Childhood tuberculosis in southern Taiwan, with emphasis on central nervous system complications

Background/PurposeChildhood tuberculosis (TB) continues to be a major public health problem in Taiwan. Taiwan remains a highly endemic area despite neonatal Bacillus Calmette–Guérin (BCG) vaccination and the availability of anti-TB therapy. The presentation is highly variable and it is often difficult to make an accurate diagnosis. This study was designed to evaluate the demographic, clinical, and laboratory findings and outcomes of TB in children with emphasis on central nervous system (CNS) complications.MethodsThe medical records of 80 children diagnosed with TB at a medical center in southern Taiwan over the past 24 years (1988–2012) were reviewed.ResultsAmong them, 48.8% (39/80) had pulmonary TB, 27.5% (22/80) had isolated extrapulmonary TB, and 23.7% (19/80) had disseminated TB. Most infected cases were aged either < 4 years or > 12 years. TB contact history was found in 42.5% (34/80) cases. Fourteen (17.5%) of the cases had CNS involvement. The most common presentations were fever (85.7%), signs of increased intracranial pressure (71.4%), drowsiness (64.3%), and focal neurological signs (57.1%). The major radiological findings were tuberculoma (50%), basilar enhancement (41.6%), infarction (41.6%), hydrocephalus (16.6%), and transverse myelitis (16.6%). The case fatality of CNS TB was 14.3% and 21.4% had neurologic sequelae.ConclusionFindings suggest that positive exposure history and suspicious clinical presentations are important clues for further confirmatory laboratory and image studies in childhood TB. CNS TB usually presented as part of disseminated TB in children. Early diagnosis and treatment may lead to favorable outcomes in CNS TB

Cumingianoside A, a Phyto-Triterpenoid Saponin Inhibits Acquired BRAF Inhibitor Resistant Melanoma Growth via Programmed Cell Death

Mutated proto-oncogene BRAF is a bona fide therapeutic target for melanomas. Regrettably, melanoma acquires resistance to BRAF inhibitors, e.g., vemurafenib (PLX4032) casting doubt on this promising melanoma targeted therapy. In this study, we explored the bioactivity of triterpenoid saponin cumingianoside A (CUMA), isolated from leaves and twigs of Dysoxylum cumingianum against PLX4032-resistant BRAFV 600E mutant melanoma A375-R in vitro and in vivo. Our data show that CUMA treatment inhibited A375-R melanoma cell proliferation in a time- and dose-dependent manner. CUMA also suppressed the activity of CDK1/cyclin B1 complex and led to G2/M-phase arrest of A375-R cells. Furthermore, CUMA treatment resulted in induction of apoptosis as shown by the increased activation of caspase 3 and caspase 7, and the proteolytic cleavage of poly(ADP-ribose) polymerase (PARP). We also observed that CUMA induced autophagy-like activity in A375-R cells, as shown by the increased expression of autophagy-related genes and increased formation of autophagosomes. Moreover, we found that CUMA treatment induced ER stress response and co-treatment with an ER stress inhibitor (4-PBA) could attenuate apoptosis induced by CUMA. Importantly, orally administered CUMA as a single agent or in combination with PLX4032 exhibited strong tumor growth inhibition in a PLX4032-resistant A375-R xenograft mouse model, and with little toxicity. This is the first report to explore the anti-tumor activity of CUMA in vitro and in vivo mechanistically, and our results imply that this triterpenoid saponin may be suitable for development into an anti-melanoma agent

Long-term Characteristics of Healthcare-associated Infections in a Neonatal Intensive Care Unit

Background/PurposeHealthcare-associated infections in neonatal intensive care units (NICUs) are associated with a significant risk of morbidity and mortality. Knowledge regarding pathogens, primary sources of infection and antibiotic resistance in the NICU is essential for developing management strategies. This study aimed to analyze the long-term characteristics of healthcare-associated infections in a tertiary referral center in southern Taiwan.MethodsInfants < 30 days old, with positive blood, cerebrospinal fluid, urine or tissue fluid cultures during hospitalization in the NICU of National Cheng Kung University Hospital from July 1989 to June 2008 were included in the study.ResultsIn total, 1,417 organisms and episodes were identified during the study period. Gram-positive organisms, Gram-negative organisms and fungi constituted 923 (65.1%), 358 (25.3%) and 136 (9.6%) of the pathogens, respectively. Of the Gram-positive organisms, coagulase-negative staphylococci (51.5%), Staphylococcus aureus (34.8%) and Enterococcus spp. (6.1%) were the major pathogens; and 27% of Staphylococcus aureus isolates were oxacillin-resistant. For the Gram-negative organisms, Klebsiella pneumoniae (22%), Pseudomonas aeruginosa (21.8%), Escherichia coli (16.7%) and Enterobacter cloacae (16.7%) were dominant. Also, Candida albicans accounted for 50% of fungal infections. The most common source of infection was bloodstream infection (59.0%), and 5.6% of these were catheter-related. Skin and soft tissue infections were also frequent (26.3%).ConclusionBloodstream and skin/soft tissue infections caused by commensal species play an important role in healthcare-associated infections in the NICU. New measures should be developed in response to the changing patterns in the NICU

Lateral mobility of FcγRIIa is reduced by protein kinase C activation

AbstractThe lateral mobility of membrane proteins can reflect the extent of various protein-protein interactions. Using the fluorescence recovery after photobleaching technique, we have studied the lateral mobility of human FcγRIIa and some FcγRIIa mutants expressed in either P388D1 cells, a mouse macrophagelike cell line, or in Chinese hamster ovary (CHO) cells [1]. After treatment with phorbol myristate acetate (PMA), only the FcγRIIa molecules capable of mediating rapid endocytosis of immune complexes exhibited a reduced lateral diffusion coefficient with respect to untreated controls. Wild type FcγRIIa expressed in CHO cells, and nonfunctional FcγRIIa mutants expressed in P388D1 cells did not show any differences upon PMA treatment. This finding suggests that protein kinase C activation evokes additional protein-protein interactions with the cytoplasmic domain of functional FcγRIIa, which reduced receptor lateral mobility. The identity of these putative interacting proteins and the nature of the interactions remain to be elucidated

Case report: Distinct neurologic manifestation and cytokine profile of a child with COVID-19-associated acute fulminant encephalitis

The neurologic manifestations of coronavirus disease 2019 (COVID-19) may range from mild symptoms such as headache or confusion to profound encephalopathy with variable outcomes and sequelae. Here, we reported a case of fatal COVID-19-associated encephalitis with acute fulminant cerebral edema, presenting first with visual hallucination and then a rapid progression into comatose status in a few hours. Serial brain computed tomography depicted cerebral edematous changes from bilateral ventral temporal lobe to the whole brain leading to brain herniation. Multiple cytokines in serum and cerebrospinal fluid (CSF) were increased, with a more prominent rise in the CSF. Therefore, we postulated a hypothesis regarding the mechanism of this fulminant encephalitis that the SARS-CoV-2 virus attacked ventral temporal lobes initially, triggered a severe cytokine storm, and then led to subsequent disruption of the blood-brain barrier, diffuse brain edema, and brain herniation. The trend of cytokine profiles over time may aid in diagnosing and evaluating the severity and prognosis of COVID-19-associated encephalitis

TRAIL and IP-10 dynamics in pregnant women post COVID-19 vaccination: associations with neutralizing antibody potency

IntroductionThe aim of this study is to investigate changes in TNF-related apoptosis-inducing ligand (TRAIL) and gamma interferon-induced protein 10 (IP-10) after COVID-19 vaccination in pregnant women and to explore their association with neutralizing antibody (Nab) inhibition.MethodsThe study evaluated 93 pregnant women who had previously received two (n=21), three (n=55) or four (n=17) doses of COVID-19 vaccine. Also we evaluated maternal blood samples that were collected during childbirth. The levels of TRAIL, IP-10 and Nab inhibition were measured using enzyme-linked immunosorbent assays (ELISA).Results and discussionOur study revealed four-dose group resulted in lower TRAIL levels when compared to the two-dose and three-dose groups (4.78 vs. 16.07 vs. 21.61 pg/ml, p = 0.014). The two-dose group had reduced IP-10 levels than the three-dose cohort (111.49 vs. 147.89 pg/ml, p=0.013), with no significant variation compared to the four-dose group. In addition, the four-dose group showed stronger Nab inhibition against specific strains (BA.2 and BA.5) than the three-dose group. A positive correlation was observed between TRAIL and IP-10 in the two-dose group, while this relationship was not found in other dose groups or between TRAIL/IP-10 and Nab inhibition. As the doses of the COVID-19 vaccine increase, the levels of TRAIL and IP-10 generally increase, only by the fourth dose, the group previously vaccinated with AZD1222 showed lower TRAIL but higher IP-10. Despite these changes, more doses of the vaccine consistently reinforced Nab inhibition, apparently without any relation to TRAIL and IP-10 levels. The variation may indicate the induction of immunological memory in vaccinated mothers, which justifies further research in the future

Efficacy of a paper-based interleukin-6 test strip combined with a spectrum-based optical reader for sequential monitoring and early recognition of respiratory failure in elderly pneumonia—a pilot study

Introduction: Community-acquired pneumonia (CAP) is lethal in elderly individuals who are more vulnerable to respiratory failure and require more emergency ventilation support than younger individuals. Interleukin-6 (IL-6) plays a crucial role and has predictive value in CAP; high serum IL-6 concentrations in adults are associated with high respiratory failure and mortality rates. Early detection of IL-6 concentrations can facilitate the timely stratification of patients at risk of acute respiratory failure. However, conventional enzyme-linked immunosorbent assay (ELISA) IL-6 measurement is laborious and time-consuming.Methods: The IL-6 rapid diagnostic system combined with a lateral flow immunoassay-based (LFA-based) IL-6 test strip and a spectrum-based optical reader is a novel tool developed for rapid and sequential bedside measurements of serum IL-6 concentrations. Here, we evaluated the correlation between the IL-6 rapid diagnostic system and the ELISA and the efficacy of the system in stratifying high-risk elderly patients with CAP. Thirty-six elderly patients (median age: 86.5 years; range: 65–97 years) with CAP were enrolled. CAP diagnosis was established based on the Infectious Diseases Society of America (IDSA) criteria. The severity of pneumonia was assessed using the CURB-65 score and Pneumonia Severity Index (PSI). IL-6 concentration was measured twice within 24 h of admission.Results: The primary endpoint variable was respiratory failure requiring invasive mechanical or non-invasive ventilation support after admission. IL-6 rapid diagnostic readouts correlated with ELISA results (p &lt; 0.0001) for 30 samples. Patients were predominantly male and bedridden (69.4%). Ten patients (27.7%) experienced respiratory failure during admission, and five (13.9%) died of pneumonia. Respiratory failure was associated with a higher mortality rate (p = 0.015). Decreased serum IL-6 concentration within 24 h after admission indicated a lower risk of developing respiratory failure in the later admission course (Receiver Operating Characteristic [ROC] curve = 0.696).Conclusion: Sequential IL-6 measurements with the IL-6 rapid diagnostic system might be useful in early clinical risk assessment and severity stratification of elderly patients with pneumonia. This system is a potential point-of-care diagnostic device for sequential serum IL-6 measurements that can be applied in variable healthcare systems

Plasma Protein Biomarkers Distinguish Multisystem Inflammatory Syndrome in Children from Other Pediatric Infectious and Inflammatory Diseases

Background: Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious hyperinflammatory complication following infection with severe acute respiratory syndrome coronavirus 2. The mechanisms underpinning the pathophysiology of MIS-C are poorly understood. Moreover, clinically distinguishing MIS-C from other childhood infectious and inflammatory conditions, such as Kawasaki disease or severe bacterial and viral infections, is challenging due to overlapping clinical and laboratory features. We aimed to determine a set of plasma protein biomarkers that could discriminate MIS-C from those other diseases. Methods: Seven candidate protein biomarkers for MIS-C were selected based on literature and from whole blood RNA sequencing data from patients with MIS-C and other diseases. Plasma concentrations of ARG1, CCL20, CD163, CORIN, CXCL9, PCSK9 and ADAMTS2 were quantified in MIS-C (n = 22), Kawasaki disease (n = 23), definite bacterial (n = 28) and viral (n = 27) disease and healthy controls (n = 8). Logistic regression models were used to determine the discriminatory ability of individual proteins and protein combinations to identify MIS-C and association with severity of illness. Results: Plasma levels of CD163, CXCL9 and PCSK9 were significantly elevated in MIS-C with a combined area under the receiver operating characteristic curve of 85.7% (95% confidence interval: 76.6%-94.8%) for discriminating MIS-C from other childhood diseases. Lower ARG1 and CORIN plasma levels were significantly associated with severe MIS-C cases requiring inotropes, pediatric intensive care unit admission or with shock. Conclusion: Our findings demonstrate the feasibility of a host protein biomarker signature for MIS-C and may provide new insight into its pathophysiology