding: a clinical imperative.

Hospital breastfeeding initiation rates (75%) show that most mothers in the United States want to breastfeed and are trying to do so. Even from the very start, however, mothers may not be getting the breastfeeding support they need. Low breastfeeding rates at 3, 6, and 12 months illustrate that women face multiple additional barriers to maintaining breastfeeding. What can we do to help more mothers be more successful? As healthcare providers, we need to be believers that breastfeeding is worth the effort. Perhaps most important for us is to realize that human milk is not simply a food but rather a complex, human infant support system. We can then articulate to families the importance of breastfeeding as a clinical imperative, a preventer of acute and chronic illness and disease. It will take integration, normalization, and mainstreaming of breastfeeding into our culture for acceptance and growth of the practice. Once we assist families in making educated decisions about breastfeeding, we need to provide supportive environments in our hospitals, medical practices, workplaces, and communities that implement the best ways to support breastfeeding. Breast milk is worth the effort, and the time has come to be ardent supporters of mothers and infants and their breastfeeding intentions.

The treatment of migraine headaches in children and adolescents.

Effective management of migraine headache in children and adolescents requires a balanced approach with an individually tailored regimen targeted to treat an acute attack at its onset, blended with bio-behavioral measures, and, in about 1/3 of patients, daily preventive medicines. The key first step is to assess the disability imposed by the recurrent headache pattern, the headache "burden." Once the burden is established decisions can be made toward selecting the most appropriate course of action. All patients will benefit from some basic bio-behavioral suggestions such as regular sleep, exercise, and eating schedule, moderation of caffeine, and identification of triggers. In addition, all patients should have a readily available analgesic to be used at the onset of a migraine attack. A subset of migraineurs will have sufficient headache burden to necessitate use of daily preventative medications. Unfortunately, there is limited controlled data to provide a comprehensive, evidence-based guideline, however, the most rigorously studied agents for acute treatment are ibuprofen, acetaminophen, and "triptan" nasal spray forms of sumatriptan and zolmitriptan; all of these have shown safety and efficacy in controlled trials. For preventive treatment, flunarizine, not available in the U.S., is the only agent that has demonstrated efficacy in placebo controlled trials, but encouraging data is emerging regarding the use of several antiepileptic agents such as topiramate, disodium valproate, and levetiracetam, as well as the antihistamine cyproheptadine and the antidepressant amitriptyline.

Unusual headache syndromes in children.

Headaches represent one of the most common reasons why children and adolescents seek medical attention and are the primary reason that they are referred to pediatric neurology practices. The most common headache syndromes diagnosed are migraine, tension-type, and chronic daily headache, and the bulk of recent medical literature regarding headache in children has focused on these clinical entities. Children are prone to have unusual headache syndromes, most of which fall under the category of "primary headache," most notably as manifestations of migraine with aura. Included within this group are basilar-type and hemiplegic migraine. The most intriguing subset included in the International Headache Society's classification system is the so-called "periodic syndromes of childhood that are precursors to migraine." These syndromes, quite peculiar to children, present a wide variety of episodic symptoms, including movement disorders, vomiting, ataxia, and vertigo, and may not include headache at all. This article provides an overview of some of the more unusual headache syndromes in children and adolescents.