Hyaluronic acid injections for treatment of pediatric sickle cell avascular necrosis of the humeral head.

BACKGROUND: Avascular necrosis (AVN) can impact up to 50% of patients with sickle cell disease (SCD) and can result in significant pain, decline in physical function and decreased quality of life. While hyaluronic acid (HA) has been used in the adult population for shoulder osteoarthritic pain, we present the first published pediatric case of HA injections in the glenohumeral joint, used to improve function and pain control. CASE PRESENTATION: The patient is a 12-year-old woman with SCD, who suffered from chronic pain due to AVN of the humeral and femoral head. Despite engaging in a multidisciplinary pain management plan, she continued to have severe decline in physical functioning and became a wheelchair user. As a result, she was scheduled for a right total hip arthroplasty, which necessitated aggressive postoperative therapies using the glenohumeral joint. To improve this pain and to facilitate postoperative recovery, the patient underwent 4 weekly HA injections into the glenohumeral joint. Over a 2-month period, the patient was able to improve physical functioning, decrease opiate use and participate in all postoperative therapies. CONCLUSION: Conservative options to improve functioning and pain are especially important in pediatric patients where it may be desirable to delay surgical interventions until skeletal maturity. Our case report demonstrates the benefits of intra-articular HA as part of a multidisciplinary pain management plan to improve function and decrease pain related to AVN of the humeral head. Future studies should assess the long-term benefits of HA injections for AVN in the setting of SCD.

Effectiveness of liposomal bupivacaine in adductor canal blocks for pediatric knee procedures: A case series.

Adductor canal block (ACB) using liposomal bupivacaine (LB) has been shown to be effective in achieving prolonged postoperative pain control for knee procedures in adults. However, published literature on the use of ACB with LB in pediatric patients continues to be lacking. We present a case series on the effectiveness of ACB using LB in achieving extended postoperative pain control for pediatric patients undergoing knee surgeries. Our patients reported at least 96 h of pain relief with zero postoperative opioid requirements and no major adverse reactions from LB.

Ilioinguinal/Iliohypogastric Pulsed Radiofrequency for the Treatment of Pediatric Chronic Abdominal Pain: A Case Report.

Chronic abdominal pain in the pediatric population has the potential to interfere with all aspects of life and daily functioning. Pain may originate from various sites including the viscera, fascial layers, muscles, or peripheral nerves. The incidence of somatic neuritis, more specifically ilioinguinal and iliohypogastric neuralgia, remains unknown. We report a case highlighting the use of pulsed radiofrequency in the treatment of lower abdominal pain secondary to ilioinguinal and iliohypogastric neuralgia. In carefully selected patients, as part of a multimodal regimen, pulsed radiofrequency can aid recovery by providing effective and long-lasting pain relief, thus allowing time for effective rehabilitation.

Horner's Syndrome and Upper Extremity Weakness After Quadratus Lumborum Block for Postcesarean Section Analgesia: A Case Report.

A healthy, 34-year-old primigravida at 41 weeks gestational age presented for cesarean delivery due to a category 2 fetal heart tracing remote from delivery. After completion of the surgery under epidural anesthesia, bilateral quadratus lumborum blocks were performed for postoperative pain. Approximately 4 hours later, the patient developed left-sided arm weakness, left miosis, and ptosis. These symptoms resolved within 24 hours. Considering the time course of her symptoms, we believe that the quadratus lumborum block was the likely culprit.

PIAS1 regulates breast tumorigenesis through selective epigenetic gene silencing.

Epigenetic gene silencing by histone modifications and DNA methylation is essential for cancer development. The molecular mechanism that promotes selective epigenetic changes during tumorigenesis is not understood. We report here that the PIAS1 SUMO ligase is involved in the progression of breast tumorigenesis. Elevated PIAS1 expression was observed in breast tumor samples. PIAS1 knockdown in breast cancer cells reduced the subpopulation of tumor-initiating cells, and inhibited breast tumor growth in vivo. PIAS1 acts by delineating histone modifications and DNA methylation to silence the expression of a subset of clinically relevant genes, including breast cancer DNA methylation signature genes such as cyclin D2 and estrogen receptor, and breast tumor suppressor WNT5A. Our studies identify a novel epigenetic mechanism that regulates breast tumorigenesis through selective gene silencing.

Control of specificity and magnitude of NF-kappa B and STAT1-mediated gene activation through PIASy and PIAS1 cooperation.

NF-kappaB and STATs regulate multiple cellular processes through the transcriptional activation of genes with diversified functions. Although the molecular mechanisms that can turn on/off the overall NF-kappaB/STAT signaling have been extensively studied, how NF-kappaB/STAT-target genes can be differentially regulated is poorly understood. Here we report that PIASy, a member of the PIAS (for protein inhibitor of activated STAT) protein family, is a physiologically important transcriptional repressor of NF-kappaB and STAT1. Piasy deletion in dendritic cells resulted in enhanced expression of a subset of NF-kappaB and STAT1-dependent genes in response to LPS or IFN-gamma treatment, respectively. Consistently, Piasy null mice are hypersensitive to the LPS-induced endotoxic shock. Furthermore, PIASy and PIAS1 display specific as well as redundant effects on the regulation of NF-kappaB/STAT1 signaling. Pias1-/-Piasy-/- embryos died before day 11.5. The disruption of one allele of Pias1 in the Piasy-/- background significantly enhanced the effect of Piasy deletion on the transcriptional induction of NF-kappaB/STAT1-dependent genes, and vice versa. Our results demonstrate that PIASy cooperates with PIAS1 to regulate the specificity and magnitude of NF-kappaB/STAT1-mediated gene activation.

Proinflammatory stimuli induce IKKalpha-mediated phosphorylation of PIAS1 to restrict inflammation and immunity.

How inflammatory stimuli signal to the nucleus to restrict inflammation is poorly understood. Protein inhibitor of activated STAT1 (PIAS1), a transcriptional regulator that possesses small ubiquitin-related modifier (SUMO) E3 ligase activity, inhibits immune responses by selectively blocking the binding of NF-kappaB and STAT1 to gene promoters. We report here that PIAS1 becomes rapidly phosphorylated on Ser90 residue in response to various inflammatory stimuli. Mutational studies indicate that Ser90 phosphorylation is required for PIAS1 to repress transcription. Upon TNF treatment, wild-type PIAS1, but not the Ser90A mutant, becomes rapidly associated with the promoters of NF-kappaB target genes. Furthermore, IKKalpha, but not IKKbeta, interacts with PIAS1 in vivo and mediates PIAS1 Ser90 phosphorylation, a process that requires the SUMO ligase activity of PIAS1. Our results identify a signaling pathway in which proinflammatory stimuli activate the IKKalpha-mediated sumoylation-dependent phosphorylation of PIAS1 for the immediate repression of inflammatory gene activation.

Murine gammaherpesvirus 68 open reading frame 45 plays an essential role during the immediate-early phase of viral replication.

Murine gammaherpesvirus 68 (MHV-68) has been developed as a model for the human gammaherpesviruses Epstein-Barr virus and human herpesvirus 8/Kaposi's sarcoma-associated herpesvirus (HHV-8/KSHV), which are associated with several types of human diseases. Open reading frame 45 (ORF45) is conserved among the members of the Gammaherpesvirinae subfamily and has been suggested to be a virion tegument protein. The repression of ORF45 expression by small interfering RNAs inhibits MHV-68 viral replication. However, the gene product of MHV-68 ORF45 and its function have not yet been well characterized. In this report, we show that MHV-68 ORF45 is a phosphorylated nuclear protein. We constructed an ORF45-null MHV-68 mutant virus (45STOP) by the insertion of translation termination codons into the portion of the gene encoding the N terminus of ORF45. We demonstrated that the ORF45 protein is essential for viral gene expression immediately after the viral genome enters the nucleus. These defects in viral replication were rescued by providing ORF45 in trans or in an ORF45-null revertant (45STOP.R) virus. Using a transcomplementation assay, we showed that the function of ORF45 in viral replication is conserved with that of its KSHV homologue. Finally, we found that the C-terminal 23 amino acids that are highly conserved among the Gammaherpesvirinae subfamily are critical for the function of ORF45 in viral replication.

Murine gammaherpesvirus 68 open reading frame 31 is required for viral replication.

Murine gammaherpesvirus 68 (MHV-68) is genetically related to the human gammaherpesviruses, Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) and Epstein-Barr virus (EBV). It has been proposed as a model for gammaherpesvirus infection and pathogenesis. Open reading frame 31 (ORF31) is conserved among the Beta- and Gammaherpesvirinae subfamily, and there is no known mammalian homologue of this protein. The function of MHV-68 ORF31 and its viral homologues has not yet been determined. We described here a primary characterization of this protein and its requirement for lytic replication. The native MHV-68 ORF31 was detected at peak levels by 24 h postinfection, and the FLAG-tagged and green fluorescent protein fusion ORF31 were localized in the cytoplasm and nucleus in a diffuse pattern. Two independent experimental approaches were then utilized to demonstrate that ORF31 was required for lytic replication. First, small interfering RNA generated against ORF31 expression blocked protein expression and virus production in transfected cells. Then, two-independent bacterial artificial chromosome-derived ORF31-null MHV-68 mutants (31STOP) were generated and found to be defective in virus production in fibroblast cells. This defect can be rescued in trans by MHV-68 ORF31 and importantly by its KSHV homologue. A repair virus of 31STOP was also generated by homologous recombination in fibroblast cells. Finally, we showed that the defect in ORF31 blocked late lytic protein expression. Our results demonstrate that MHV-68 ORF31 is required for viral lytic replication, and its function is conserved in its KSHV homologue.