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Mutations Affecting Cellular Levels of Cobalamin (Vitamin B12) Confer Tolerance to Bactericidal Antibiotics in Burkholderia cenocepacia

  • Dongju Lee;Jongwook Park;Heenam Stanley Kim
    • Journal of Microbiology and Biotechnology
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    • v.34 no.8
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    • pp.1609-1616
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    • 2024
  • The Burkholderia cepacia complex (Bcc) consists of opportunistic pathogens known to cause pneumonia in immunocompromised individuals, especially those with cystic fibrosis. Treating Bcc pneumonia is challenging due to the pathogens' high multidrug resistance. Therefore, inhalation therapy with tobramycin powder, which can achieve high antibiotic concentrations in the lungs, is a promising treatment option. In this study, we investigated potential mechanisms that could compromise the effectiveness of tobramycin therapy. By selecting for B. cenocepacia survivors against tobramycin, we identified three spontaneous mutations that disrupt a gene encoding a key enzyme in the biosynthesis of cobalamin (Vitamin B12). This disruption may affect the production of succinyl-CoA by methylmalonyl-CoA mutase, which requires adenosylcobalamin as a cofactor. The depletion of cellular succinyl-CoA may impact the tricarboxylic acid (TCA) cycle, which becomes metabolically overloaded upon exposure to tobramycin. Consequently, the mutants exhibited significantly reduced reactive oxygen species (ROS) production. Both the wild-type and mutants showed tolerance to tobramycin and various other bactericidal antibiotics under microaerobic conditions. This suggests that compromised ROS-mediated killing, due to the impacted TCA cycle, underlies the mutants' tolerance to bactericidal antibiotics. The importance of ROS-mediated killing and the potential emergence of mutants that evade it through the depletion of cobalamin (Vitamin B12) provide valuable insights for developing strategies to enhance antibiotic treatments of Bcc pneumonia.

Measures of Work-life Balance and Interventions of Reasonable Accommodations for the Return to Work of Cancer Survivors: A Scoping Review

  • Giuliana Buresti;Bruna Maria Rondinone;Antonio Valenti;Fabio Boccuni;Grazia Fortuna;Sergio Iavicoli;Maria Cristina Dentici;Benedetta Persechino
    • Safety and Health at Work
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    • v.15 no.3
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    • pp.255-262
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    • 2024
  • Background: Nearly half of patients diagnosed with cancer are in the middle of their traditional working age. The return to work after cancer entails challenges because of the cancer or treatments and associated with the workplace. The study aimed at providing more insight into the occupational outcomes encountered by workers with cancer and to provide interventions, programs, and practices to support their return to work. Methods: A scoping review was conducted using the Arksey and O'Malley framework and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for scoping review guidelines. Relevant studies were systematically searched in PubMed/MEDLINE, SCOPUS and Grey literature from 01 January 2000 to 22 February 2024. Results: The literature search generated 3,017 articles; 53 studies were considered eligible for this review. Most of the studies were longitudinal and conducted in Europe. Three macroarea were identified: studies on the impact of cancer on workers in terms of sick leave, employment, return to work, etc.; studies reporting wider issues that may affect workers, such as the compatibility of treatment and work and employment; studies reporting interventions or policies aiming to promote the return to work. Conclusion: There is a lack in the literature in defining multidisciplinary interventions combining physical, psycho-behavioural, educational, and vocational components that could increase the return-to-work rates. Future studies should focus on interdisciplinary return to work efforts with multiple stakeholders with the involvement of an interdisciplinary teamwork (healthcare workers and employers) to combine these multidisciplinary interventions at the beginning of sick leave period.

The Efficacy of Interferon(IFN)-${\gamma}$ in Idiopathic Pulmonary Fibrosis (특발성 폐섬유화증에서 Interferon-${\gamma}$의 효과)

  • Park, Joo Hun;Oh, Yeon Mok;Shim, Tae Sun;Lim, Chae-Man;Koh, Younsuck;Lee, Sang-Do;Kim, Woo Sung;Kim, Won Dong;Kim, Dong Soon
    • Tuberculosis and Respiratory Diseases
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    • v.56 no.6
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    • pp.611-618
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    • 2004
  • Background : Idiopathic pulmonary fibrosis(IPF), a subtype of IIP(idiopathic interstitial pneumonia), is a fatal disease with a 3-5 year median survival. Many attempts at treating this condition have failed to demonstrate a survival benefit in IPF. Recently Ziesche et $al^{12}$ reported the efficacy of IFN-${\gamma}$ for treating IPF but there is still some controversy. The aim of this study was to determine the efficacy of IFN-${\gamma}$ in patients with advanced IPF who had not been responsive to steroid and cytotoxic agents. Method : Nine patients with advanced IPF(age: $55.4{\pm}15.3$ years, Male: Female=8:1) were enrolled. One year treatment regime with 2 million IU of IFN-${\gamma}$ administered subcutaneously three times a week, and low dose prednisolone(10-30 mg/d) was also used. In the case of a definite aggravation and serious side effects, the IFN-${\gamma}$ was discontinued. During the IFN-${\gamma}$ trial, a pulmonary function test and chest radiography were checked every three month throughout the study. Result : 1) Among 9 patients, only 4 patients were able to complete the 12 month treatment with IFN-${\gamma}$, and 5 patients died during the treatment period. 2) No improvement either in the respiratory symptoms or pulmonary functions were observed any of the patients, even in those who completed the 12 months trial of IFN-${\gamma}$, 3) At the time of IFN-${\gamma}$ trial, the survivors who finished the IFN-${\gamma}$ treatment for 12 months had a higher oxygen level($81.3{\pm}2.8$ vs. $67.4{\pm}8.4$, P=0.024) and a better pulmonary function(FVC: $61.3{\pm}5.1$ % predicted vs. $45.7{\pm}12.3%$, P=0.048, and $D_Lco$: $45.0{\pm}5.0%$ predicted vs. $30.8{\pm}11.2%$, P=0.048) than the non-survivors. Conclusion : Our data suggested that IFN-${\gamma}$ therapy was not effective in the patients with advanced IPF refractory compared with other therapeutic agents. Furthermore, these results suggest that severe impairment of the pulmonary function and hypoxemia during the IFN-${\gamma}$ therapy requires special attention.

The Prognostic Role of B-type Natriuretic Peptide in Acute Exacerbation of Chronic Obstructive Pulmonary Disease (만성폐쇄성폐질환의 급성 악화시 예후 인자로서의 혈중 B-type Natriuretic Peptide의 역할)

  • Lee, Ji Hyun;Oh, So Yeon;Hwang, Iljun;Kim, Okjun;Kim, Hyun Kuk;Kim, Eun Kyung;Lee, Ji-Hyun
    • Tuberculosis and Respiratory Diseases
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    • v.56 no.6
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    • pp.600-610
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    • 2004
  • Background : The plasma B-type natriuretic peptide(BNP) concentration increases with the degree of pulmonary hypertension in patients with chronic respiratory disease. The aim of this study was to examine the prognostic role of BNP in the acute exacerbation of chronic obstructive lung disease (COPD). Method : We selected 67 patients who were admitted our hospital because of an acute exacerbation of COPD. Their BNP levels were checked on admission at the Emergency Department. Their medical records were analyzed retrospectively. The patients were divided into two groups according to their in-hospital mortality. The patients' medical history, comobidity, exacerbation type, blood gas analysis, pulmonary function, APACHE II severity score and plasma BNP level were compared. Results : Multiple logistic regression analysis identified three independent predictors of mortality: $FEV_1$, APACHE II score and plasma BNP level. The decedents group showed a lower $FEV_1$($28{\pm}7$ vs. $37{\pm}15%$, p=0.005), a higher APACHE II score($22.4{\pm}6.1$ vs. $15.8{\pm}4.7$, p=0.000) and a higher BNP level ($201{\pm}116$ vs. $77{\pm}80pg/mL$, p=0.000) than the sSurvivors group. When the BNP cut-off level was set to 88pg/mL using the receiver operating characteristic curve, the sensitivity was 90% and the specificity was 75% in differentiating between the survivors and decedents. On Fisher's exact test, the odds ratio for mortality was 21.2 (95% CI 2.49 to 180.4) in the patients with a BNP level > 88pg/mL. Conclusion : The plasma BNP level might be a predictor of mortality in an acute exacerbation of COPD as well as the $FEV_1$ and APACHE II score.

Changes in the Outcomes of Very Low Birth Weight Infants (신생아 집중치료를 받은 극소저출생체중아 치료성적의 시기에 따른 변화)

  • Kim, Shung Shin;Kim, Moon Hee;Shin, Jae Won;Ko, Sun Young;Lee, Eun Kyung;Chang, Yun Sil;Kang, I Seok;Park, Won Soon;Lee, Mun Hyang;Lee, Sang Il;Lee, Heung Jae
    • Clinical and Experimental Pediatrics
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    • v.45 no.7
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    • pp.828-835
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    • 2002
  • Purpose : The outcomes of infants weighing less than 1,500 gm(very low birth weight infant : VLBWI) reflect recent progress in neonatal intensive care. In this study, we analyzed changes over time in survival rate and morbidity of VLBWIs during the past seven years. Methods : A retrospective review of medical records was analyzed for VLBWIs admitted to the neonatal intensive care unit of Samsung Medical Center within three days from birth. We compared the outcomes of previous corresponding data(period I : Oct. 1994 to Sept. 1996), with the outcomes of period II(Oct. 1996 to Dec. 1998) and period III(Jan. 1999 to Dec. 2000). Results : As shown in Tables 1 and 3, the distribution of birth weight, gestational age(GA), gender, and inborn admissions did not change during the 7-year study. The overall survival rate of VLBWI increased significantly over time(period I : 72% vs period III : 88.3%, P<0.05). Between period I and period II, the birth weight-specific survival rate increased by 23.6%(75% vs 92.7%, P<0.05) for infants 1,000 to 1,249 gm. Between period II and period III, the birth weight-specific survival rate increased three times(20% vs 66.7%, P<0.05) for infants <750 gm. The survivors of lowest birth weight included infants at 624 gm(GA : $26^{+5}$ weeks), 667 gm(GA : $25^{+6}$ weeks) and 480 gm(GA : $26^{+2}$ weeks) in each period. The gestational age-specific survival rate in period III increased significantly in GA 25-26 weeks and 29-30 weeks(vs period I & period II, P<0.05). The survivors of lowest gestational age included infants at GA 26 weeks(970 gm), GA $23^{+5}$ weeks(791 gm) and GA $24^{+1}$ weeks(740 gm) in each period. The incidence of severe IVH(grade III, IV) and the early death rate(< seven days) decreased in period III(vs period I; P<0.05), reflecting improvements in neonatal intensive care. Conclusion : The survival rate of VLBWI continues to increase, particularly for BW < 750 gm, GA < 26 weeks. This increase in survival is not associated by any increase in major morbidities.

Utility of B-type Natriuretic Peptide in Patients with Acute Respiratory Distress Syndrome (급성호흡곤란증후군 환자에 있어서 B-type Natriuretic Peptide의 유용성)

  • Rhee, Chin Kook;Joo, Young Bin;Kim, Seok Chan;Park, Sung Hak;Lee, Sook Young;Koh, Yoon Seok;Kim, Young Kyoon
    • Tuberculosis and Respiratory Diseases
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    • v.62 no.5
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    • pp.389-397
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    • 2007
  • Background B-type natriuretic peptide (BNP) has been shown to be strong mortality predictors in a wide variety of cardiovascular syndromes. Little is known about BNP in patients with acute respiratory distress syndrome (ARDS). We studied whether BNP can predict mortality in patients with ARDS. Method Echocardiographic study was done to all patients with ARDS, and we excluded patient with low ejection fraction (less than 50%) or showing any features of diastolic dysfunction. 47 patients were enrolled between December, 2003 and February, 2006. Parameters including BNP were obtained within 24h hours at the time of enrollment. Result Mean BNP concentrations and APACHE II scores differed between the survivors and nonsurvivors (BNP, $219.5{\pm}57.7pg/mL$ vs $492.3{\pm}88.8pg/mL$; p=0.013, APACHE II score, $17.4{\pm}1.6$ vs $23.1{\pm}1.3$, p=0.009, respectively). With the use of the threshold value for BNP of 585 pg/mL, the specificity for the prediction of mortality was 94%. The threshold value for APACHE II of 15.5 showed sensitivity of 87%. 'APACHE II + $11{\times}logBNP$' showed sensitivity 63%, and specificity 82%, using threshold value for 46.14. Conclusion BNP concentrations and APCHE II scores were more elevated in nonsurvivors than survivors in patients with ARDS who have normal ejection fraction. BNP can predict mortality. Further study should be done.

Significance of Corticosteroids and Their Relationship with Other Parameters in Patients with Sepsis (패혈증에서 혈중 스테로이드의 의의 및 기타 혈중 지표와의 연관성)

  • Lee, Keu Sung;Baik, Seung Hee;Lee, Hyoung No;Park, Joo Hun;Oh, Yoon Jung;Sheen, Seung Soo;Choi, Young Hwa;Park, Kwang Joo;Hwang, Sung Chul
    • Tuberculosis and Respiratory Diseases
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    • v.61 no.4
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    • pp.356-365
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    • 2006
  • Background: Corticosteroids are known to be significant prognostic parameters in sepsis. Recently, an absolute and relative insufficiency of the corticosteroids system has often been reported to often develop particularly in severe sepsis. Degree of such an adrenal insufficiency not only has prognostic implications but also can be used to guide corticosteroids replacement therapy. The 24-hour urinary cortisol levels as well as serum cortisol concentrations were measured to assess the clinical significance and their relationship with the other parameters of sepsis, and also evaluated the clinical implications of the relative adrenal insufficiency. Methods: 26 consecutive patients with sepsis were enrolled. The basal random serum cortisol, ACTH, ADH, lactate levels and 24-hour urinary free cortisol amount were measured. The rapid ACTH ($250{\mu}g$) stimulation test was also performed. Results: Basal serum cortisol levels were higher in the non-survivors than in the survivors. The 24-hour urinary free cortisol levels were higher in the patients with severe sepsis than in those without. The serum cortisol levels strongly correlated with the serum ADH and lactate levels. The 24-hour urinary free cortisol levels strongly correlated with the serum cortisol and lactate levels. The fractional changes in the cortisol levels after the rapid ACTH stimulation tests correlated with the serum cortisol, ADH, and lactate levels. Conclusion: Both the serum cortisol and 24-hour urinary cortisol were found to be significant prognostic factors in sepsis, and showed a strong correlation with the other parameters. The relative adrenal insufficiency might also be an important clinical parameter.

Inhibition of Escherichia coli 0157:H7 by Clove (Eugenia Caryophyllata Thumb) (Clove(Eugenia Caryophyllata Thumb)에 의한 Escherichia coli 0157:H7의 증식과 생존억제)

  • 박찬성
    • Korean journal of food and cookery science
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    • v.14 no.1
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    • pp.9-15
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    • 1998
  • The inhibitory effect of clove (Eugenia caryophyllata Thumb) on the growth of Escherichia coli 0157:H7 was determined. Tryptic soy broth (TSB) containing 0∼0.5% (w/v) of clove was inoculated with 10/sup/5∼10/sup/7 CFU/ml of E. coli and incubated at 5 different temperature (35, 5, -20, 50 and $55^{\circ}C$). The growth of E. coli was not inhibited at 0.1% clove and growth occured at 0.3% after a prolonged lag period while viable cells of E. coli decreased at 0.5% clove during storage at $35^{\circ}C$. During 32 days of refrigerated storage at $5^{\circ}C$, survivors of E. coli were decreased with the progress of time and increasing clove concentration. At the presence of 0.3 or 0.4% clove, bacterial cells were dead at the end of refrigerated storage. During frozen storage at -$20^{\circ}C$, survivors of E. coli at the presence of 0∼0.4% clove were decreased 2.9∼4.07 log cycles for 4 days of early period and then decreased 1.0∼2.1 log cycles through the frozen storage. There were small changes in populations of E. coli in TSB between different concentrations of clove during frozen storage. The D-values for E. coli at $50^{\circ}C$ were 105.26, 22.47, 13.76, 11.14 and 10.17 min at clove 0, 0.1, 0.2, 0.3, 0.4%, respectively. The D-values for E. coli at $55^{\circ}C$ were 10.75, 8.95, 7.40, 5.96 and 4.96 min at clove 0, 0.1, 0.2, 0.3, 0.4%, respectively. Antibacterial activity of clove against E. coli was more effective at $50^{\circ}C$ than at $55^{\circ}C$.

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Outcome of Continuous Renal Replacement Therapy in Children (소아에서 지속적 신대체요법의 치료 결과)

  • LIm, Yeon Jung;Jin, Hyun-seung;Hahn, Hyewon;Oh, Sei Ho;Park, Seong Jong;Park, Young Seo
    • Clinical and Experimental Pediatrics
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    • v.48 no.1
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    • pp.68-74
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    • 2005
  • Purpose : There is growing use of continuous renal replacement therapy(CRRT) for pediatric patients, but reports about the use and outcome of CRRT in children is rare in Korea. We report our experiences of CRRT in critically ill pediatric patients. Methods : We reviewed the medical records of 23 pediatric patients who underwent CRRT at Asan Medical Center between May 2001 and May 2004. We evaluated underlying diseases, clinical features, treatment courses, CRRT modalities and outcomes. Results : Ages ranged from three days to 16 years with a median of five years. Patients weighed 2.4 to 63.9 kg(median 23.0 kg; 10 patients ${\leq}20kg$). The underlying diseases were malignancy(nine cases), multiple organ dysfunction syndrome(five cases), hyperammonemia(four cases), acute renal failure associated with liver failure(three cases), dilated cardiomyopathy(one case) and congenital nephrotic syndrome(one case). Pediatric Risk of Mortality(PRISM) III score was $17.6{\pm}7.6$ and the mean number of failing organs was $3.0{\pm}1.7$. Duration of CRRT was one to 27 days(median : nine days). Eleven patients(47.8%) survived. Chronic renal failure developed in two cases, intracranial hemorrhage in one case, and chylothorax in one case among the survivors. PRISM III score and the number of vasopressor before the start of CRRT was significantly lower in the survivors($12.7{\pm}4.2$ and $0.9{\pm}1.1$) compared with nonsurvivors($22.1{\pm}7.8$ and $2.4{\pm}1.4$)(P<0.05). Conclusion : CRRT driven in venovenous mode is an effective and safe method of renal support for critically-ill infants and children to control fluid balance and metabolic derangement. Survival is affected by PRISM III score and the number of vasopressors at the initiation of CRRT.

Clinical Outcome and Prognostic Factors of Acute Respiratory Distress Syndrome in Children (소아 급성 호흡곤란 증후군의 치료 성적 및 예후 인자)

  • Ko, Jung-Min;Ha, Eun-Ju;Lee, Eun-Hee;Lee, So-Youn;Kim, Hyo-Bin;Hong, Soo-Jong;Park, Seong-Jong
    • Clinical and Experimental Pediatrics
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    • v.48 no.6
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    • pp.599-605
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    • 2005
  • Purpose : The purpose of this study was to examine the causes, clinical courses and outcomes in children with acute respiratory distress syndrome(ARDS), and evaluate the physiologic variables as prognostic factors in the patients. Methods : Retrograde medical chart review was carried out in 24 patients who were diagnosed with ARDS at the pediatric intensive care unit(PICU) during 20-month period. Results : The incidence of ARDS among all PICU admission was 3.7 percent and the mortality rate was 37.5 percent, which was 14.8 percent of overall deaths in PICU. The most common causes of ARDS were pneumonia and sepsis. We found significant differences between survivors and nonsurvivors in $PaO_2/FiO_2$ ratio(P/F ratio), alveolar arterial oxygen gradient and oxygenation index(OI) on the second day from the onset of ARDS. Therapies for ARDS such as high frequency oscillator ventilation(HFOV), recruitment maneuver and low dose corticosteroid improved the P/F ratio and OI, especially in survivors. Conclusion : The mortality rate of children with ARDS was 37.5 percent; an important cause of death in PICU. HFOV, recruitment maneuver and low dose corticosteroid seemed to be effective in pediatric ARDS. The P/F ratio, alveolar arterial oxygen gradient and OI on the second day from the onset of ARDS may be useful as prognostic factors.