Impact of age and tumor size on the development of the Kasabach-Merritt phenomenon in patients with kaposiform hemangioendothelioma: a retrospective cohort study.

Introduction: The Kasabach-Merritt phenomenon (KMP) is a severe complication of kaposiform hemangioendothelioma (KHE). The risk factors for KMP need further investigation. Methods: The medical records of patients with KHE were reviewed. Univariate and multivariate logistic regression models were used for the risk factors for KMP, and the area under the receiver operator characteristic (ROC) curve was used to assess the predictive power of risk factors. Results: A total of 338 patients with KHE were enrolled. The incidence of KMP was 45.9%. Age of onset (P < 0.001, odds ratio [OR] 0.939; 95% confidence interval [CI] 0.914-0.966), lesion size (P < 0.001, OR 1.944; 95% CI 1.646-2.296), mixed type (P = 0.030, OR 2.428; 95% CI 1.092-5.397), deep type (P = 0.010, OR 4.006; 95% CI 1.389-11.556), and mediastinal or retroperitoneal lesion location (P = 0.019, OR 11.864; 95% CI 1.497-94.003) were correlated with KMP occurrence through multivariate logistic regression. ROC curve analysis revealed that the optimal cutoffs were 4.75 months for the age of onset (P < 0.001, OR 7.206, 95% CI 4.073-12.749) and a lesion diameter of 5.35 cm (P < 0.001, OR 11.817, 95% CI 7.084-19.714). Bounded by a lesion size of 5.35 cm, we found significant differences in tumor morphology, age of onset, treatments, and hematological parameters. Using an onset age of 4.75 months as a cutoff, we found significant differences in tumor morphology, lesion size, hematological parameters, and prognosis. Conclusion: For KHE patients with an onset age <4.75 months and/or lesion diameter >5.35 cm, clinicians should be wary of the occurrence of KMP. Active management is recommended to improve the prognosis.

Performance of the PRISM I, PIM2, PELOD-2 and PRISM IV scoring systems in western China: a multicenter prospective study.

BACKGROUND: The aim of this study was to evaluate the performance of the four scoring tools in predicting mortality in pediatric intensive care units (PICUs) in western China. METHODS: This was a multicenter, prospective, cohort study conducted in six PICUs in western China. The performances of the scoring systems were evaluated based on both discrimination and calibration. Discrimination was assessed by calculating the area under the receiver operating characteristic curve (AUC) for each model. Calibration was measured across defined groups based on mortality risk using the Hosmer-Lemeshow goodness-of-fit test. RESULTS: A total of 2034 patients were included in this study, of whom 127 (6.2%) died. For the entire cohort, AUCs for Pediatric Risk of Mortality Score (PRISM) I, Pediatric Index of Mortality 2 (PIM2), Pediatric Logistic Organ Dysfunction Score-2 (PELOD-2) and PRISM IV were 0.88 [95% confidence interval (CI) 0.85-0.92], 0.84 (95% CI 0.80-0.88), 0.80 (95% CI 0.75-0.85), and 0.91 (95% CI 0.88-0.94), respectively. The Hosmer-Lemeshow goodness-of-fit Chi-square value was 12.71 (P = 0.12) for PRISM I, 4.70 (P = 0.79) for PIM2, 205.98 (P < 0.001) for PELOD-2, and 7.50 (P = 0.48) for PRISM IV [degree of freedom (df) = 8]. The standardized mortality ratios obtained with the PRISM I, PIM2, PELOD-2, and PRISM IV models were 0.87 (95% CI, 0.75-1.01), 0.97 (95% CI, 0.85-1.12), 1.74 (95% CI, 1.58-1.92), and 1.05 (95% CI, 0.92-1.21), respectively. CONCLUSIONS: PRISM IV performed best and can be used as a prediction tool in PICUs in Western China. However, PRISM IV needs to be further validated in NICUs.

Exome sequencing contributes to identify comorbidities in a rare case of infant ARDS induced by the CD40LG mutation.

BACKGROUND: Acute respiratory distress syndrome (ARDS) causes significant mortality in young children with certain diseases. Early diagnosis and treatment can reduce infant mortality. Here, we report a rare case of exome sequencing in the early diagnosis of immunodeficiency in an infant. CASE PRESENTATION: A four-month-old full-term male infant presented with severe shortness of breath, hypoxemia, and unexplained parenchymal lung lesions. A series of examinations were performed to search for potential culprit viruses but negative results were obtained with the only exception being the rhinovirus that tested positive. The child's family history revealed he had a brother who died of severe infection at the age of two years. We performed an exome sequencing analysis and a mutation analysis of CD40LG to obtain genetic data on the patient. Besides, we used flow cytometry to measure the CD40LG expression levels of activated T cells. A retrospective review of all the CD40LG mutant-induced X-linked hyper IgM syndromes (XHIGM) had been conducted to assess the differences between clinical and genetic molecular features. Finally, a regular intravenous immunoglobulin (IVIG) regimen led to steady breathing, the correction of hypoxemia, and a progressive improvement of lung CT scans. During follow-up, the patient received an IVIG regimen and his CT images improved. Moreover, his parents took advantage of pre-implantation genetic testing with in vitro fertilization to have a healthy twin offspring who did not carry such a mutation according to the early exome sequencing for the proband. Compared with other CD40LG mutant cases in our center, this proband displayed a normal plasma immunoglobulin level and he should be the youngest infant to have a molecular diagnosis of XHIGM. CONCLUSION: Usually, XHIGM would not be suspected with a normal plasma immunoglobulin concentration. However, as we could not identify a potential comorbidity or risk factor, exome sequencing helps target this patient's real facts. Thus, this case report calls for exome sequencing to be performed in the case of unexplained infections when immunodeficiency is suspected after general immunological tests, especially for cases with a contributive family history among infants as the maternal transfused immunoglobulin might mask immune deficiency.

A prospective multicenter study of sirolimus for complicated vascular anomalies.

OBJECTIVE: Complicated vascular anomalies (VAs) can be intractable and uncontrollable using conventional treatment and can result in lethal outcomes. We undertook a prospective, multicenter phase II trial to evaluate the efficacy and safety of sirolimus in pediatric patients with complicated VAs. METHODS: Eligible patients were required to be aged 0 to 14 years and to have a complicated VA. The patients were treated with daily oral sirolimus for 12 months. The primary endpoint was the response, which was measured using sequential volumetric magnetic resonance imaging. The secondary endpoints were the disease severity score and quality of life. RESULTS: Of 126 patients enrolled on an intention-to-treat basis, 98 (77.8%) had had an objective response to sirolimus, with a ≥20% decrease in lesion volume. Compared with those with arteriovenous malformations, the response rates were higher (>80%) for patients with common lymphatic malformations, venous malformations, kaposiform hemangioendothelioma, and combined malformations with a prominent venous and/or lymphatic component (P < .05). Improvements in the disease severity score and quality of life were obtained in 83.3% and 79.4% of patients, respectively. The most common adverse event was mucositis in 47 patients. More serious adverse events included reversible grade 4 pneumonitis in 3 patients and grade 4 upper respiratory infection in 1 patient. All these adverse events were considered at least possibly related to the treatment. CONCLUSIONS: Sirolimus is an apparently effective option for pediatric patients with various types of complicated VAs. Close monitoring of possible adverse events is required. The results from the present trial are the basis for future prospective studies using new therapeutic approaches.

Efficacy and Safety of Propranolol vs Atenolol in Infants With Problematic Infantile Hemangiomas: A Randomized Clinical Trial.

Importance: Propranolol has become the first-line therapy for problematic infantile hemangiomas (IHs) that require systemic therapy. However, different adverse events have been reported during propranolol treatment. The positive efficacy and safety of atenolol raise the question of whether it could be used as a promising therapy for IH. Objective: To compare the efficacy and safety of propranolol vs atenolol in infants (between age 5 and 20 weeks) with problematic IHs who required systemic therapy. Design, Setting, and Participants: This was a prospective, multicenter, randomized, controlled, open-label clinical trial conducted in collaboration among 6 separate investigation sites in China from February 1, 2015, to December 31, 2018. A total of 377 patients met the criteria for inclusion and were randomized to the propranolol (190 [50.4%]) and atenolol (187 [49.6%]) groups. Data were analyzed in June 2020. Interventions: Participants were randomized to receive either propranolol or atenolol for at least 6 months. They completed efficacy assessments at 2 years after the initial treatment. Main Outcomes and Measures: The primary outcome was any response or nonresponse at 6 months. The key secondary outcome was changes in the hemangioma activity score. Results: Of 377 participants, 287 (76.1%) were female, and the mean (SD) age was 10.2 (4.0) weeks in the propranolol group and 9.8 (4.1) weeks in the atenolol group. After 6 months of treatment, in the propranolol and atenolol groups, the overall response rates were 93.7% and 92.5%, respectively (difference, 1.2%; 95% CI, -4.1% to 6.6%). At 1 and 4 weeks after treatment, and thereafter, the hemangioma activity score in the atenolol group aligned with the propranolol group (odds ratio, 1.034; 95% CI, 0.886-1.206). No differences between the propranolol group and atenolol group were observed in successful initial responses, quality of life scores, complete ulceration healing times, or the rebound rate. Both groups presented a similar percentage of complete/nearly complete responses at 2 years (82.1% vs 79.7%; difference, 2.4%; 95% CI, -5.9% to 10.7%). Adverse events were more common in the propranolol group (70.0% vs 44.4%; difference, 25.6%; 95% CI, 15.7%-34.8%), but the frequency of severe adverse events did not differ meaningfully between the groups. Conclusions and Relevance: In this randomized clinical trial, when compared with propranolol, atenolol had similar efficacy and fewer adverse events in the treatment of infants with problematic IHs. The results suggest that oral atenolol can be used as an alternative treatment option for patients with IH who require systemic therapy. Trial Registration: ClinicalTrial.gov Identifier: NCT02342275.

Screening for infantile hepatic hemangioma in patients with cutaneous infantile hemangioma: A multicenter prospective study.

BACKGROUND: Abdominal ultrasonography has been proposed to screen for infantile hepatic hemangioma (IHH) in patients with multiple cutaneous infantile hemangiomas (IHs). OBJECTIVES: The aim of this study was to establish the optimal cutoff point for the number of cutaneous IHs needed to screen for IHH. METHODS: We performed a prospective, multicenter study to screen for IHH in patients younger than 9 months who had multiple cutaneous IHs (n ≥ 3) on ultrasonography. For comparison, a group of patients with 1 or 2 focal cutaneous IHs was also recruited. RESULTS: In total, 676 patients with at least 3 cutaneous IHs and 980 patients with 1 or 2 focal cutaneous IHs were enrolled. Thirty-one patients were found to have IHH. A higher number of cutaneous IHs was associated with an increased risk of IHH (R = 0.973; P < .001). Receiver operating characteristic curve analysis showed that 5 cutaneous IHs was the optimal cutoff point to screen for IHH, with an area under the curve of 0.872 (P < .001; 95% confidence interval, 0.789-0.955). LIMITATIONS: This was an uncontrolled study. CONCLUSIONS: Screening for IHH is recommended in patients younger than 9 months who present with 5 or more cutaneous IHs.

Chronic lymphedema in patients with kaposiform hemangioendothelioma: incidence, clinical features, risk factors and management.

OBJECTIVES: There are no cohort studies of chronic lymphedema in patients with kaposiform hemangioendothelioma (KHE). We sought to characterize the incidence, clinical features, risk factors and management of chronic lymphedema in patients with KHE. METHODS: We conducted a multicenter retrospective analysis of patients who had a minimum of 3 years of follow-up after the onset of KHE and/or Kasabach-Merritt phenomenon (KMP). Clinical features were reviewed to determine the possible cause of chronic lymphedema. The degree of lymphedema, risk factors and management strategies were analyzed. RESULTS: Among the 118 patients, chronic lymphedema was confirmed by lymphoscintigraphy 1 year after the onset of KHE and/or KMP in 13 patients. In 8 patients with lymphedema, extremity swelling was evident in the presence of KHE and/or KMP. In all patients with lymphedema, a unilateral extremity was affected, along with ipsilateral KHE. Most (84.6%) patients reported moderate lymphedema. Lymphedema was more common in patients with larger (≥ 10 cm) and mixed lesions involving the extremities (P < 0.01). A history of KMP and sirolimus treatment were not predictors of lymphedema (P > 0.05). Overall, 76.9% of patients received sirolimus treatment after referral, including 53.8% who presented extremity swelling before referral. Seven (53.8%) patients received compression therapy. Five (38.5%) patients reported lymphedema-associated decreased range of motion at the last follow-up. CONCLUSIONS: Chronic lymphedema is a common sequela of KHE and can occur independently of KMP and sirolimus treatment. Patients with large and mixed KHE involving extremities should be closely monitored for this disabling complication.

Sestrin 2 attenuates sepsis-associated encephalopathy through the promotion of autophagy in hippocampal neurons.

Sepsis-associated encephalopathy (SAE) has typically been associated with a poor prognosis. Although sestrin 2 (SESN2) plays a crucial role in metabolic regulation and the stress response, its expression and functional roles in SAE are still unclear. In the present study, SAE was established in mice through caecal ligation and puncture (CLP). The adeno-associated virus 2 (AAV2)-mediated SESN2 expression (ie overexpression and knockdown) system was injected into the hippocampi of mice with SAE, and subsequently followed by electron microscopic analysis, the Morris water maze task and pathological examination. Our results demonstrated an increase of SESN2 in the hippocampal neurons of mice with SAE, 2-16 hours following CLP. AAV2-mediated ectopic expression of SESN2 attenuated brain damage and loss of learning and memory functions in mice with SAE, and these effects were associated with lower pro-inflammatory cytokines in the hippocampus. Mechanistically, SESN2 promoted unc-51-like kinase 1 (ULK1)-dependent autophagy in hippocampal neurons through the activation of the AMPK/mTOR signalling pathway. Finally, AMPK inhibition by SBI-0206965 blocked SESN2-mediated attenuation of SAE in mice. In conclusion, our findings demonstrated that SESN2 might be a novel pharmacological intervention strategy for SAE treatment through promotion of ULK1-dependent autophagy in hippocampal neurons.

Concurrent lymphoma and hemophilia B in a pediatric patient: A case report.

INTRODUCTION: Lymphoma is the third most common cancer among children in the United States and Europe. Hemophilia is a congenital bleeding disorder characterized by deficiency of coagulation factor VIII or IX. Hemophilia B is a consequence of factor IX deficiency and has an incidence of 1 in 20,000 male births. A concurrence of these 2 uncommon diseases is rare except in patients infected with the human immunodeficiency virus (HIV). We report a case of a patient with both Burkitt lymphoma and hemophilia B; this is only such report in China since 1987. PATIENT CONCERNS: A 3-year-old boy was admitted to our hospital because of melena and jaundice for several days. His older brother had died due to hemophilia B and ventricular septal defect. The patient had not experienced any previous episodes of severe bleeding. Gradual abdominal distention was observed after admission; the patient's superficial lymph nodes were not enlarged. Results of blood routine and bone marrow examinations showed no abnormalities. He was diagnosed with sclerosing cholangitis, abdominal infection, and hepatitis. However, after treatment of reducing enzyme activity and eliminating jaundice, the patient's condition deteriorated. Hydrops abdominis was detected on abdominal ultrasonography. Tumor cells were found by pathological examination of peritoneal effusion. Both a c-myc gene translocation and a c-myc-IgH gene fusion were detected. DIAGNOSIS: Burkitt lymphoma and hemophilia B. INTERVENTIONS: The patient was transferred to the Pediatric Hematology Department of our hospital and treated with a modified B-NHL-BFM-95 protocol. During chemotherapy, platelet changes were monitored regularly and blood products were infused timely. OUTCOMES: The patient died of infection and bleeding after chemotherapy. CONCLUSION: Concurrent hemophilia and lymphoma are rare, especially in children. When encountering a patient with unexplained obstructive jaundice and massive ascites, the possibility of a tumor should be considered. Early diagnosis and adequate treatment of such tumor may improve prognosis.

Kaposiform hemangioendothelioma without cutaneous involvement.

PURPOSE: We sought to characterize the clinical features and management of patients diagnosed as Kaposiform hemangioendothelioma (KHE) without cutaneous involvement. METHODS: The electronic patient chats at six Triple A hospitals in China were searched to find all patient diagnoses with KHE without cutaneous involvement. RESULTS: Of 30 patients (mean age at diagnosis, 55.6 months), 17 (56.7%) were male. Fourteen (46.7%) patients were associated with Kasabach-Merritt phenomenon (KMP). Patients with KMP were significantly more likely to have lesions involving truck compared to patients without KMP (odds ratio 10.000; 95% confidence interval 1.641-60.921; P = 0.011). Other common complication included severe anemia and decreased range of motion. In the majority of cases (93.3%), the lesions were highly infiltrative and locally invasive with ill-defined margins. Histological examination was required in all patients without KMP for precise diagnosis. In all, 16 (53.3%) patients received corticosteroid treatment, 19 (63.3%) received oral sirolimus treatment, 7 (23.3%) received intravenous vincristine, and 5 (16.7%) patients used propranolol. Patients had varied responses to conventional drugs, whereas all patients receiving sirolimus treatment had better response. In all, three patients (10%) died of disease, all presented with KMP. Feature of these recalcitrant cases (death) included young age, visceral location, extensive involvement, and lack of improvement with high-dose corticosteroids. CONCLUSIONS: Our study clearly demonstrated that KHE without cutaneous involvement could be associated with important complication, which might result in death or severe morbidity. Increased awareness of KHE without cutaneous involvement is required for early diagnosis and aggressive therapy in an attempt to prevent complication.

Musculoskeletal complication in kaposiform hemangioendothelioma without Kasabach-Merritt phenomenon: clinical characteristics and management.

PURPOSE: Musculoskeletal complications have been associated with kaposiform hemangioendothelioma (KHE) and can lead to disability and reduced quality of life. We aimed to determine the clinical characteristics of musculoskeletal complication in patients with KHE without Kasabach-Merritt phenomenon (KMP) in order to identify features that may aid clinicians in KHE treatment. PATIENTS AND METHODS: We conducted a cohort study of KHE without KMP associated with musculoskeletal complication between January 2006 and February 2017 at three tertiary medical centers in China. The study included 29 nonthrombocytopenic patients with KHE and musculoskeletal complication. RESULTS: The mean age at diagnosis of KHE was 4.5 years (range, 0.3-50.0 years). The mean follow-up was 4.1 years (range, 0.5-9.0 years). In most cases (72.4%), decreased range of motion (ROM) appeared within 2 years of KHE onset. Associated chronic pain was reported in 12 patients. Bone-joint changes were common in patients with decreased ROM (75.9%). All the patients received at least one medical therapy including corticosteroids, vincristine, propranolol, and sirolimus. Sirolimus demonstrated the highest efficacy rate, with 94.7% of patients showing improvements in ROM and chronic pain. CONCLUSION: Musculoskeletal complication can occur early in the disease course of KHE without KMP. Although no uniformly effective treatment modality was found, sirolimus demonstrated the best response in patients with KHE with decreased ROM and chronic pain.

Intolerable side effects during propranolol therapy for infantile hemangioma: frequency, risk factors and management.

Currently, propranolol is the most preferred systemic therapy for problematic infantile hemangiomas (IHs). However, the side effects such as bronchial hyperreactivity may be intolerable. The aim of this study was to evaluate the frequency, risk factors and management of intolerable side effects (ISEs) during propranolol therapy. In total, 1260 children were studied. The incidence of ISEs was 2.1% (26 patients). Severe sleep disturbance was the most common reason for propranolol cessation, accounting for 65.4% of cases. In total, 23 and 3 patients received atenolol and prednisolone as second-line therapy, respectively. Treatment response was observed in 92.3% (24/26) of cases (showing excellent or good response to therapy). No toxicity-related permanent treatment discontinuation occurred during atenolol or prednisolone therapy. In the univariate analysis, younger age, premature birth, and lower body weight were associated with ISEs (P < 0.05). In the multivariate analysis, only age (95% confidence interval [CI]: 1.201-2.793, P = 0.009) and body weight (95% CI: 1.036-1.972, P = 0.014) were associated with ISEs. Our study suggests that ISEs are rare in patients with IHs who are treated with propranolol. Predictive factors for ISEs include younger age and lower body weight. Atenolol and prednisolone are effective and safe alternatives to propranolol in the treatment of refractory IHs.

Sirolimus for the treatment of progressive kaposiform hemangioendothelioma: A multicenter retrospective study.

Kaposiform hemangioendothelioma (KHE) is an aggressive disease with high morbidity and mortality. The aim of this study was to retrospectively evaluate the efficacy and safety of sirolimus for the treatment of progressive KHE. A multicenter, retrospective cohort study was conducted in patients with progressive KHE treated with sirolimus. A total of 52 patients were analyzed. Thirty-seven (71%) patients exhibited Kasabach-Merritt phenomenon (KMP) and were significantly younger than the patients without KMP [95% confidence interval (CI), 14.39-41.61; p < 0.001]. Patients without KMP were all treated with sirolimus alone, whereas 21 KMP patients with severe symptoms received short-term combination therapy with prednisolone. Overall, 96% and 98% of patients showed improved relief of notable symptoms and/or improved complications at 6 and 12 months after treatment, respectively. After sirolimus treatment, significant decreases in mean severity scores occurred at 6 months (95% CI, 2.23-2.54, p < 0.001) and 12 months (95% CI, 1.53-1.90, p < 0.001). Compared to KMP patients, patients without KMP showed a response that was similar to but less pronounced during the 12 months of treatment (95% CI, 40.87-53.80; p < 0.001). For subgroup analysis of KMP patients, there were no significant differences in tumor shrinkage between those treated with combination therapy and those receiving sirolimus alone (95% CI, 18.11-25.02; p > 0.05). No patients permanently discontinued treatment due to toxicity-related events, and no drug-related deaths occurred. Sirolimus was effective and safe for the treatment of progressive KHE. Sirolimus may be considered as a first-line therapy or as part of a multidisciplinary approach for the treatment of KHE.

AMPK activates FOXO3a and promotes neuronal apoptosis in the developing rat brain during the early phase after hypoxia-ischemia.

AMP-activated protein kinase (AMPK) is a key metabolic and stress sensor/effector. Few investigations have been performed to study the role of AMPK in developing rat brain with hypoxia-ischemia (HI). Forkhead transcriptional factor (FOXO3a) has been revealed to be a critical effector of AMPK-mediated celluar apoptosis. However, it is not clear whether AMPK/FOXO3a pathway is involved in neuronal apoptosis in the developing rat brain after HI. In this study, we generated hypoxia-ischemia brain damage (HIBD) model using postnatal day 7 rats. We found that activation of AMPK was accompanied by the decrease of p-mTOR, p-Akt and p-FOXO3a, which induced FOXO3a translocation into the nucleus and up-regulated the expression of Bim and cleaved caspase 3 (CC3). Furthermore, we discovered that AMPK inhibition by Compound C, a selective inhibitor for AMPK activity, significantly increased the phosphorylation levels of mTOR, Akt and FOXO3a, attenuated the nuclear translocation of FOXO3a, and inhibited Bim and CC3 expression after HI. Moreover, AMPK inhibition reduced cellular apoptosis, attenuated brain infarct volume and promoted neurological recovery in the developing rat brain after HI. Our findings suggest that AMPK participates in the regulation of FOXO3a-mediated neuronal apoptosis in the developing rat brain after HI. Agents targeting AMPK may offer promise for rescuing neurons from HI-induced damage.

[Role of c-Jun N-terminal kinase-mediated FOXO3a nuclear translocation in neuronal apoptosis in neonatal rats with hypoxic-ischemic brain damage].

OBJECTIVE: To explore the mechanisms of neuroprotective effects of c-Jun N-terminal kinase (JNK)/FOXO3a transcription factor signaling pathway inhibition on hypoxic-ischemic neuronal apoptosis in neonatal rats with hypoxic-ischemic brain damage (HIBD). METHODS: Sixty-four 7-day-old Sprague-Dawley rats were divided into four groups: hypoxia-ischemia (HI), sham-operated, JNK specific inhibitor AS601245-treated, and DMSO vehicle. Rats' cerebral cortexes were collected at 24 hours after HI. Western blot was used to detect the protein expression of JNK, p-JNK, FOXO3a, nuclear and cytoplasmic FOXO3a, Bim, and CC3. TUNEL staining was used to detect the apoptotic cells. RESULTS: Compared with the sham-operated group, p-JNK protein increased (P<0.01), nuclear protein of FOXO3a increased (P<0.01), cytoplasmic protein decreased (P<0.01), and pro-apoptotic proteins Bim and CC3 increased 24 hours after HI (P<0.01). Compared with the HI and DMSO vehicle groups, p-JNK protein was reduced (P<0.01), nuclear protein of FOXO3a was also reduced (P<0.01), cytoplasmic protein increased (P<0.01), and Bim and CC3 proteins decreased (P<0.01) in the AS601245-treated group 24 hours after HI. TUNEL positive cells were reduced in the AS601245-treated rats compared with the HI and DMSO vehicle groups 24 hours after HI (P<0.01). CONCLUSIONS: JNK activity increases in the neonatal rat brain with HI damage. JNK activity inhibition can inhibit FOXO3a translocation from cytoplasm to nucleus and downregulate the levels of pro-apoptotic proteins Bim and CC3, leading to the reduction of neuronal apoptosis.

Clinical features and management of multifocal hepatic hemangiomas in children: a retrospective study.

Multifocal hepatic hemangioma (MHH) is a benign hepatic tumor that is commonly diagnosed in children with multiple cutaneous infantile hemangiomas (IHs). We present a review of all children with MHH at our institutions. Of the 42 patients, the median age at presentation of MHH was 2.5 months. Thirty-six (85.7%) patients had cutaneous IHs. Twelve (28.6%) patients were symptomatic at presentation. There was no significant association between the number of hepatic hemangiomas and the number of cutaneous IHs. Fourteen (33.3%) patients received some form of treatment for hepatic hemangiomas. The most common type of treatment was oral prednisone in 8 patients, followed by oral propranolol in 6 patients. Two patients were totally resistant to prednisone treatment. They died from congestive heart failure or respiratory distress and coagulopathy. Two patients with problematic facial IH were treated with intralesional triamcinolone injection. The remaining 26 patients were managed with imaging surveillance. On follow-up, all of the survivors had a favorable outcome. Our study suggests that the clinical features of MHH are variable. Our data emphasize the treatment strategy that aggressive treatment is indicated in symptomatic or progressive MHHs, whereas observation management of asymptomatic patients with a few small lesions is safe and appropriate.

Infantile Hepatic Hemangioendothelioma Associated With Congestive Heart Failure: Two Case Reports With Different Outcomes.

Infantile hepatic hemangioendothelioma (IHH) is rare which can regress spontaneously. Arteriovenous shunts within hemangiomas, however, may result in pulmonary artery hypertension (PAH) and congestive heart failure (CHF).The authors report 2 young infants suffering from multifocal IHH associated with CHF were both treated with glucocorticoid and transcatheter arterial embolization (TAE), but had different outcomes. The PAH decreased immediately and the symptoms of CHF were alleviated after TAE for both of them. For the Tibetan infant, the development was normal with tumor regression by follow-up. For the Han ethnic neonate, PAH increased again in the seventh day with progressive cardiovascular insufficiency. Ultrasound showed a persisting perfusion caused by collateralization around occluded main feeders. Furthermore, a pulmonary infection occurred and ventilation was performed. As a result, the infant died from multiorgan failure caused by CHF and infection.TAE is a treatment of reducing shunting for hemangiomas. Fistula recanalization in multifocal IHH, however, might be an important risk factor affecting the outcome of TAE. TAE should be further evaluated with special attention to anatomy of feeding and draining vessels, and cardiopulmonary conditions. In addition, the patients were susceptible to secondary pulmonary infection because of lung congestion. As well, the infant from the high altitude area showed better adaptability to hypoxia.

Fluorescent detection of protein kinase based on positively charged gold nanoparticles.

Herein, we report a fluorometric method for monitoring the activity and inhibition of protein kinase based on positively charged gold nanoparticles, (+)AuNPs. In this assay, when the cationic substrate peptide (S-peptide) is phosphorylated by protein kinase, the resulting negatively charged product peptide (P-peptide) will be adsorbed onto (+)AuNPs through electrostatic interaction, and the fluorescence of fluorescein isothiocyanate (FITC) on the peptide will be quenched by (+)AuNPs. Thus, the fluorescence of solution can respond to the activity of protein kinase. The feasibility of this (+)AuNPs-based method has been demonstrated by sensitive measurement of the activity of cAMP-dependent protein kinase (PKA) with a low detection limit (0.5 mU µL(-1)). Furthermore, the system is successfully applied to estimate the IC50 value of PKA inhibitor H-89. The fast mix-and-readout detection process as well as the simple synthesis of the unmodified (+)AuNPs makes this proposed method a promising candidate for simple and cost-effective kinase activity detection and a good potential in high-throughput screening of kinase-related drugs.