Impact of de-escalation therapy on clinical outcomes for intensive care unit-acquired pneumonia

Introduction

De-escalation therapy is a strategy currently used for the management of nosocomial pneumonia. In this study, we evaluated clinical outcomes and risk factors related to de-escalation therapy in patients with intensive care unit (ICU)-acquired pneumonia.

Methods

This was a retrospective observational cohort study of ICU patients who developed pneumonia more than 48 hours after admission to the ICU at Samsung Medical Center from September 2004 to December 2007.

Results

The 137 patients comprised 44 (32.1%) who received de-escalation therapy and 93 in the non-de-escalation group. The de-escalation group showed a lower pneumonia-related mortality rate than the non-de-escalation group by day 14 (2.3% vs. 10.8%, respectively; P = 0.08) and by day 30 (2.3% vs. 14%, respectively; P = 0.03) after the diagnosis of pneumonia. The variables independently associated with ICU-acquired pneumonia-related mortality included the Acute Physiology and Chronic Health Evaluation II (APACHE II) score and the modified Clinical Pulmonary Infection Score (CPIS) after 5 days with pneumonia. The non-de-escalation group had significantly higher APACHE II score and modified CPIS after 5 days with ICU-acquired pneumonia compared to the de-escalation group. Among all patients, 20.4% (28 of 137) had negative cultures for pathogens, and 42.9% (12 of 28) received de-escalation therapy. The latter 12 patients received de-escalation therapy and survived 30 days after the diagnosis of pneumonia.

Conclusions

Patients in the de-escalation group showed a significantly lower mortality rate compared to patients in the non-de-escalation group. De-escalation therapy can be safely provided to patients with ICU-acquired pneumonia if they are clinically stable by day 5, even in those whose respiratory specimen cultures yield no specific pathogens.     

Intellectual Functioning of Pediatric Patients with Chronic Kidney Disease: Results from the KNOW-Ped CKD

BackgroundChronic kidney disease (CKD) has a negative impact on growth and development in children and is a risk factor for neurocognitive impairment; however, there is limited research on the cognitive function of children and adolescents with CKD. This study therefore aimed to investigate the mean intelligence and risk factors for low intelligence in children and adolescents with CKD.MethodsEighty-one patients with CKD under 18 years old were included in the KoreaN cohort study for Outcomes in patients With Pediatric Chronic Kidney Disease (KNOW-Ped CKD). Participants completed either the Wechsler Intelligence Scale for Children (6–16 years), or Wechsler Adult Intelligence Scale (> 16 years).ResultsThe mean full-scale intelligence quotient (IQ) was 91 ± 19; 24.7% of participants scored a full-scale IQ below 80. Participants with a short stature (height Z scores < −1.88), failure to thrive (weight Z scores < −1.65), more severe CKD stage (≥ IIIb), longer duration of CKD (≥ 5 years), and those who were Medicare or Medicaid beneficiaries, had significantly lower mean full-scale IQs.ConclusionOn linear regression analysis, the association between the full-scale IQ, and longer duration of CKD and growth failure, remained significant after controlling for demographic and clinical variables. It is therefore necessary to investigate cognitive impairment in pediatric patients with CKD who exhibit growth failure or for a longer postmorbid period. It is believed that early interventions, such as kidney transplantation, will have a positive effect on IQ in children with CKD, as the disease negatively affects IQ due to poor glomerular filtration rate over time.Trial RegistrationClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT02165878","term_id":"NCT02165878"}}NCT02165878     

Differential perinatal risk factors in children with attention-deficit/hyperactivity disorder by subtype

We compared the attention-deficit/hyperactivity disorder(ADHD) combined subtype (ADHD-C) to the ADHD inattentive subtype (ADHD-I) in terms of genetic, perinatal, and developmental risk factors as well as clinical and neuropsychological characteristics. A total of 147 children diagnosed with ADHD between the ages of 6 and 15 years participated in this study. The parents of the children completed the structured diagnostic interview, the ADHD Rating Scale-IV, the Children’s Behavior Checklist, and structured questionnaires on perinatal risk factors, and the children underwent a neuropsychological test and were genotyped. A total of 502 children without ADHD were recruited from the community as a healthy control group. The ADHD-C children showed more severe externalizing symptoms, showed more deficits in a continuous performance test, and were more likely to have comorbid disorders. Maternal stress during pregnancy, postpartum depression, and changes in the primary caretaker during first 3 years were significantly associated with both ADHD-I and ADHD-C. The ADHD-I group was less likely to have received regular prenatal check-ups and more likely to have had postnatal medical illness than the ADHD-C group. There were no significant differences in the genotype frequencies of the dopamine transporter (DAT1) and the serotonin transporter –linked polymorphic region (5-HTTLPR) polymorphisms between ADHD-I and ADHD-C groups. This study shows that the inattentive subtype of ADHD is different from the combined subtype in many parameters including severity of symptoms, comorbidity, neuropsychological characteristics, and environmental risk factors.     

Two cases of Plasmodium vivax Malaria with the clinical picture resembling toxic shock

Fatal complications of Plasmodium falciparum malaria have been reported. However, complicated P. vivax malaria is rare. We observed two unusual cases of P. vivax malaria who presented with clinical pictures of toxic shock. Both showed disseminated intravascular coagulation with marked thrombocytopenia, oliguric renal failure, and pulmonary edema. Examination of initial blood smears showed a P. vivax parasitemia of 2,352/microL and 12,376/microL, respectively. The patients were treated with hydroxychloroquine and primaquine without an antibacterial agent. These cases emphasize the importance of considering the possibility of P. vivax malarial infection in patients with a clinical picture resembling toxic shock if they have a travel history to malaria-endemic areas.     

An extensive study of human IgE cross-reactivity of Blo t 5 and Der p 5

BACKGROUND: Dual sensitization by Blomia tropicalis and Dermatophagoides pteronyssinus mites is common in tropical and subtropical countries. The human IgE cross-reactivity between clinical important group 5 allergens, Blo t 5 and Der p 5, remains controversial. OBJECTIVE: This study was undertaken to assess the levels of the IgE cross-reactivity between Blo t 5 and Der p 5 by using sera from a large cohort of asthmatic children in subtropical and tropical countries. METHODS: Purified recombinant Blo t 5 and Der p 5 were produced in Pichia pastoris and tested against sera from 195 asthmatic children. The IgE cross-reactivity was examined by direct, inhibitory and competitive human IgE enzyme-linked immunosorbent assay as well as skin prick tests. RESULTS: The Blo t 5 IgE responses were 91.8% (134 of 146) and 73.5% (36 of 49) for Taiwanese and Malaysian sera, respectively. The Blo t 5 specific IgE titers were significantly higher than those of Der p 5 (P <.02). The correlation of IgE reactivity between Blo t 5 and Der p 5 was low, and only limited cross-reactivity was observed. This was further confirmed by the dose-response inhibition studies. Skin prick tests performed on asthmatic children in Thailand also showed differential IgE response to Blo t 5 and Der p 5. CONCLUSION: By using a large panel of asthmatic sera and a combination of in vitro and in vivo assays, the major allergen of B tropicalis in tropical and subtropical regions, Blo t 5, exhibits low levels of IgE cross-reactivity with homologous Der p 5. These findings suggest that highly specific clinical reagents are necessary for precise diagnosis and immunotherapeutic treatment of sensitization to group 5 mite allergens.     

DNA immunization for the production of monoclonal antibodies to Blo t 11, a paramyosin homolog from Blomia tropicalis

BACKGROUND: Blo t 11 is a high molecular weight allergen from Blomia tropicalis with significant immunoglobulin (Ig)E binding frequency. Native and recombinant Blo t 11 are susceptible to degradation and the isolation and expression of the allergen is problematic thus obtaining sufficient amounts of purified Blo t 11 for antibody production is limiting. DNA-based immunization is an attractive alternative strategy that bypasses antigen purification for antibody production. OBJECTIVES: To use a DNA-based immunization protocol for the production and characterization of Blo t 11 monoclonal antibodies (mAbs). METHODS: The 2625 bp cDNA coding for Blo t 11 was cloned into a mammalian expression vector and immunized intramuscularly with electroporation into mice. Monoclonal antibodies to Blo t 11 were generated using a methylcellulose-based hybridoma cloning kit. These mAbs were utilized for native Blo t 11 isolation and the development of sandwich enzyme-linked immunosorbent assay (ELISA). RESULTS: Six mAbs recognizing the native and recombinant Blo t 11 were generated and characterized. Native Blo t 11 was affinity purified from Bt extract and its identity was confirmed by matrix assisted laser desorption/ionization - time of flight mass spectrometry. The native Blo t 11 showed IgE reactivity with 67% of mite allergic sera. A two-site ELISA developed showed a detection limit of 100 pg/ml of Blo t 11. CONCLUSION: A DNA-based immunization protocol was successfully used to generate Blo t 11 mAbs with a spectrum of distinct epitopes located throughout the whole molecule, and they are useful for immunoaffinity purification and immunoassays.     

新型乙酰胆碱酯酶抑制剂5H-噻唑并[3,2-a]嘧啶类化合物的设计、合成与生物活性研究

目的 寻找作为乙酰胆碱酯酶抑制剂的具有新化学结构类型的化合物。方法 采用分子对接的虚拟筛选方法寻找新型乙酰胆碱酯酶抑制剂，设计了10个5H-噻唑并[3,2-a]嘧啶类化合物。以芳醛、硫脲等为起始原料，通过Biginelli反应生成二氢嘧啶类化合物，再与氯代苯乙酮作用经Hantzsch环合反应制得目标化合物，其结构经红外光谱、质谱、核磁共振氢谱和碳谱确证。采用Ellman方法进行体外抑制乙酰胆碱酯酶活性测试。 结果 合成了10个5H-噻唑并[3,2-a]嘧啶类化合物，体外抑制乙酰胆碱酯酶活性测试结果显示，所有目标化合物均具有乙酰胆碱酯酶抑制活性，其中3个目标化合物在10 μmol.L^-1时抑制活性均超过50%。结论5H-噻唑并[3,2-a]嘧啶类化合物是潜在的乙酰胆碱酯酶抑制剂。将计算机辅助药物分子设计、有机合成和生物活性测试相结合是发现和设计新型乙酰胆碱酯酶抑制剂的有效途径。     

Protein kinase CK2alpha as an unfavorable prognostic marker and novel therapeutic target in acute myeloid leukemia.

INTRODUCTION: Protein kinase CK2 is implicated in cellular proliferation and transformation. However, the clinical and biological significances of CK2 have not been elucidated in acute myeloid leukemia (AML). EXPERIMENTAL DESIGN: We evaluated the biological significances of catalytic subunit of CK2 (CK2alpha) expression in leukemia cell lines and primary leukemic blasts obtained from AML patients. RESULTS: In this study, the expression of CK2alpha was elevated in a substantial proportion of AML. In AML patients with normal karyotype, the disease-free survival and overall survival rates were significantly lower in the CK2alpha-high compared with the CK2alpha-low AML cases (P=0.0252 and P=0.0392, respectively). An induced overexpression of CK2alpha increased the levels of Ser473 phosphorylated (p)-Akt/protein kinase B (PKB), p-PDK1, pFKHR, p-BAD, Bcl-2, Bcl-xL, Mcl-1, and XIAP. Treatment of U937 cell line and primary AML blasts with selective CK2 inhibitor, tetrabromobenzotriazole or apigenin, reduced the levels of these molecules in a dose-dependent manner. CK2alpha small interfering RNA treatment also resulted in a down-regulation of p-Akt/PKB and Bcl-2 in U937 cells. Apigenin-induced cell death was preferentially observed in the CK2alpha-high leukemia cell lines, HL-60 and NB4, which was accompanied by cytoplasmic release of SMAC/DIABLO and proteolytic cleavage of procaspase-9, procaspase-3, procaspase-8, and poly(ADP)ribose polymerase. An induced overexpression of CK2alpha potentially enhanced the sensitivity of U937 cells to the apigenin-induced cell death. Apigenin-induced cell death was significantly higher in CK2alpha-high AML compared with CK2alpha-low AML (P<0.0001) or normal bone marrow samples (P<0.0001). CONCLUSION: These findings strongly suggest protein kinase CK2alpha as an unfavorable prognostic marker and novel therapeutic target in AML.