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Introduction: Intrauterine herpes simplex virus (HSV) infection is uncommon and challenging to diagnose, requiring detection of HSV in skin lesions within 48 h post-birth. Case Presentation: A preterm female infant presented with the typical triad of blisters, microcephaly, and chorioretinitis, but the initial diagnostic approach was elusive due to negative results for TORCH pathogens from vesicles/serum. Referred at 7 months for developmental delay and epilepsy, her brain imaging showed calcification and cortical dysplasia. Polymerase chain reaction (PCR) of her preserved dried umbilical cord detected HSV-2 DNA, diagnosing intrauterine HSV infection. HSV-2 was later found in relapsed blisters at 8 months but not in cerebrospinal fluid or brain tissue. A literature review identified 104 congenital/intrauterine HSV cases; 28.8% presented the typical triad, and 50% were diagnosed using specimens collected 48 h post-birth. Conclusion: This case marks the first retrospective diagnosis of intrauterine HSV infection via PCR on preserved umbilical cord, underscoring its diagnostic value. Plain Language Summary: Congenital intrauterine infection occurs when mother-to-fetus transmission of infection occurs during pregnancy, disrupting fetal development. Intrauterine HSV infection is rare and difficult to diagnose because HSV needs to be detect in specimens collected within 48 h of birth. Here, we present the case of an infant with typical signs of intrauterine HSV infection, including the brain, eye, and skin lesions, diagnosed retrospectively at the age of 7 months using preserved dried umbilical cord. Additionally, we conducted a literature review of methods used for the diagnosis of intrauterine HSV infection. A female infant was born with the typical signs, but was not diagnosed during the neonatal period because skin and blood samples tested negative. She was referred to our hospital at the age of 7 months because of developmental delay and seizures. Polymerase chain reaction (PCR) of a preserved dried umbilical cord specimen detected HSV type 2, confirming the diagnosis of intrauterine HSV infection. In Japan, umbilical cords are traditionally dried and preserved at home after birth as a symbol of the mother-child bond. Detection of virus in umbilical cord specimens strongly suggests infection before birth. We reviewed 104 previously reported cases of congenital or intrauterine HSV infection, of which 28.8% had the typical triad (skin, brain, and eye lesions), and 50% were diagnosed using specimens collected after 48 h post-birth. To our knowledge, this is the first retrospective diagnosis of intrauterine HSV infection based on PCR testing of preserved dried umbilical cord, underscoring its diagnostic value. [ABSTRACT FROM AUTHOR]

Introduction: Interleukin (IL)-33 and its receptor ST2L play key roles in the IL-33/ST2 signaling pathway. Soluble ST2 (sST2) inhibits the proper function of IL-33. sST2 levels are increased in patients with several neurological diseases, but in infants with hypoxic-ischemic encephalopathy (HIE), IL-33 and sST2 levels have not been studied. This study aimed to investigate whether serum levels of IL-33 and sST2 are useful as biomarkers of HIE severity and prognostic factors for infants with HIE. Methods: Twenty-three infants with HIE and 16 controls (gestational age ≥36 weeks and ≥1,800 g birth weight) were enrolled in this study. Serum levels of IL-33 and sST2 were measured at <6 h, 1–2, 3, and 7 days of age. Hydrogen-1 magnetic resonance spectroscopy was performed, and ratios of peak integrals of lactate/N-acetylaspartate (Lac/NAA) were calculated as objective indicators of brain damage. Results: In the moderate and severe HIE, serum sST2 concentrations were increased and there was a good correlation between serum sST2 and HIE severity on days 1–2, whereas no variation was observed in serum IL-33. Serum sST2 levels were positively correlated with Lac/NAA ratios (Kendall's rank correlation coefficient = 0.527, p = 0.024), and both sST2 and Lac/NAA ratios were significantly higher in HIE infants with neurological impairment (p = 0.020 and <0.001, respectively). Conclusions: sST2 may be a useful predictor of severity and later neurological outcomes in infants with HIE. Further investigation is required to elucidate the relationship between the IL-33/ST2 axis and HIE. [ABSTRACT FROM AUTHOR]

Osteomyelitis is characterized by progressive inflammatory bone destruction accompanied by severe pain and disability. However, with the exception of antibiotic therapies, there is no established therapy to protect the bone from infectious osteolysis. The anti‐receptor activator of nuclear factor‐kB ligand (RANKL) monoclonal antibody (anti‐RANKL Ab) is a potential drug based on its proven effectiveness in preventing joint bone erosion in rheumatoid arthritis; however, the efficacy and adverse effects of anti‐RANKL Ab in osteomyelitis remain to be investigated. In this study, we investigated the effects of anti‐mouse RANKL Ab on acute osteomyelitis and compared them with those of zoledronic acid (ZA) using a murine model. Mice were inoculated with bioluminescent Staphylococcus aureus (Xen 29) on their left femur and then treated with ZA, anti‐RANKL Ab, or phosphate‐buffered saline as control. A 21‐day longitudinal observational study using microcomputed tomography showed that both anti‐RANKL Ab and ZA had an osteoprotective effect against infectious osteolysis. However, it was also demonstrated through bioluminescence imaging that ZA delayed the spontaneous reduction of bacterial load and through histology that it increased the amount of necrotic bone, while anti‐RANKL Ab did not. Findings from histopathological and in vitro studies suggest that an intense inflammatory response around the necrotic bone could induce osteoclasts in a RANKL‐independent manner, leading to the removal of necrotic bone, even after administration of the anti‐RANKL Ab therapy. Collectively, anti‐RANKL Ab may exert an osteoprotective effect without hampering the removal of the necrotic bone, which serves as a nidus for infection in osteomyelitis. [ABSTRACT FROM AUTHOR]

This study aimed to determine the results of radiolunate arthrodesis for rheumatoid arthritis (RA) after a long-term follow-up period of up to 20 years under tight postoperative medical control of RA. We also compared the results between patients with and without degenerative changes in the midcarpal joints at follow-up. We determined the radiologic factors predictive of secondary degenerative changes in the midcarpal joint. This was a long-term retrospective analysis of 16 wrists of 14 patients with RA treated with radiolunate arthrodesis first reported in 2013. The mean follow-up period was 14 years (range, 8–23 years; SD, 4.6 years). Ten wrists had a Larsen classification of grade III, whereas 6 wrists had grade IV. The range of motion was assessed, and clinical outcomes were graded using the Mayo Wrist Score and Stanley classification system. The Carpal Height Index, Ulnar Translation Index, and changes in the midcarpal joint contour were determined from radiographs. We categorized the changes in the midcarpal joint as unchanged or degenerative. At final follow-up, the clinical scores improved; however, the extension and flexion range of motion was significantly reduced compared with that before surgery. The Carpal Height Index and Ulnar Translation Index improved immediately after surgery and remained stable at final follow-up. The changes in the midcarpal joint were categorized as unchanged in 6 wrists and degenerative in 10 wrists. The clinical outcomes were similar between the groups. The mean preoperative Ulnar Translation Index was significantly higher in the degenerative group than in the unchanged group. Radiolunate arthrodesis in patients with RA maintained good clinical results and corrected alignment, even during long-term follow-up. Preoperative severe ulnar translation deformity was a risk factor for postoperative degeneration of the midcarpal joint, and pre-existing degenerative changes at the midcarpal joint might lead to loss of wrist range of motion. Therapeutic IV. [ABSTRACT FROM AUTHOR]

Abstract Background Z-360 is an orally active cholecystokinin-2 (CCK2)/gastrin receptor antagonist currently under development as a therapeutic drug for pancreatic cancer. It was previously reported that Z-360 treatment in combination with gemcitabine prolonged the survival period in a lethal pancreatic cancer xenograft model in mice. In a phase Ib/IIa clinical study, Z-360 treatment displayed a trend of reduced pain in patients with advanced pancreatic cancer in combination with gemcitabine including analgesics such as opioids. Here, we investigated the mechanism of analgesic action of Z-360 in a severe cancer-induced pain model in mice, which is considered to be opioid-resistant, by examining ephrin B1 gene expression, N-methyl-D-aspartate receptor NR2B subunit phosphorylation, and interleukin-1β (IL-1β) production. Results In a mouse model of cancer-induced pain, ephrin B1 gene expression in dorsal root ganglia (DRGs) and the phosphorylation of NR2B in the spinal cord were induced. Z-360 treatment inhibited both ephrin B1 gene expression and the phosphorylation of NR2B. In addition, IL-1β production increased in the cancer-inoculated hind paw of mice, but could be suppressed by treatment with Z-360. Moreover, we observed that the CCK1 receptor antagonist devazepide similarly suppressed up-regulation of ephrin B1 gene expression and IL-1β production, and that the intraperitoneal injection of sulfated CCK-8 induced the production of IL-1β in the cancer-inoculated region. Conclusions We have identified a novel pain cascade, in which IL-1β production in cancer-inoculated regions induces ephrin B1 gene expression in DRGs and then ephrin B1 enhances the tyrosine phosphorylation of NR2B via Eph B receptor in the spinal cord. Notably, Z-360 relieves cancer-induced pain by preventing this pain cascade through the suppression of IL-1β production, likely via the blockade of CCK1 receptor. The pre-clinical results presented here support the analgesic action of Z-360 in pancreatic cancer patients with severe, opioid-resistant pain. Pre-clinical and clinical results have demonstrated that Z-360 combined with gemcitabine represents a promising pancreatic cancer therapy approach with characteristic analgesic effects in addition to the prolongation of survival.

ABSTRACT: The lack of an effective drug therapy against ossification of spinal ligament (OSL) warrants investigation into the therapeutic target of this disease. An endogenous inhibitor of biomineralization, pyrophosphate (PPi) is a potential therapy for ectopic ossification; however, exogenous PPi is rapidly hydrolyzed by tissue non‐specific alkaline phosphatase (TNAP) present in body fluids. In this study, we examined whether a drug therapy targeting PPi is efficacious for the treatment of OSL using the Enpp1ttw/ttw (twy) mouse model. Twenty male twy mice were randomized into four groups: (i) vehicle (Control); (ii) alkaline phosphatase inhibitor levamisole (5 mg/kg/day sc continuously); (iii) levamisole + exogenous PPi (160 µmol/kg/day sc continuously); and (iv) nuclear retinoic acid receptor‐γ (RARγ) agonist (6 µg/kg sc daily). The RARγ agonist, which is a proven inhibitor of ectopic endochondral ossification, was used as a positive control. Treatments commenced when the mice were 5 weeks of age and continued for 4 weeks. Longitudinal micro‐computed tomography and postmortem histological analysis were performed. Administration of levamisole alone and in combination with PPi increased serum PPi concentration by 17% and 52%, respectively, compared to that in vehicle‐treated mice. The development of OSL in twy mice was suppressed by levamisole + PPi and RARγ agonist treatments, but not by levamisole alone. The levamisole + PPi therapy did not cause osteoporosis, whereas RARγ agonist‐treated mice developed osteoporosis. Treatment of twy mice with levamisole in combination with exogenous PPi increased serum PPi level, which slowed the progression of OSL without producing adverse effect on bone. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1256–1261, 2018. [ABSTRACT FROM AUTHOR]