"Truffle sign". A suspicious malignant pattern of lymphadenopathies in children observed on ultrasound. Preliminary study.

BACKGROUND: The differential diagnosis of lymphadenopathies in children including benign and malignant conditions is often difficult to identify by ultrasound (US). The lymphadenopathies in children are frequent and mostly benign, therefore it is essential to decide what patients should undergo further studies. OBJECTIVE: To describe the potential usefulness of a new suspicious ultrasound sign on pediatric lymphadenopathies that can orient the diagnosis of malignancy. MATERIALS AND METHODS: We retrospectively reviewed all pediatric cases with lymphadenopathy suspicious of lymphoma or lymphoproliferative syndrome on soft tissue ultrasound from 2014 to 2021. Two expert ultrasound radiologists reviewed ultrasound images of these patients, associating the internal structure of infiltrated adenopathy with the internal structure of the truffles. RESULTS: On ultrasound, twelve cases presented enlarged lymphadenopathy with loss of internal structure, without hilum; mostly hypoechoic parenchyma, with some fine echogenic serpiginous linear surrounding hypoechoic pseudo nodular images, resembling the inner structure of black truffles. This US pattern looked suspicious and histological study was recommended. In 9 cases a lymphomatous infiltrated adenopathy was confirmed on biopsy. CONCLUSION: The truffle sign is a new potential suspicious ultrasound sign, that can suggest malignant lymphadenopathy in children. This ultrasound pattern can have some probable usefulness to the radiologist in order to recommend further studies, including histological study, that need to be validated by a larger sample. It is important to recognize easily and early the lymphomatous compromise in a lymph node.

Granuloma annulare on ultrasound: a diagnosis to consider in pediatric skin lesions.

BACKGROUND: Granuloma annulare (GA) is a rare, benign, inflammatory, self-limited, granulomatous dermatosis that affects children and young adults. The most frequent clinical form is localized GA. Deep GA generally presents as painless palpable subcutaneous nodules in the lower extremities, buttocks, hands and scalp. They may have a fast-growing firm subcutaneous mass presentation, mimicking a malignant lesion which requires an imaging evaluation. Diagnosis of deep GA can be more difficult and imaging evaluation is frequently performed, ultrasound being one of the techniques used. OBJECTIVE: To describe the US characteristics of GA in a pediatric series. MATERIALS AND METHOD: Descriptive, retrospective, 14-year study of all pediatrics GA cases. RESULTS: Twelve pediatric cases with GA. 66% females. The lesions were mainly distributed in the extremities: 50% in the lower extremities and 42% in the upper extremities, mostly with multiple lesions. A total of 45 lesions were analyzed, 8 superficial lesions and 37 deep lesions. On ultrasound, the superficial GA corresponded to hypoechoic poorly defined solid plaque like or nodular lesions, located in the dermal-epidermal plane. The deep GA presented as solid nodular, poorly defined hypoechoic lesions that compromised the deep subcutaneous-aponeurotic plane. CONCLUSION: GA is an inflammatory lesion that presents as a superficial or deep palpable nodule that predominantly affects children. Superficial and deep GA present characteristic findings on US that can guide the diagnosis. The radiologist needs to know its US appearance to be able to suggest the diagnosis, especially in multiples lesions.

Chemically Modified Variants of Fenofibrate with Antiglioblastoma Potential.

Anticancer effects of a common lipid-lowering drug, fenofibrate, have been described in the literature for a quite some time; however, fenofibrate has not been used as a direct anticancer therapy. We have previously reported that fenofibrate in its unprocessed form (ester) accumulates in the mitochondria, inhibits mitochondrial respiration, and triggers a severe energy deficit and extensive glioblastoma cell death. However, fenofibrate does not cross the blood brain barrier and is quickly processed by blood and tissue esterases to form the PPARα agonist fenofibric acid, which is practically ineffective effective in triggering cancer cell death. To address these issues, we have made several chemical modifications in fenofibrate structure to increase its stability, water solubility, tissue penetration, and ultimately anticancer potential. Our data show that, in comparison to fenofibrate, four new compounds designated here as PP1, PP2, PP3, and PP4 have improved anticancer activity in vitro. Like fenofibrate, the compounds block mitochondrial respiration and trigger massive glioblastoma cell death in vitro. In addition, one of the lead compounds, PP1, has improved water solubility and is significantly more stable when exposed to human blood in comparison to fenofibrate. Importantly, mice bearing large intracranial glioblastoma tumors demonstrated extensive areas of tumor cell death within the tumor mass following oral administration of PP1, and the treated mice did not show any major signs of distress, and accumulated PP1 at therapeutically relevant concentrations in several tissues, including brain and intracranial tumors.

Aging phenotype(s) in kidneys of diabetic mice are p66ShcA dependent.

The p66ShcA protein controls cellular responses to oxidative stress, senescence, and apoptosis. Here, we test the hypothesis that aging phenotype(s) commonly associated with the broad category of chronic kidney disease are accelerated in diabetic kidneys and linked to the p66ShcA locus. At the organ level, tissue stem cells antagonize senescent phenotypes by replacing old dysfunctional cells. Using established methods, we isolated a highly purified population of stem cell antigen-1-positive mesenchymal stem cells (Sca-1+ MSCs) from kidneys of wild-type (WT) and p66 knockout (p66 KO) mice. Cells were plated in culture medium containing normal glucose (NG) or high glucose (HG). Reactive oxygen species (ROS) metabolism was substantially increased in WT MSCs in HG medium in association with increased cell death by apoptosis and acquisition of the senescent phenotype. DNA microarray analysis detected striking differences in the expression profiles of WT and p66 KO-MSCs in HG medium. Unexpectedly, the analysis for p66 KO-MSCs revealed upregulation of Wnt genes implicated in self-renewal and differentiation. To test the in vivo consequences of constitutive p66 expression in diabetic kidneys, we crossed the Akita diabetic mouse with the p66KO mouse. Homozygous mutation at the p66 locus delays or prevents aging phenotype(s) in the kidney that may be precursors to diabetic nephropathy.

Risk factors for wheezing in infants born in Cuba.

BACKGROUND: Cuba is a unique country, and despite limited economic development, has an excellent health system. However, the prevalence of asthma symptoms in children in Havana, Cuba, is unusually high. AIM: As early life exposures are critical to the aetiology of asthma, we have studied environmental influences on the risk of wheezing in Cuban infants. DESIGN: Cross-sectional study. METHODS: A random sample of 2032 children aged 12-15 months living in Havana was selected for inclusion in the cohort. Data were collected using questionnaires administered by researchers. RESULTS: Of 2032 infants invited to participate, 1956 (96%) infants provided data. The prevalence of any wheeze was 45%, severe wheeze requiring use of emergency services was 30% and recurrent wheeze on three or more occasions was 20%. The largest adjusted risk factors for any wheeze were presence of eczema [odds ratio (OR) 2.09; 95% confidence interval (CI) 1.48-2.94], family history of asthma (OR 2.05; 95% CI 1.60-2.62), poor ventilation in the house (OR 1.99; 95% CI 1.48-2.67), attendance at nursery (OR 1.78; 95% CI 1.24-2.57), male sex (OR1.52; 95% CI 1.19-1.96) and the number of smokers in the house (P < 0.03 for trend), OR 1.64 (95% CI 1.17-2.31) for three or more smokers in the house compared to no smokers in the household. CONCLUSION: We have identified several risk factors for any wheeze in young infants living in modern day Cuba. As the prevalence of smoking in the house is high (51%), intervention studies are required to determine effective strategies to improve infant health.

IL-7Rα deficiency in p53null mice exacerbates thymocyte telomere erosion and lymphomagenesis.

Interleukin-7 (IL-7) is an essential T-cell survival cytokine. IL-7 receptor (IL-7Rα) deficiency severely impairs T-cell development due to substantial apoptosis. We hypothesized that IL-7Rα(null)-induced apoptosis is partially contributed by an elevated p53 activity. To investigate the genetic association of IL-7/IL-7Rα signaling with the p53 pathway, we generated IL-7Rα(null)p53(null) (DKO) mice. DKO mice exhibited a marked reduction of apoptosis in developing T cells and an augmented thymic lymphomagenesis with telomere erosions and exacerbated chromosomal anomalies, including chromosome duplications, breaks, and translocations. In particular, Robertsonian translocations, in which telocentric chromosomes fuse at the centromeric region, and a complete loss of telomeres at the fusion site occurred frequently in DKO thymic lymphomas. Cellular and molecular investigations revealed that IL-7/IL-7Rα signaling withdrawal diminished the protein synthesis of protection of telomere 1 (POT1), a subunit of telomere protective complex shelterin, leading to telomere erosion and the activation of the p53 pathway. Blockade of IL-7/IL-7Rα signaling in IL-7-dependent p53(null) cells reduced POT1 expression and caused telomere and chromosome abnormalities similar to those observed in DKO lymphomas. This study underscores a novel function of IL-7/IL-7Rα during T-cell development in regulating telomere integrity via POT1 expression and provides new insights into cytokine-mediated survival signals and T-cell lymphomagenesis.

Treatment of pulmonary metastatic tumors in mice using lentiviral vector-engineered stem cells.

Active cancer immunotherapy relies on functional tumor-specific effector T lymphocytes for tumor elimination. Dendritic cells (DCs), as most potent antigen-presenting cells, have been popularly employed in clinical and experimental tumor treatments. We have previously demonstrated that lentiviral vector-mediated transgene delivery to DC progenitors, including bone marrow cells and hematopoietic stem cells, followed by transplantation supports systemic generation of great numbers of tumor antigen-presenting DCs. These DCs subsequently stimulate marked and systemic immune activation. Here, we examined whether this level of immune activation is sufficient to overcome tumor-induced tolerogenic environment for treating an established aggressive epithelial tumor. We showed that a combination treatment of granulocyte macrophage-colony stimulating factor and cytosine-phosphate-guanine-containing oligonucleotide stimulated large numbers of tumor antigen-presenting DCs in situ from transgene-modified stem cells. Moreover, these in situ generated and activated DCs markedly stimulated activation of antigen-specific CD4 and CD8 T cells by augmenting their numbers, as well as function, even in a tumor-bearing tolerogenic environment. This leads to significant improvement in the therapeutic efficacy of established pulmonary metastases. This study suggests that lentiviral vector-modified stem cells as DC progenitors may be used as an effective therapeutic regimen for treating metastatic epithelial tumors.

A constitutively active ERBB4/HER4 allele with enhanced transcriptional coactivation and cell-killing activities.

In the normal breast, ERBB4 regulates epithelial differentiation and functions as a nuclear chaperone for signal transducer and activator of transcription (STAT) 5A, thereby stimulating milk-gene expression. In addition, ERBB4 functions as a proapoptotic protein, suppressing the growth of malignant cells. We hypothesize that these ERBB4 activities can be marshaled to suppress the growth of breast tumors. To this end, we have created an ERBB4 allele harboring an activating transmembrane mutation (ERBB4-CA) by substituting isoleucine 658 for glutamic acid. This base substitution forms a valine-glutamic acid-glycine activation domain first identified in oncogenic ERBB2/HER2/Neu. Ectopic expression of ERBB4-CA in HEK293T cells resulted in a fivefold increase in receptor tyrosine phosphorylation. Functionally, ERBB4-CA exhibited higher levels of nuclear translocation than wild-type ERBB4, leading to significantly enhanced ERBB4-induced STAT5A simulation of the beta-casein promoter. Activated ERBB4 has been demonstrated to induce cell killing of breast tumor cells. Significantly, ERBB4-CA potentiated the proapoptotic function of ERBB4 in each breast, prostate and ovarian cancer cell line tested. Untransformed cell lines were resistant to both ERBB4 and ERBB4-CA-mediated apoptosis underscoring the potential utility of active ERBB4 signaling for the therapeutic intervention of human cancer.

The synthetic peptide PFWT disrupts AF4-AF9 protein complexes and induces apoptosis in t(4;11) leukemia cells.

The MLL gene at chromosome band 11q23 is commonly involved in reciprocal translocations detected in acute leukemias. A number of experiments show that the resulting MLL fusion genes directly contribute to leukemogenesis. Among the many known MLL fusion partners, AF4 is relatively common, particularly in acute lymphoblastic leukemia in infants. The AF4 protein interacts with the product of another gene, AF9, which is also fused to MLL in acute leukemias. Based on mapping studies of the AF9-binding domain of AF4, we have developed a peptide, designated PFWT, which disrupts the AF4-AF9 interaction in vitro and in vivo. We provide evidence that this peptide is able to inhibit the proliferation of leukemia cells with t(4;11) chromosomal translocations expressing MLL-AF4 fusion genes. Further, we show that this inhibition is mediated through apoptosis. Importantly, the peptide does not affect the proliferative capacity of hematopoietic progenitor cells. Our findings indicate that the AF4-AF9 protein complex is a promising new target for leukemia therapy and that the PFWT peptide may serve as a lead compound for drug development.

CD4+ T cell-independent vaccination against Pneumocystis carinii in mice.

Host defenses are profoundly compromised in HIV-infected hosts due to progressive depletion of CD4+ T lymphocytes. Moreover, deficient CD4+ T lymphocytes impair vaccination approaches to prevent opportunistic infection. Therefore, we investigated a CD4+ T cell-independent vaccine approach to a prototypic AIDS-defining infection, Pneumocystis carinii (PC) pneumonia. Here, we demonstrate that bone marrow-derived dendritic cells (DCs) expressing the murine CD40 ligand, when pulsed ex vivo by PC antigen, elicited significant titers of anti-PC IgG in CD4-deficient mice. Vaccinated animals demonstrated significant protection from PC infection, and this protection was the result of an effective humoral response, since adoptive transfer of CD4-depleted splenocytes or serum conferred this protection to CD4-deficient mice. Western blot analysis of PC antigen revealed that DC-vaccinated, CD4-deficient mice predominantly reacted to a 55-kDa PC antigen. These studies show promise for advances in CD4-independent vaccination against HIV-related pathogens.

Heart rate and oxygen saturation correlates of infant apnea.

OBJECTIVE: To analyze the effects of apnea duration on changes in heart rate and oxygen saturation and to examine the temporal relationships among these variables. STUDY DESIGN: An event analysis sheet was designed to analyze numerous variables reflecting changes in heart rate and oxygen saturation associated with infant apnea. From July 1, 1991 through June 30, 1992 we identified 32 infants enrolled in The Infant Apnea Program at St. Peter's Medical Center, New Brunswick, NJ who had apnea > or = 15 seconds in duration on consecutive 12-hour multichannel recordings of heart rate, thoracic impedance, nasal thermistry, and oxygen saturation. The apnea epochs of these patients were subdivided into apnea of short (10 to 14 seconds), medium (15 to 19 seconds), and long (> or = 20 seconds) duration, and a total of 236 apnea epochs were analyzed. The significance of differences was assessed by analysis of variance and Newman-Keuls multiple comparisons. RESULTS: We found that the duration of apnea has significant effects on perturbations in both heart rate and oxygen saturation, however, the degree of oxygen desaturation can not be predicted by the perturbation in heart rate. Analysis of the temporal relationship of apnea, bradycardia, and oxygen desaturation reveals that, although apnea precedes both heart rate and oxygen saturation drops in most infants as the length of apneic interval increases, the interval between apnea onset and associated drops in heart rate and/or oxygen saturation also increases. CONCLUSION: Oxygen saturation monitoring may provide important physiologic data that can not be assessed by cardiorespiratory monitoring alone.

[Idiopathic facial hemispasm: a case report]. / Hemiespasmo facial idiopático: a propósito de un caso.

A case of prolonged, slowly progressive, idiopathic hemifacial spasm in a 68-year-old man is presented. A suspected cerebellopontine angle lesion was confirmed by MRI and digital angiography. Cerebellopontine angle lesions have to be differentiated from idiopathic hemifacial spasm.

Removal of domain D2 or D3 of the human urokinase receptor does not affect ligand affinity.

The main ligand-binding determinant of the human urokinase receptor (uPAR) is located in the amino terminal domain D1, but when isolated this domain presents a 1500 fold lower affinity than the intact three-domain uPAR (D1D2D3). uPAR mutants missing either domain 2 (D1HD3) or domain 3 (D1D2) were expressed in murine LB6 cells and showed to be properly GPI-anchored to the cell surface. Binding assays with [125I]ATF demonstrated that these mutants possessed a normal (D1D2) or slightly reduced (D1HD3) affinity, indicating that a high ligand-affinity may be achieved by a combination of D1 with domain D2 or D3.

Biosynthesis and apical localization of the urokinase receptor in polarized MDCK epithelial cells.

The biosynthesis and the surface localization of the urokinase plasminogen activator receptor (uPAR) were analysed in MDCK epithelial cells and in unpolarized fibroblasts. No differences were observed with respect to rate of synthesis, nature of precursors and time of surface appearance. uPAR was localized particularly at the focal and cell-cell contacts when expressed in fibroblasts. On the contrary, in MDCK cells uPAR was found mostly on the apical surface; in agreement with its localization, down-regulation of uPAR by the uPA-PAI-1 complex was observed only from the apical membrane.

[Paraplegia following surgical repair of a ductus and of a coarctation of the aorta in childhood]. / Paraplejia tras la reparación quirúrgica de un ductus y una coartación de aorta en la edad pediátrica.

The cases of two girls with 4 and 7 years of age presented. They had a patent ductus and an aortic coarcation which were subsequently surgically repaired. After the operation paraplegia was diagnosed. With rehabilitation they are able to walk, however paraparexis persist. Anatomy of the arterial irrigation of the spinal cord is reviewed and also the pathophysiology and mechanisms of medullar ischemia.