Meir H. Scheinfeld

JNK-interacting protein-1 promotes transcription of Aβ protein precursor but not Aβ precursor-like proteins, mechanistically different than Fe65

Processing of the amyloid β protein precursor (AβPP) by the β and γ secretases leads to the production of two small peptides, amyloid β and the AβPP intracellular domain (AID, or called elsewhere AICD). Whereas the role of amyloid β in the pathogenesis of Alzheimers disease has been studied extensively, only recently has information begun to accumulate as to the role of AID. Functions identified for AID include its ability to trigger apoptosis and a role in regulating gene transcription, particularly in combination with the AβPP binding protein Fe65. Here, we report that AID in combination with Janus kinase interacting protein-1 (JIP-1) can activate gene expression. We demonstrate that the mechanism is different from activation in combination with Fe65 by first showing that although Fe65 enters the nucleus in the absence of full-length AβPP, JIP-1 does not. Additionally, JIP-1-induced activation is Tip60 independent, whereas a complex with AID, Fe65, and Tip60 is formed for Fe65-induced activation. Finally, and probably most interestingly, we show that although the AβPP family members APLP1 and APLP2 (for amyloid β precursor-like protein) can cause activation in combination with Fe65, APLP1 and APLP2 show little or no activation in combination with JIP-1. This activity for the AID fragment may help explain the unique functions of AβPP relative to its other family members, and changes in gene expression found in Alzheimers disease.

Understanding the spectral Doppler waveform of the hepatic veins in health and disease.

Duplex Doppler sonography is a fundamental component of the complete ultrasonographic examination of the liver. Accurate interpretation of the spectral Doppler tracing from the hepatic veins is valuable, as it reflects important cardiac and hepatic physiology. Normally, there are four phases: A, S, V, and D; the S and D waves indicate flow in the antegrade direction toward the heart. In hepatic and cardiac disease, these normal waves may be absent, a finding indicative of flow in a nonphysiologic manner. In addition, transient patient factors such as phase of the respiratory cycle may influence the appearance of the spectral tracing. Familiarity with the normal and abnormal spectral Doppler waveforms from the hepatic veins and knowledge of their respective physiology and pathophysiology provide valuable insights. Systematic analysis of the direction, regularity, and phasicity of the spectral tracing and the ratio of the amplitudes of the S and D waves allows one to arrive at the correct differential diagnosis in most situations.

Hyperphosphorylation of JNK-interacting Protein 1, a Protein Associated with Alzheimer Disease

The c-Jun N-terminal kinase (JNK) group of mitogen-activated protein (MAP) kinases are activated by pleiotropic signals including environmental stresses, growth factors, and hormones. JNK-interacting protein 1 (JIP1) is a scaffold protein that assembles and facilitates the activation of the mixed lineage kinase-dependent JNK module and also establishes an interaction with β-amyloid precursor protein that has been partially characterized. Here we show that, similarly to other proteins involved in various neurological diseases, JIP1 becomes hyperphosphorylated following activation of stress-activated and MAP kinases. By immobilized metal affinity chromatography and a combined microcapillary LC/MALDI-TOF/ESI-ion trap mass spectrometry approach, we identified 35 sites of mitotic phosphorylation within JIP1, among which eight were present within (Ser/Thr)-Pro sequence. This motif is modified by various kinases in aggregates of the microtubule-associated protein tau, which generates typical intraneuronal lesions occurring in Alzheimer disease. Most of the post-translational modifications found were located within the JNK, MAP kinase kinase, and RAC-α Ser/Thr protein kinase binding regions; no modifications occurred in protein Src homology 3 and phosphotyrosine interaction domains, which are essential for binding to kinesin, β-amyloid precursor protein, and MAP kinase kinase kinase. Protein phosphorylation is known to affect stability and protein-protein interactions. Thus, the findings that JIP1 is extensively phosphorylated after activation of stress-activated and MAP kinases indicate that these signaling pathways might modulate JIP1 signaling by regulating its stability and association with some, but not all, interacting proteins.

Evidence for a role of the nerve growth factor receptor TrkA in tyrosine phosphorylation and processing of β-APP

The cytoplasmic tail of the beta-amyloid precursor protein (APP) contains a Y(682)ENPTY(687) sequence through which APP associates with phosphotyrosine binding (PTB) domain containing proteins in a tyrosine phosphorylation-independent manner. We have recently found that tyrosine phosphorylation of APP-Y(682) promotes docking of Shc proteins that modulate growth factor signaling to the ERK and PI3K/Akt pathways. We have also shown that APP is phosphorylated on Y(682) in cells that overexpress a constitutively active form of the tyrosine kinase abl. Here we present evidence that the nerve growth factor receptor TrkA may also promote phosphorylation of APP. Overexpression of TrkA, but not of mutated, kinase inactive TrkA resulted in tyrosine phosphorylation of APP. Site-directed mutagenesis studies showed that TrkA overexpression was associated with phosphorylation of APP-Y(682). Moreover, overexpression of TrkA also affected APP processing reducing the generation of the APP intracellular domain (AID). Thus, tyrosine phosphorylation of APP may functionally link APP processing and neurotrophic signaling to intracellular pathways associated with cellular differentiation and survival.

Imaging of Penile and Scrotal Emergencies

Penile and scrotal emergencies are uncommon, but when they do occur, urgent or emergent diagnosis and treatment are necessary. Emergent conditions of the male genitalia are primarily infectious, traumatic, or vascular. Infectious conditions, such as epididymitis and epididymo-orchitis, are well evaluated at ultrasonography (US), and their key findings include heterogeneity and hyperemia. Pyocele and abscess may also be seen at US. Fournier gangrene is best evaluated at computed tomography, which depicts subcutaneous gas. Vascular conditions, such as testicular torsion, infarction, penile Mondor disease, and priapism, are well evaluated at duplex Doppler US. The key imaging finding of testicular torsion and infarction is a lack of blood flow in the testicle or a portion of the testicle. Penile Mondor disease is characterized by a lack of flow to and noncompressibility of the superficial dorsal vein of the penis. Clinical examination and history are usually adequate for diagnosis of priapism, but Doppler US may help confirm the diagnosis. Traumatic injuries of the penis and scrotum are initially imaged with US, which depicts whether the penile corpora and testicular seminiferous tubules are contained by the tunicae albuginea; herniation of contents and discontinuity of the tunica albuginea indicate rupture. In some cases, magnetic resonance imaging may be performed because of its ability to directly depict discontinuity of the tunica albuginea. Radiologists must closely collaborate with emergency physicians, surgeons, and urologists to quickly and efficiently diagnose or rule out emergent conditions of the male genitalia to facilitate prompt and appropriate treatment.

Beyond Ultrasound: CT and MRI of Ectopic Pregnancy

OBJECTIVEnAlthough ultrasound is the primary modality used in the diagnosis of ectopic pregnancy, various forms of this condition and their complications may occasionally be further evaluated with MRI or may be incidentally detected on CT or MRI when an alternative diagnosis is suspected.nnnCONCLUSIONnVarious types of ectopic pregnancy have characteristic imaging features. Radiologists should be familiar with these features and should always consider the possibility of ectopic pregnancy in the setting of hemoperitoneum or a pelvic mass in a woman of child-bearing age. Familiarity with the typical CT and MRI appearances of various forms of ectopic pregnancy facilitates prompt and accurate diagnosis and treatment.

Acetabular Fractures: What Radiologists Should Know and How 3D CT Can Aid Classification

Correct recognition, description, and classification of acetabular fractures is essential for efficient patient triage and treatment. Acetabular fractures may result from high-energy trauma or low-energy trauma in the elderly. The most widely used acetabular fracture classification system among radiologists and orthopedic surgeons is the system of Judet and Letournel, which includes five elementary (or elemental) and five associated fractures. The elementary fractures are anterior wall, posterior wall, anterior column, posterior column, and transverse. The associated fractures are all combinations or partial combinations of the elementary fractures and include transverse with posterior wall, T-shaped, associated both column, anterior column or wall with posterior hemitransverse, and posterior column with posterior wall. The most unique fracture is the associated both column fracture, which completely dissociates the acetabular articular surface from the sciatic buttress. Accurate categorization of acetabular fractures is challenging because of the complex three-dimensional (3D) anatomy of the pelvis, the rarity of certain acetabular fracture variants, and confusing nomenclature. Comparing a 3D image of the fractured acetabulum with a standard diagram containing the 10 Judet and Letournel categories of acetabular fracture and using a flowchart algorithm are effective ways of arriving at the correct fracture classification. Online supplemental material is available for this article.

Do Clinical Outcomes Suffer During Transition to an Ultrasound-First Paradigm for the Evaluation of Acute Appendicitis in Children?

OBJECTIVEnThe objective of our study was to examine whether the rate of complicated appendicitis and the hospital length of stay (LOS) increased during the transition to an ultrasound-first paradigm for the imaging evaluation of acute appendicitis.nnnMATERIALS AND METHODSnAll pediatric patients with surgically proven appendicitis from 2005 to 2011 were identified by searching the hospital billing database for the discharge diagnosis codes for simple appendicitis (ICD-9 [International Classification of Diseases, 9th revision] code 540.9) and complicated appendicitis (ICD-9 codes 540.0 and 540.1). Annual trends of the proportions of these patients who underwent ultrasound and CT were determined and plotted for the study period. Correlation of complicated appendicitis and median hospital LOS with calendar year was assessed using the Spearman (ρ) rank correlation test. RESULTS. Eight hundred four patients met the inclusion criteria. The percentage of patients who underwent CT only showed a moderate downward association with year (ρ = -0.32, p < 0.01), and the percentage of patients who underwent ultrasound first showed a moderate upward trend (ρ = 0.44, p < 0.01). The percentage of patients with ultrasound as the only study performed before appendectomy increased moderately over the 7-year study period (ρ = 0.33, p < 0.01). The percentage of patients with complicated appendicitis and the median hospital LOS did not increase significantly over the study duration (ρ = -0.01, p = 0.74 and ρ = -0.04, p = 0.25, respectively).nnnCONCLUSIONnThe transition to an ultrasound-first pathway for the imaging workup of acute appendicitis in children occurred without evidence of a corresponding increase in the proportion of patients with complicated appendicitis or in the median hospital LOS.

Imaging of Male Pelvic Trauma

Prompt imaging plays an important role in the evaluation of male pelvic soft tissue trauma. Using appropriate imaging modalities, with optimization of contrast administration when appropriate, is essential for accurate diagnosis. Traumatic bladder rupture, either extraperitoneal or intraperitoneal, is diagnosed with high accuracy using computed tomography cystography. Suspicion of urethral injury warrants evaluation with retrograde urethrography to evaluate for the presence of injury and injury location. Early identification of laceration of the testicular tunica albuginea is essential. Understanding both normal penile anatomy and the imaging appearance of corpus rupture (as opposed to a hematoma) is imperative for proper diagnosis and management.

Can lab data be used to reduce abdominal computed tomography (CT) usage in young adults presenting to the emergency department with nontraumatic abdominal pain

We sought to determine whether laboratory parameters could be found, predictive of a negative abdominal CT scan in young adults with nontraumatic abdominal pain. Following institutional review board approval, we evaluated CT reports of 522 patients, aged 21–35xa0years old, who presented to the Emergency Department with nontraumatic abdominal pain. Bivariate analyses relating ten laboratory parameters to whether the CT detected a cause for abdominal pain were conducted. A multivariate logistic regression model was then derived, with all variables in the final model significant at pu2009<u20090.05. Variables were dichotomized to yield odds ratios and 95% confidence intervals. Of the 522 patients meeting inclusion criteria, 45% had a cause for pain demonstrated by CT. Predictors of a negative CT in men were normal hematocrit and negative urine blood (pu2009=u20090.045, pu2009=u20090.016, respectively), and in women normal hematocrit, granulocyte percent, and alkaline phosphatase (pu2009=u20090.023, pu2009=u20090.039, pu2009<u20090.0001, respectively). When standard normal values were used to calculate descriptive statistics, only granulocyte percent in women had a significant confidence interval (odds ratio 2.5, confidence interval 1.6–4.0). Among the 208 women with normal granulocyte percent, the final clinical diagnosis was appendicitis, cholecystitis, and diverticulitis, in three, three, and two cases, respectively (4% combined). In summary, no laboratory test was sufficient to offer reassurance that a CT is not necessary in a young adult patient with nontraumatic abdominal pain. Alternative strategies should be considered to decrease the use of CT, and its associated radiation exposure, in young adults with nontraumatic abdominal pain.