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Cytokines and effector molecules are important immunoregulatory molecules in human malaria. Tumor necrosis factor (TNF)-alpha limits malaria parasitemia but also promotes pathogenesis at high concentrations, whereas prostaglandin E2 (PGE2) inhibits TNF-alpha production and is reduced in childhood malaria, at least in part, through suppression of cyclooxygenase (COX)-2 following the ingestion of Plasmodium falciparum hemozoin (pfHz; malarial pigment) by peripheral blood mononuclear cells (PBMCs). Although molecular interactions between TNF-alpha and PGE2 are largely unexplored in human malaria, results presented here show that pfHz-induced suppression of PBMC COX-2 gene products induces overproduction of TNF-alpha. Moreover, addition of exogenous PGE2 to pfHz-treated PBMCs dose-dependently decreased TNF-alpha production, whereas experimental COX inhibitors and antipyretics used during human malaria generated increased TNF-alpha production. Healthy, malaria-exposed children had elevated levels of circulating bicyclo-PGE2/TNF-alpha, compared with children with malarial anemia (P<.01), with systemic bicyclo-PGE2 and TNF-alpha significantly associated with hemoglobin concentrations (r=0.745; P<.01). The results of the present study illustrate that pfHz-induced suppression of PGE2 promotes overproduction of TNF-alpha, which is associated with enhanced malarial anemia. [ABSTRACT FROM AUTHOR]

Background: To examine post-operative pain (PP) after conventional irrigation and sonic activation methods, with and without laser disinfection in mandibular molars., Methods: Eighty patients with symptomatic apical periodontitis were included in this randomized clinical study. There were four study groups. In group 1, conventional irrigation only was applied. In group 2, a sonic irrigation activation system (EDDY (VDW, Munich, Germany)), was applied. In groups 3 and 4, irradiation with a 980-nm diode laser was performed, following irrigation with the conventional method and sonic irrigation activation system, respectively. The patients were instructed to record their PP and analgesic intake using a numerical rating scale 8, 24, 48 h and 7 days post-procedure. A chi-square test, Fisher's exact chi-square test and Fisher-Freeman-Halton exact test were used to assess qualitative data. Inter-group and intra-group parameters were assessed using the Kruskal-Wallis test and Wilcoxon's test at a significance level of p < 0.05., Results: There was no statistically significant difference among the groups in terms of age, sex, pre-operative pain, PP and analgesic intake (p > 0.05)., Conclusions: The use of sonic irrigation activation system in the final irrigation protocol and irradiation with the 980-nm diode laser did not significantly reduce PP levels and analgesic intake., (© 2022. The Author(s).)

Aims To examine the effect of the quality of root canal fillings and prosthetic restorations on the frequency of apical periodontitis (AP).Methodology A total of 200 radiographs of 1,098 teeth with indirect restorations were selected. Each case was documented by age, sex, tooth location, tooth type, restoration type and presence of root canal treatment (RCT). Teeth were categorised as healthy or diseased considering periapical health. The quality of RCT and prosthetic restorations was categorised by radiographic and clinical examinations. Data were analysed using chi-squared test and logistic regression.Results Inadequate prosthetic restorations were found to be less healthy than the adequate ones. Statistical significance was found in teeth with RCT, which had a higher rate of AP (15.8%). Root-filled teeth categorised as inadequately treated (24.1%) were significantly unhealthier than the adequately root-filled teeth. Teeth with inadequate prosthetic restorations and RCT had an increase in AP risk of 6.41 and 20.74 times, respectively (p <0.05).Conclusions Results showed that AP risk was increased by both inadequate RCT and prosthetic restorations. Quality of RCT significantly affected periapical health more than the quality of prosthetic restorations. Not only radiographic but also clinical examination of restorations is required for successful evaluation., (© 2021. The Author(s), under exclusive licence to the British Dental Association.)

The aim of this study was to assess the effectiveness of irrigation activation techniques on postoperative pain (PP) in mandibular premolar teeth with irreversible pulpitis after single-visit endodontic treatment. A total of 160 patients with symptomatic irreversible pulpitis were included in this prospective randomized clinical study. Four different activation methods were used in mandibular premolar teeth. In group 1, teeth were irrigated with side-port endodontic needles (NI) without any agitation; in groups 2 and 3, sonic activation was performed using EDDY and EndoActivator (EA), respectively; and in group 4, passive ultrasonic irrigation (PUI) was used. Patients' analgesic intake-as well as pain intensity during and after treatment-were recorded at 8, 24, 48 h and 7 days. The data relating to age, sex and analgesic intake was evaluated using the Chi-square test and the preoperative pain and PP intensity at different time intervals was evaluated with the Kruskal-Wallis test at a 5% significance level. Highest PP was recorded at 8 h, pain intensity decreased in all groups by the time. Pain in the NI group was found higher than that of EDDY group at 24 h (P < 0.05). EA and PUI had caused mild pain and had similar pain scores at 24 h. (P > 0.05). No statistically difference was found among the groups with regard to analgesic intake (P > 0.05). Although there were slight differences in PP levels between the groups at 24 h, pain levels decreased in all groups after 24 h. Activation of the irrigation solution did not make any difference in terms of PP after 24 h.

Background: In phase 3 trials, inactivated varicella zoster virus (VZV) vaccine (ZV IN ) was well tolerated and efficacious against herpes zoster (HZ) in autologous hematopoietic stem cell transplant (auto-HSCT) recipients and patients with solid tumor malignancies receiving chemotherapy (STMc) but did not reduce HZ incidence in patients with hematologic malignancies (HMs). Here, we describe ZV IN immunogenicity from these studies., Methods: Patients were randomized to ZV IN or placebo (4 doses). Immunogenicity was assessed by glycoprotein enzyme-linked immunosorbent assay (gpELISA) and VZV interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) assay in patients receiving all 4 doses without developing HZ at the time of blood sampling., Results: Estimated geometric mean fold rise ratios (ZV IN /placebo) by gpELISA and IFN-y ELISPOT ~28 days post-dose 4 were 2.02 (95% confidence interval [CI], 1.53-2.67) and 5.41 (95% CI, 3.60-8.12) in auto-HSCT recipients; 1.88 (95% CI, 1.79-1.98) and 2.10 (95% CI, 1.69-2.62) in patients with STMc; and not assessed and 2.35 (95% CI, 1.81-3.05) in patients with HM., Conclusions: ZV IN immunogenicity was directionally consistent with clinical efficacy in auto-HSCT recipients and patients with STMc even though HZ protection and VZV immunity were not statistically correlated. Despite a lack of clinical efficacy in patients with HM, ZV IN immunogenicity was observed in this population. Immunological results did not predict vaccine efficacy in these 3 populations., Clinical Trial Registration: NCT01229267, NCT01254630., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objectives : To assess the safety and reactogenicity of single oral dose of heat-stable rotavirus vaccine (HSRV) in healthy adults aged 18-45 years followed by assessment of safety, reactogenicity, and immunogenicity of three doses of HSRV in healthy infants aged 6-8 weeks at enrollment. Trial Design : Single-center randomized controlled, sequential, blinded (adults) and open-label (infants). Setting : Single site at International Center for Diarrheal Disease Research, Bangladesh (icddr,b). Participants : Fifty eligible adults randomized in 1:1 ratio (HSRV: Placebo) followed by 50 eligible infants randomized in 1:1 ratio (HSRV: Comparator (RotaTeq®, pentavalent human-bovine (WC3) reassortant live-attenuated, rotavirus vaccine)). Intervention : Adults received either a single dose of HSRV or placebo and followed for 14 days. Infants received three doses of either HSRV or comparator with a follow-up for 28 days after each dose. Main Outcome Measures : Solicited and unsolicited adverse events (AEs) along with any serious adverse events (SAEs) were part of the safety and reactogenicity assessment in adults and infants whereas serum anti-rotavirus IgA response rates were part of immunogenicity assessment in infants only. Post-vaccination fecal shedding of vaccine-virus rotavirus strains was also determined in adults and infants. Results : In this study, HSRV, when compared with placebo, did not result in increase in solicited adverse events (solicited AEs) in adults. In infants, HSRV had a safety profile similar to comparator vis-à-vis solicited AEs. In infants, fecal shedding of vaccine-virus strains was not detected in HSRV recipients but was observed in two comparator recipients. Percentage of infants exhibiting threefold rise in serum anti-rotavirus IgA titers from baseline to 1-month post-dose 3 in HSRV group was 88% (22/25) and 84% (21/25) in comparator group. Conclusion : HSRV was found to be generally well-tolerated in both adults and infants and immunogenic in infants.

Background: Patients who are immunocompromised because of malignancy have an increased risk of herpes zoster and herpes zoster-related complications. We aimed to investigate the efficacy and safety of an inactivated varicella zoster virus (VZV) vaccine for herpes zoster prevention in patients with solid tumour or haematological malignancies., Methods: This phase 3, two-arm, randomised, double-blind, placebo-controlled, multicentre trial with an adaptive design was done in 329 centres across 40 countries. The trial included adult patients with solid tumour malignancies receiving chemotherapy and those with haematological malignancies, either receiving or not receiving chemotherapy. Patients were randomly assigned (1:1) to receive four doses of VZV vaccine inactivated by γ irradiation or placebo approximately 30 days apart. The patients, investigators, trial site staff, clinical adjudication committee, and sponsor's clinical and laboratory personnel were masked to the group assignment. The primary efficacy endpoint was herpes zoster incidence in patients with solid tumour malignancies receiving chemotherapy, which was assessed in the modified intention-to-treat population (defined as all randomly assigned patients who received at least one dose of inactivated VZV vaccine or placebo). The primary safety endpoint was serious adverse events up to 28 days after the fourth dose in patients with solid tumour malignancies receiving chemotherapy. Safety endpoints were assessed in all patients who received at least one dose of inactivated VZV vaccine or placebo and had follow-up data. This trial is registered (NCT01254630 and EudraCT 2010-023156-89)., Findings: Between June 27, 2011, and April 11, 2017, 5286 patients were randomly assigned to receive VZV vaccine inactivated by γ irradiation (n=2637) or placebo (n=2649). The haematological malignancy arm was terminated early because of evidence of futility at a planned interim analysis; therefore, all prespecified haematological malignancy endpoints were deemed exploratory. In patients with solid tumour malignancies in the modified intention-to-treat population, confirmed herpes zoster occurred in 22 of 1328 (6·7 per 1000 person-years) VZV vaccine recipients and in 61 of 1350 (18·5 per 1000 person-years) placebo recipients. Estimated vaccine efficacy against herpes zoster in patients with solid tumour malignancies was 63·6% (97·5% CI 36·4 to 79·1), meeting the prespecified success criterion. In patients with solid tumour malignancies, serious adverse events were similar in frequency across treatment groups, occurring in 298 (22·5%) of 1322 patients who received the vaccine and in 283 (21·0%) of 1346 patients who received placebo (risk difference 1·5%, 95% CI -1·7 to 4·6). Vaccine-related serious adverse events were less than 1% in each treatment group. Vaccine-related injection-site reactions were more common in the vaccine group than in the placebo group. In the haematological malignancy group, VZV vaccine was well tolerated and estimated vaccine efficacy against herpes zoster was 16·8% (95% CI -17·8 to 41·3)., Interpretation: The inactivated VZV vaccine was well tolerated and efficacious for herpes zoster prevention in patients with solid tumour malignancies receiving chemotherapy, but was not efficacious for herpes zoster prevention in patients with haematological malignancies., Funding: Merck & Co, Inc., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: A phase III, randomized, double-blind, placebo-controlled clinical study was conducted in China to assess the efficacy, safety, and immunogenicity of the pentavalent rotavirus vaccine (RotaTeq TM , RV5) among Chinese infants. The efficacy and safety data have been previously reported. This report presents the immunogenicity data of the study., Methods: 4,040 infants aged 6-12 weeks were randomly assigned in a 1:1 ratio to receive 3 oral doses of RV5 or placebo. Trivalent oral poliovirus vaccine (tOPV) and diphtheria, tetanus, and acellular pertussis vaccine (DTaP) were administered in a staggered-use (N = 3,240) or concomitant-use (N = 800) schedule. Immunogenicity of RV5 was evaluated in 800 participants (400 participants from each staggered- and concomitant-use immunogenicity subgroup). Geometric mean titers (GMTs) and seroresponse rates (≥3-fold rise from baseline to PD3) were measured for anti-rotavirus IgA in the staggered- and concomitant-use subgroups and measured for serum neutralizing antibodies (SNAs) to human rotavirus serotypes G1, G2, G3, G4, P1A[8] in the staggered-use subgroup. Immune responses to tOPV and DTaP co-administered with RV5 were also evaluated in the concomitant-use immunogenicity subgroup. (ClinicalTrials.gov registry: NCT02062385) RESULTS: The PD3 GMT and seroresponse rate of anti-rotavirus IgA were higher in the RV5 group (82.42 units/mL, 89.4%) compared to the placebo group (0.33 units/mL, 10.1%). Rotavirus type-specific SNA responses were also higher in the RV5 group compared to the placebo group. In the concomitant-use subgroup, the seroprotection rates of anti-poliovirus type 1, 2, 3 in the participants who received RV5 were non-inferior to those who received placebo, and the antibody responses to DTaP antigens were comparable between the two vaccination groups., Conclusions: RV5 was immunogenic in Chinese infants. Immune responses induced by tOPV and DTaP were not affected by the concomitant use of RV5., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Recipients of autologous haemopoietic stem-cell transplants (auto-HSCT) have an increased risk of herpes zoster and herpes zoster-related complications. The aim of this study was to establish the efficacy and safety of an inactivated varicella zoster vaccine for the prevention of herpes zoster after auto-HSCT., Methods: In this randomised, double-blind, placebo-controlled phase 3 trial, participants were recruited from 135 medical centres (ie, stem-cell transplant centres and hospitals) in North America, South America, Europe, and Asia. Patients were eligible if they were aged 18 years or older, scheduled to receive an auto-HSCT within 60 days of enrolment, and had a history of varicella infection or were seropositive for antibodies to varicella zoster virus, or both. Exclusion criteria included a history of herpes zoster within the previous year of enrolment, and intended antiviral prophylaxis for longer than 6 months after transplantation. Participants were randomly assigned according to a central randomisation schedule generated by the trial statistician, to receive either the inactivated-virus vaccine from one of three consistency lots, a high-antigen lot, or placebo, stratified by age (<50 vs ≥50 years) and intended duration of antiviral prophylaxis after transplantation (≤3 months vs >3 to ≤6 months). Participants, investigators, trial staff, and the funder's clinical and laboratory personnel were masked to group assignment. Participants were given four doses of inactivated vaccine or placebo, with the first dose 5-60 days before auto-HSCT, and the second, third, and fourth doses at about 30, 60, and 90 days after transplantation. The primary efficacy endpoint was the incidence of herpes zoster, confirmed by PCR or adjudication by a masked clinical committee, or both, assessed in all participants randomly assigned to the vaccine consistency lot group or placebo group who received at least one dose of vaccine and had auto-HSCT. Safety was assessed in all randomised participants who received at least one dose of vaccine and had follow-up data. A prespecified vaccine efficacy success criterion required the lower bound of the 95% CI be higher than 25% for the relative reduction of the hazard ratio of herpes zoster infection in participants given the vaccine from one of the consistency lots compared with those given placebo. This trial is registered on ClinicalTrials.gov (NCT01229267) and EudraCT (2010-020150-34)., Findings: Between Dec 7, 2010, and April 25, 2013, 560 participants were randomly assigned to the vaccine consistency lot group, 106 to the high-antigen lot group, and 564 to the placebo group. 249 (44%) of patients in the vaccine consistency lot group, 35 (33%) in the high-antigen lot group, and 220 (39%) in the placebo group discontinued before study end, mostly because of death or withdrawal. 51 participants were excluded from the primary efficacy endpoint analyses because they did not undergo auto-HSCT or were not vaccinated, or both (22 [4%] in the vaccine consistency lot group, and 29 [5%] in the placebo group). Mean follow-up for efficacy was 2·4 years (SD 1·3) in the vaccine consistency lot group and 2·3 years (SD 1·3) in the placebo group. 42 (8%) of 538 participants in the vaccine consistency lot group (32·9 per 1000 person-years) and 113 (21%) of 535 in the placebo group (91·9 per 1000 person-years) had a confirmed case of herpes zoster. The estimated vaccine efficacy was 63·8% (95% CI 48·4-74·6), meeting the pre-specified success criterion. For the combined vaccine groups versus the placebo group, the proportion of patients with serious adverse events (216 [33%] of 657 vs 181 [33%] of 554; risk difference 0·2%, 95% CI -5·1 to 5·5) and serious vaccine-related adverse events (five [1%] vs five [1%]; risk difference 0·1%, -1·4 to 1·1) were similar. Vaccine-related injection-site adverse events occurred more frequently in participants given vaccine than those given placebo (191 [29%] vs 36 [7%]; risk difference 22·6%, 95% CI 18·5-26·6; p<0·0001)., Interpretation: This study shows for the first time in a large phase 3 trial that early vaccination of auto-HSCT recipients during the peri-transplant period can be effective for the prevention of an opportunistic infection like herpes zoster and that the vaccine is well tolerated., Funding: Merck & Co., Inc., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: ZOSTAVAX (ZVL; Zoster Virus Live), is a single dose, live, attenuated vaccine licensed for the prevention of herpes zoster (HZ) and post herpetic neuralgia (PHN) in adults ≥50 years of age. Injection site adverse events (AEs) of erythema, swelling and pain were solicited within 5 days post vaccination in the 2 pivotal studies of ZVL; ZEST (ZOSTAVAX Efficacy and Safety Trial) and SPS (Shingles Prevention Study). Protocol specified criteria were used to report the frequency and intensity of injection site AEs in ZEST and SPS studies. Subsequently, the FDA Toxicity Grading Scale provided guidance for uniform assessment of AEs across all adult vaccine clinical trials. The objective of this post-hoc analysis was to categorize the previously reported injection site AEs in two pivotal trials of ZVL according to the current FDA Toxicity Grading Scale., Methods: The current FDA Toxicity Grading Scale provides a measure for classifying injection site AEs by four grades [Grade 1 (mild); Grade 2 (moderate); Grade 3 (severe) and Grade 4 (life threatening)]. Injection site erythema, swelling, and pain intensity gradings were assigned to the respective FDA Toxicity Grade based on this appropriation. A descriptive analysis of the proportion and risk difference (within 95% confidence intervals) of injection site AEs per the FDA Toxicity Grading Scale is provided., Results: The frequency of injection site AEs (erythema, swelling, pain) after subcutaneous vaccination with ZVL were higher in recipients of ZVL compared with placebo. Majority of the injection site AEs observed were Grade 1 (mild) or Grade 2 (moderate) in intensity. Additionally, Grade 3 (severe) injection site AEs were observed infrequently., Conclusions: Application of the FDA Toxicity Grading Scale provides a uniform AE assessment tool across different adult vaccines. This post hoc summary of injection site AEs using FDA Toxicity Grading Scale provides further evidence of low frequency of severe injection site AEs post ZVL vaccination.

Background: A randomized, double-blind, placebo-controlled multicenter trial was conducted in healthy Chinese infants to assess the efficacy and safety of a pentavalent live human-bovine reassortant rotavirus vaccine (RotaTeq™, RV5) against rotavirus gastroenteritis (RVGE)., Methods: 4040 participants aged 6-12weeks were enrolled and randomly assigned to either 3 oral doses of RV5 (n=2020) or placebo (n=2020), administered ∼4weeks apart. The participants also received OPV and DTaP in a concomitant or staggered fashion. The primary objective was to evaluate vaccine efficacy (VE) against naturally-occurring RVGE at least 14days following the third dose. Key secondary objectives included: VE against naturally-occurring severe RVGE and VE against severe and any-severity RVGE caused by rotavirus serotypes contained in the vaccine, occurring at least 14days after the third dose. All adverse events (AEs) were collected for 30days following each dose. Serious AEs (SAEs) and intussusception cases were collected during the entire study. (ClinicalTrials.gov registry: NCT02062385)., Results: VE against RVGE of any-severity caused by any serotype was 69.3% (95% CI: 54.5, 79.7). The secondary efficacy analysis showed an efficacy of: 78.9% (95% CI: 59.1, 90.1) against severe RVGE caused by any serotype; 69.9% (95% CI: 55.2, 80.3) and 78.9% (95% CI: 59.1, 90.1) against any-severity and severe RVGE caused by serotypes contained in the vaccine, respectively. Within 30days following any vaccination, 53.5% (1079/2015) and 53.3% (1077/2019) of participants reported at least one AE, and 5.8% (116/2015) and 5.7% (116/2019) reported SAEs in the vaccine and placebo groups, respectively. No SAEs were considered vaccine-related in recipients of RV5. Two intussusception cases were reported in recipients of RV5 who recovered after receiving treatment. Neither was considered vaccine-related., Conclusions: In Chinese infants, RV5 was efficacious against any-severity and severe RVGE caused by any serotype and generally well-tolerated with respect to AEs., (Copyright © 2017. Published by Elsevier Ltd.)

Although clinical trials of the pentavalent rotavirus vaccine (RotaTeq®, RV5) have demonstrated efficacy against RV gastroenteritis (RGE) in low and high-income settings, a clear correlate of protection or a measure of immune response that could predict efficacy has yet to be identified. This is the first time that immunogenicity data with both serum neutralized antibody (SNA) titers and anti-RV IgA titers from several clinical efficacy trials were pooled to provide a unique context for evaluating the correlation between immunogenicity and RGE risk or efficacy of RV5. The correlation between immunogenicity and RGE risk is evaluated with data at the individual subject level. The analyses show that higher Postdose 3 (PD3) G1 SNA titers are associated with lower odds of contracting any RGE. The correlation between immunogenicity and efficacy is assessed using aggregated population level data, which shows higher efficacy associated with higher PD3 G1 SNA geometric mean titer (GMT) ratio (between RV5 and placebo) and PD3 serum anti-RV IgA GMT ratio. Among high-income countries, efficacy plateaus over the range of PD3 G1 SNA GMT ratios and PD3 serum anti-RV IgA GMT ratios. From both individual- and population-level analyses, PD3 G1 SNA titers correlated most closely with the RGE risk or efficacy for RV5.

Background: Rotavirus is the leading cause of severe diarrhea in infants and young children. The current formulation of pentavalent rotavirus vaccine (RV5) must be stored refrigerated at 2-8°C. A modified formulation of RV5 (RV5mp) has been developed with stability at 37°C for 7 days and an expiry extended to 36 months when stored at 2-8°C., Methods: This study (ClinicalTrials.gov identifier: NCT01600092; EudraCT number: 2012-001611-23) evaluated the safety, tolerability and immunogenicity of RV5mp versus the currently marketed RV5 in infants. To maintain blinding, both vaccine formulations were stored refrigerated at 2-8°C for the duration of the study. Immunogenicity endpoints were (1) serum neutralizing antibody titers to human rotavirus serotypes G1, G2, G3, G4 and P1A[8] and (2) proportion of subjects with a ≥3-fold rise from baseline for serum neutralizing antibody to human rotavirus serotypes G1, G2, G3, G4 and P1A[8] and serum antirotavirus immunoglobulin A., Results: The RV5mp group (n = 505) and RV5 group (n = 509) had comparable safety profiles. There were no deaths and no vaccine-related serious adverse events in this study. With respect to immunogenicity, RV5mp was noninferior compared with RV5. Serum neutralizing antibody responses by country and breast-feeding status were generally consistent with the overall results., Conclusions: RV5mp enhances storage requirements while maintaining the immunogenicity and safety profile of the currently licensed RV5. A vaccine that is stable at room temperature may be more convenient for vaccinators, particularly in places where the cold chain is unreliable, and ultimately will permit more widespread use.

Background: Immunocompromised patients can experience significant morbidity and occasional mortality from complications associated with herpes zoster (HZ), but live attenuated HZ vaccine is contraindicated for these patients. Inactivated zoster vaccine (ZV IN ) is in development for prevention of HZ in immunocompromised patients. However, there are limited data in the literature regarding the effect of anti-CD20 monoclonal antibodies on vaccine-related cell-mediated immune response. This study evaluated safety and immunogenicity of ZV IN in patients with hematologic malignancies (HM) receiving anti-CD20 monoclonal antibodies (alone or in combination chemotherapy regimens) and not likely to undergo hematopoietic cell transplant (HCT) (n=80)., Methods: This was an open-label, single-arm, multicenter Phase I study (NCT01460719) of a 4-dose ZV IN regimen (∼30days between doses) in patients ⩾18years old. Blood samples were collected prior to dose 1 and 28days Postdose 4 to measure varicella zoster virus (VZV)-specific T-cell responses using interferon-γ enzyme-linked immunospot (IFN-γ ELISPOT). The primary hypothesis was that ZV IN would elicit significant VZV-specific immune responses at ∼28days Postdose 4, with a geometric fold rise (GMFR) >1.0. All vaccinated patients were evaluated for adverse events (AE) through 28days Postdose 4., Results: ZV IN elicited a statistically significant VZV-specific immune response measured by IFN-γ ELISPOT at 28days Postdose 4 (GMFR=4.34 [90% CI:3.01, 6.24], p-value<0.001), meeting the pre-specified success criterion. Overall, 85% (68/80) of patients reported ⩾1 AE, 44% (35/80) reported ⩾1 injection-site AE, and 74% (59/80) reported ⩾1 systemic AE. The majority of systemic AEs were non-serious and considered unrelated to vaccination by the investigator. Frequencies of AEs did not increase with subsequent doses of vaccine. No recipient of ZV IN had rash polymerase chain reaction (PCR) positive for VZV vaccine strain., Conclusions: In adults with HM receiving anti-CD20 monoclonal antibodies, ZV IN was well-tolerated and elicited statistically significant VZV-specific T-cell responses ∼28days Postdose 4. CLINICALTRIALS.GOV identifier: NCT01460719., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Biomarkers of inflammation and immune activation were correlated with rotavirus vaccine responses in 68 human immunodeficiency virus type 1 (HIV-1)–infected (and 116 HIV-exposed but uninfected (HEU) African infants receiving pentavalent rotavirus vaccine (RV5) in a clinical trial. Prevaccination, HIV-1+ infants had significantly higher concentrations of interferon γ (IFNγ), interleukin1β, interleukin 2, interleukin 6, interleukin 10 (IL-10), and soluble CD14 compared with HEU infants. Postvaccination concentrations of neutralizing antibodies to RV5 were negatively correlated with prevaccination concentrations of IL-10 (RV5 surface proteins G1 and P1) and IFNγ (G1) in the HIV-1+ infants, whereas antirotavirus immunoglobulin A (IgA) levels were not. Heightened inflammation and immune activation in HIV-1+ infants did not alter IgA responses associated with protection from rotavirus disease., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objective: Although many HIV-infected (HIV+) and HIV-exposed but uninfected (HEU) infants have received live rotavirus vaccines since the WHO recommended universal administration of these vaccines to infants, there has been limited prospective information on their safety and immunogenicity in either group of infants., Design/methods: We performed a randomized, double-blinded, placebo-controlled trial of the safety and immunogenicity of oral pentavalent rotavirus vaccine (RV5) administered to HIV+ and HEU infants in four African countries. Ninety-three percent of HIV+ infants were receiving antiretroviral therapy prior to vaccination. Participants were followed for safety. Immune responses were measured 14 days after three doses of RV5, including serum antirotavirus neutralizing and IgA antibodies, IgA antibody in stool, and antirotavirus memory B and T-cell FluoroSpot. Shedding of RV5 in stool was monitored., Results: A total of 76 HIV+ and 126 HEU infants were enrolled from 2009 to 2013. No significant differences were found in adverse event rates, including grade 3 events, between RV5 and placebo recipients, for either HIV+ or HEU infants. The proportion of antirotavirus IgA responders (at least three-fold increase from baseline) after RV5 administration was 81% in both HIV+ and HEU infants, which was approximately 2.5-fold higher than in placebo recipients (P < 0.001). Neutralizing antibody responses to three of five serotypes were significantly higher after RV5 regardless of HIV status, and those of HIV+ infants were equal or greater than responses of HEU infants to all five serotypes. Only one HIV+ RV5 recipient had RV5 isolated from stool., Conclusion: RV5 was immunogenic in both HIV+ and HEU infants and no safety signals were observed.

Background: Rotavirus is the leading cause of severe diarrhea worldwide in young children. Although rotavirus vaccine efficacy is high in developed countries, efficacy is lower in developing countries. Here, we investigated heterogeneity of rotavirus vaccine efficacy by infant characteristics in developing countries., Methods: An exploratory, post hoc analysis was conducted using randomized controlled trial data of the pentavalent rotavirus vaccine (RV5) conducted in Africa and Asia (NCT00362648). Infants received either 3 doses of vaccine/placebo and were followed for up to 2 years. Within subgroups, vaccine efficacies and 95% confidence intervals (CIs) against rotavirus gastroenteritis (RVGE) were estimated using Poisson regression. We assessed heterogeneity of efficacy by age at first dose, gender, breastfeeding status and nutrition status., Results: African children receiving the first dose at <8 weeks had lower efficacy (23.7%; 95% CI: -8.2%-46.3%) than those vaccinated at ≥8 weeks (59.1%; 95% CI: 34.0%-74.6%). Marginally statistically significant differences were observed by age at first dose, gender and underweight status in Ghana and gender in Asian countries., Conclusions: Heterogeneity of efficacy was observed for age at first dose in African countries. This was an exploratory analysis; additional studies are needed to validate these results.

Objectives: This study was designed to evaluate the immunogenicity and tolerability of a prophylactic 9-valent HPV (types 6/11/16/18/31/33/45/52/58) VLP (9vHPV) vaccine in young men 16-26 years of age in comparison to young women 16-26 years of age (the population that was used to establish 9vHPV vaccine efficacy). Safety and immunogenicity data from this study will be used to bridge 9vHPV vaccine efficacy findings in 16-26 year old women to 16-26 year old men., Methods: This study enrolled 1106 heterosexual men (HM) and 1101 women who had not yet received HPV vaccination. In addition, 313 men having sex with men (MSM) were enrolled and were evaluated separately for immunogenicity because previous results showed that antibody responses to quadrivalent HPV (types 6/11/16/18) VLP (qHPV) vaccine were lower in MSM than in HM. All subjects were administered a 3-dose regimen (Day 1, Month 2, Month 6) of 9vHPV vaccine. Serum samples were collected for anti-HPV assays. Safety information was collected for ∼ 12 months., Results: The geometric mean titers (GMTs) for HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 for HM were non-inferior to those of women at Month 7. For all vaccine HPV types, Month 7 GMTs were numerically lower in MSM than in HM. Over 99.5% of subjects were seropositive at Month 7 for each vaccine HPV type. Administration of 9vHPV vaccine to both 16-26 year old men and women was generally well tolerated., Conclusions: These results support bridging the efficacy findings with 9vHPV vaccine in young women 16-26 years of age to men 16-26 years of age., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Bilateral whole breast (screening) ultrasound has been well established in multiple single- and multi-institution published studies as a valuable adjunct to mammography screening for early detection of breast cancer. However, implementation of screening breast ultrasound programs has been limited and has met with resistance because of the number of potential false positives generated by ultrasound screening, and the lack of available personnel to perform the examination. Automated breast ultrasound, which has recently been approved by the US Food and Drug Administration for use in whole-breast ultrasound screening, is a potential option for providing breast ultrasound screening on a widespread basis., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Older adults who present to an emergency department (ED) generally have more-complex medical conditions with complicated care needs and are at high risk for preventable adverse outcomes during their ED visit. The Care and Respect for Elders with Emergencies (CARE) volunteer initiative is a geriatric-focused volunteer program developed to help prevent avoidable complications such as falls, delirium and use of restraints, and functional decline in vulnerable elders in the ED. The CARE program consists of bedside volunteer interventions ranging from conversation to various short activities designed to engage and reorient high-risk, older, unaccompanied individuals in the ED. This article describes the development and characteristics of the CARE program, the services provided, the experiences of the elderly patients and their volunteers, and the growth of the program over time. CARE volunteers provide elders with the additional attention needed in an often chaotic, unfamiliar environment by enhancing their care, improving satisfaction, and preventing potential decline., (© 2014, Copyright the Authors Journal compilation © 2014, The American Geriatrics Society.)

Screening mammography can detect breast cancer before it becomes clinically apparent. However, the screening process identifies many false-positive findings for each cancer eventually confirmed. Additional tools are available to help differentiate spurious findings from real ones and to help determine when tissue sampling is required, when short-term follow-up will suffice, or whether the finding can be dismissed as benign. These tools include additional diagnostic mammographic views, breast ultrasound, breast MRI, and, when histologic evaluation is required, percutaneous biopsy. The imaging evaluation of a finding detected at screening mammography proceeds most efficiently, cost-effectively, and with minimization of radiation dose when approached in an evidence-based manner. The appropriateness of the above-referenced tools is presented here as they apply to a variety of findings often encountered on screening mammography; an algorithmic approach to workup of these potential scenarios is also included. The recommendations put forth represent a compilation of evidence-based data and expert opinion of the ACR Appropriateness Criteria(®) Expert Panel on Breast Imaging., (Copyright © 2010 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

With the significant increase in the production and use of carbon nanotubes (CNTs), they will be inevitably released into aquatic environments. Therefore, the fate and transport of CNTs in aqueous solutions have attracted extensive attention. In the present work, the effects of natural organic matter (NOM), solution pH and ionic strength on adsorption of three synthetic organic chemicals (SOCs) by both pristine and surface functionalized single-walled carbon nanotubes (SWNTs) and multi-walled carbon nanotubes (MWNTs) were investigated. The three SOCs (phenanthrene, biphenyl, and 2-phenylphenol) with different planarity, polarity, and hydrogen/electron-donor/acceptor ability, representing typical scenarios for the SOC-CNT interactions, were employed as probe molecules. Among the three background solution characteristics examined, NOM showed the most significant effect on SOC adsorption, while solution pH and ionic strength exhibited minimal or negligible impacts. The presence of NOM greatly suppressed the SOC adsorption by CNTs, and the impact on the SWNTs was higher than that on the MWNTs. The planarity and hydrophobicity of SOCs were two important factors determining the effects of NOM, solution pH and ionic strength on their adsorption by CNTs., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Effects of aggregation and surface chemistry of carbon nanotubes (CNTs) on the adsorption of three synthetic organic compounds (SOCs), phenanthrene (PNT), biphenyl (BP), and 2-phenylphenol (2PP), were investigated using commercially available pristine and surface functionalized single-walled carbon nanotubes (SWNTs), and multiwalled carbon nanotubes (MWNTs). Theoretical calculations and nitrogen adsorption analysis results demonstrated that aggregation of CNTs led to a significant reduction in surface area (especially for the SWNTs), but a significant increase of pore volume (especially for the MWNTs) due to interstices trapped in the CNT aggregates. In contrast to the nitrogen gas adsorption, the liquid phase adsorption results indicated that the adsorption of SOCs by CNTs was controlled by available adsorption surface area rather than pore volume, and aggregation of CNTs was an unfavorable factor for the SOC adsorption. Surface functionalization of CNTs improved their dispersion in aqueous solutions, but decreased their adsorption capacities for the hydrophobic SOCs, which was attributed to the formation of water clusters around the oxygen-containing functional groups. Molecular configurations of SOCs also played a role in their adsorption. For the planar PNT, the SWNTs showed significantly higher adsorption capacities and site energies than the MWNTs, whereas for the nonplanar SOCs the adsorption capacity and site energy differences between the SWNTs and the MWNTs became smaller with increasing concentration of SOCs.

Abstract Current treatment guidelines recommend maintenance of HIV-1 viral load below detectable levels (<50 copies per milliliter), even in extensively treated patients with multidrug-resistant HIV-1. Given recent advances in drug development and the availability of new agents with activity against antiretroviral-resistant HIV-1 viral strains, this goal is increasingly attainable for treatment-experienced patients. A stepwise approach to management of patients harboring antiretroviral-resistant HIV is presented, including assessment of adherence, a description of the use of resistance testing and utilization of new antiretroviral agents.

The oxidative removal of natural organic matter (NOM) from waters using hydrogen peroxide and iron-coated pumice particles as heterogeneous catalysts was investigated. Two NOM sources were tested: humic acid solution and a natural source water. Iron coated pumice removed about half of the dissolved organic carbon (DOC) concentration at a dose of 3000 mg l(-1) in 24 h by adsorption only. Original pumice and peroxide dosed together provided UV absorbance reductions as high as 49%, mainly due to the presence of metal oxides including Al(2)O(3), Fe(2)O(3) and TiO(2) in the natural pumice, which are known to catalyze the decomposition of peroxide forming strong oxidants. Coating the original pumice particles with iron oxides significantly enhanced the removal of NOM with peroxide. A strong linear correlation was found between iron contents of coated pumices and UV absorbance reductions. Peroxide consumption also correlated with UV absorbance reduction. Control experiments proved the effective coating and the stability of iron oxide species bound on pumice surfaces. Results overall indicated that in addition to adsorptive removal of NOM by metal oxides on pumice surfaces, surface reactions between iron oxides and peroxide result in the formation of strong oxidants, probably like hydroxyl radicals, which further oxidize both adsorbed NOM and remaining NOM in solution, similar to those in Fenton-like reactions.

A total of 29 surface waters from different regions of Turkey were sampled once a month during 2004. Filtered raw water samples were characterized, chlorinated and the concentrations of disinfection by-products (DBPs) were measured. All waters were low in DOC ranging from 0.91 to 4.42 mg/L. The range of annual average trihalomethanes (THMs) and haloacetic acids (HAAs) concentrations in all waters was 21-189 and 18-149mug/L, respectively. Total mass contributions of halides in THMs and HAAs to absorbable organic halides (AOX) ranged between 10 and 56% in all waters on annual average basis, indicating that significant amounts of other DBPs are being formed in the majority of the tested waters. A strong linear correlation was obtained between the concentrations of THMs and HAAs. Rather poor correlations were found for THMs-AOX and HAAs-AOX levels. For both THMs and HAAs, chlorinated species dominated over brominated ones since the majority of water sources had very low bromide levels. While chloroform and trichloroacetic acid were the major THM and HAA compounds, respectively; the extent of formation and speciation of DBPs varied greatly by season and water source. No consistent general trends were observed in terms of seasonal variations in DBP levels, suggesting that the characteristics of NOM moieties and their chlorine reactivity vary by season in almost all waters tested.

Natural pumice particles were used as granular support media and coated with iron oxides to investigate their adsorptive natural organic matter (NOM) removal from waters. The impacts of natural pumice source, particle size fraction, pumice dose, pumice surface chemistry and specific surface area, and NOM source on the ultimate extent and rate of NOM removal were studied. All adsorption isotherm experiments were conducted employing the variable-dose completely mixed batch reactor bottle-point method. Iron oxide coating overwhelmed the surface electrical properties of the underlying pumice particles. Surface areas as high as 20.6m(2)g(-1) were achieved after iron coating of pumice samples, which are above than those of iron coated sand samples reported in the literature. For all particle size fractions, iron coating of natural pumices significantly increased their NOM uptakes both on an adsorbent mass- and surface area-basis. The smallest size fractions (<63 microm) of coated pumices generally exhibited the highest NOM uptakes. A strong linear correlation between the iron contents of coated pumices and their Freundlich affinity parameters (K(F)) indicated that the enhanced NOM uptake is due to iron oxides bound on pumice surfaces. Iron oxide coated pumice surfaces preferentially removed high UV-absorbing fractions of NOM, with UV absorbance reductions up to 90%. Control experiments indicated that iron oxide species bound on pumice surfaces are stable, and potential iron release to the solution is not a concern at pH values of typical natural waters. Based on high NOM adsorption capacities, iron oxide coated pumice may be a promising novel adsorbent in removing NOM from waters. Furthermore, due to preferential removal of high UV-absorbing NOM fractions, iron oxide coated pumice may also be effective in controlling the formation of disinfection by-products in drinking water treatment.

Malarial anemia (MA) is a multifactorial disease for which the complex etiological basis is only partially defined. The association of clinical, nutritional, demographic, and socioeconomic factors with parasitemia, anemia, and MA was determined for children presenting at a hospital in a holoendemic area of Plasmodium falciparum transmission in western Kenya. Parasitemia was not associated with malaria disease severity. In univariate logistic regression, fever was significantly associated with parasitemia, and wasting was associated with increased presentation of MA. Caretaker's level of education and occupation were significantly correlated with parasitemia, anemia, and MA. Housing structure was also significantly associated with parasitemia and anemia. Bed net use was protective against parasitemia but not anemia or MA. Multivariate logistic regression models demonstrated that fever, mother's occupation, and bed net use were associated with parasitemia. In the current study, none of the factors were associated with anemia or MA in the multivariate models.

The importance of combination antiretroviral therapy in HIV-infection has been well established. However, many available agents suffer shortcomings that limit their clinical value, including adverse effects, difficult dosing requirements and rapid development of resistance. Lopinavir/ritonavir (Kaletra) is a member of the protease inhibitor class, specifically designed to address some of these deficits. The drug is a coformulation of lopinavir with low-dose ritonavir, exploiting a favourable drug-drug interaction between the two that yields sustained increases in plasma levels of lopinavir. In large-scale clinical trials, lopinavir/ritonavir has demonstrated superior therapeutic efficacy when compared with other protease inhibitors. It exerts potent antiviral activity in both treatment-naive and experienced patients with an acceptable incidence of adverse effects. De novo development of resistance has not been described in large clinical trials with patients naive to antiretroviral therapy. Lopinavir/ritonavir has recently been approved for once-daily dosing in antiretroviral-naive patients.

Protease inhibitor-based antiretroviral therapy has been shown to decrease the morbidity and mortality associated with human immunodeficiency virus type 1 (HIV-1) infection. However, many of the available agents in this class suffer shortcomings, including poor tolerability, difficult dosing regimens, and variable drug concentrations which may lead to generation of viral resistance. Lopinavir/ritonavir (Kaletra) has been designed specifically to address some of these shortcomings. Excellent therapeutic efficacy has been documented for lopinavir/ritonavir in multiple clinical trials in both antiretroviral-naive and -experienced patients. Development of resistance is a rare event in persons initiating therapy with lopinavir/ritonavir as their first protease inhibitor. The main side effects associated with lopinavir/ritonavir are gastrointestinal disturbances and elevations of serum lipids. Current antiretroviral therapy guidelines list lopinavir/ritonavir as the consensus first-line protease inhibitor recommended in the initial therapeutic regimen in persons infected with HIV-1.

Although suppression of HIV-1 RNA below the limit of detection is associated with optimal outcomes, many patients can maintain or increase their CD4(+) count for prolonged time periods in the presence of persistent low-level viremia. We followed seven patients with prolonged (>5 years) discordant CD4(+)/viral load (VL) responses on protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) prospectively for 1 year to assess evolution of immune function, viral phenotype, replication capacity (RC), and resistance profile. Immune function was assessed by qualitative and quantitative measurement of cellular activation (CD38(+)HLA-DR(+) and CD38 antibodies bound per cell), and the interferon (IFN)-() ELISpot assay. Presence of syncytium-inducing (SI) or nonsyncytium-inducing (NSI) viral strains was determined by MT-2 cell culture. RC was measured by a modified rapid recombinant virus assay. The resistance profile was characterized by both genotypic and phenotypic analysis. Over the year of follow-up, IFN-() production to gag persisted, responses to other HIV antigens increased, and markers of cellular activation did not change. NSI virus predominated. The genotypic (GSS) and phenotypic (PSS) susceptibility scores remained stable. Evolution of RC was variable over the year of follow-up, but the RC of viruses remained well below that of wild-type clinical isolates. Thus, CD4(+)/VL discordance can be maintained for periods exceeding 5 years in some patients receiving PI-based HAART without significant evolution of HIV resistance.

The challenge for modern hematology laboratories is to provide accurate and reproducible results, with seamless performance between facilities, in a cost-effective manner. Beckman Coulter recently developed the Coulter LH 500 to meet the needs of smaller laboratories or serve as a backup in larger laboratories. The principal goal of this study was to validate all parameters and performance specifications of the LH 500 compared to the Coulter LH 750 predicate analyzer. A total of 245 spent clinical samples from the London Health Sciences Centre (LHSC) and 251 from the University of Pittsburgh Medical Center Health System (UPMCHS) were analyzed during the study. The samples were selected to include 75% abnormal and 25% normal blood samples. According to the results of a rank sum test, there was no significant difference between the LH 500 and LH 750 for all complete blood count parameters (P > .05) except the red cell distribution width, which showed a slight negative bias on the LH 500. Differential parameters comparing the LH 500 to a 400-cell manual differential showed correlation coefficients (r2) from 0.75 to 0.99 for all parameters except basophils. Of the samples run on the LH 500 at LHSC, the false-positive differential flagging rate was 17.32% and the false-negative rate was 3.03%. Sensitivity was 82.93%, specificity 78.95%, and efficiency 79.65%. At UPMCHS, the false-positive differential flagging rate was 13.37% and false-negative rate 2.97%. Sensitivity was 91.89%, specificity 78.91%, and efficiency 83.66%. Overall, the LH 500 performed accurately and reproducibly compared to the LH 750 and the reference procedures. It would be an excellent second instrument for larger laboratories concerned with harmonization of instrumentation and reagents or as a primary instrument for smaller hematology laboratories with limited space.

Objective: Antipyrine metabolism is a "gold standard" measure of mixed cytochrome P450 (CYP) mediated drug metabolism in humans. Cytokines (e.g., interleukin-6) and nitric oxide reduce CYP 450 activity in vitro and in vivo. Because interleukin-6 and nitric oxide production increases in children with sepsis-induced multiple organ failure, we hypothesized impaired CYP 450 mediated drug metabolism in this population., Methods: Fifty-one consecutive children with sepsis and six critically ill children without sepsis were enrolled and given 18 mg/kg antipyrine per NG. Plasma antipyrine elimination rate, elimination half-life, and apparent oral clearance were measured and calculated. Plasma interleukin-6 and nitrite plus nitrate levels were measured and organs failing scored on days 1-3 of sepsis., Results: Children with sepsis had a twofold reduction in antipyrine clearance. Children with persistent failure of three or more organs had a fourfold reduction in antipyrine clearance. Antipyrine clearance was inversely correlated to circulating interleukin-6 and nitrite plus nitrate levels and to number of organ failures., Conclusions: Interpretation CYP 450 mediated drug metabolism is decreased in children with sepsis, related in part to the degree of inflammation and organ failure. For drugs metabolized by CYP 450 enzymes there is an urgent need to reevaluate the use of standard drug dosage schedules in the sepsis population

The Fas-Fas ligand system is important for apoptosis of activated immune cells. Perturbation of this system occurs in diseases with dysregulated inflammation. Increased soluble Fas (sFas) occurs in systemic inflammatory response syndrome (SIRS) and can block apoptosis. Increased shedding of FasL (sFasL) occurs in viral infection and hepatitis. Although dysregulated inflammation is associated with sepsis-induced multiple organ failure (MOF) in children, a role for Fas has not been established. We hypothesize that 1) sFas will be increased in children with severe and persistent sepsis-induced MOF and will correlate with inflammatory markers suggesting a role for sFas in inflammatory dysregulation in severe sepsis, and 2) sFasL will be increased when viral sepsis or sepsis-induced liver failure-associated MOF is present in children. Plasma sFas, sFasL, IL-6, IL-10, nitrite + nitrates, and organ failure scores were measured on d 1 and d 3 in 92 children with severe sepsis and 12 critically ill control children. sFas levels were increased in severe sepsis, continued to increase in persistent MOF and nonsurvivors, and were correlated with serum inflammatory markers (IL-6, IL-10, nitrite + nitrate levels). In contrast, sFasL was not increased in severe sepsis and did not correlate with inflammation. sFasL was, however, increased in liver failure-associated MOF and in nonsurvivors, and was associated with viral infection. At autopsy, hepatocyte destruction and lymphocyte infiltration were associated with increased sFas and sFasL levels. sFas may interfere with activated immune cell death and contribute to dysregulation of inflammation, worsening outcome from severe sepsis. sFasL may contribute to hepatic injury and the development of liver failure-associated MOF.

Infantile myofibromatosis is the most common fibrous disorder of infancy and early childhood. Intracranial involvement is rare, with the majority of lesions being localized to the skull or dura with variable intracranial extension. We present the case of a 19-month-old girl with infantile myofibromatosis and an incidentally discovered, enlarging, calcified, posterior fossa mass. The patient underwent suboccipital craniotomy and resection of the lesion. This is the first report of the surgical removal of an intraparenchymal infantile myofibroma., (Copyright 2002 S. Karger AG, Basel)

Study Objective: Cytokines increase endothelial tissue factor (TF) and tissue plasminogen activator inhibitor type-1 (PAI-1) expression in vitro. Tissue factor interacts with factor VII to facilitate thrombosis and PAI-1 inhibits fibrinolysis by endogenous plasminogen activators. Because cytokine release is increased in children with sepsis-induced multiple organ failure (MOF), we hypothesized a cytokine associated increase in circulating TF and PAI-1 antigen release, and systemic activity in these patients., Study Design: One hundred and seven consecutive children, who met the criteria for sepsis, and 10 critically ill children without sepsis, were enrolled in the study. Plasma TF and PAI-1 antigen and activity levels, Interleukin-6 antigen levels (IL-6), nitrite + nitrate levels (marker of nitric oxide production) and number of organs failing were measured on days 1-3 of sepsis., Results: Increased TF and PAI-1 antigen, and PAI-1 activity levels were associated with increasing IL-6 and nitrite + nitrate levels (p <0.05), the development of MOF (p <0.05), and mortality (p <0.05). Increased systemic PAI-1 activity was associated with cardiovascular, renal. and hepatic failure (p <0.05). Increased systemic TF activity was associated with the development of coagulopathy (p <0.05) and tended to be associated with mortality (p = 0.06, power .77), Conclusions: A shift to an anti-fibrinolytic endothelium phenotype characterizes children who develop sepsis-induced MOF and mortality. Children with coagulopathy have a shift to a pro-coagulant phenotype. These findings support potential therapeutic roles for PAI-1 and TF pathway inhibitors in reversal of this devastating pathophysiologic process.

Purpose: To evaluate the clinical utility of bilateral whole-breast ultrasonography (US) as an adjunct examination to mammography in asymptomatic women with dense (Breast Imaging Reporting and Data System [BI-RADS] density category 3 or 4) breast tissue., Materials and Methods: Between July 1998 and April 2000, 1,862 patients with negative findings at clinical examinations, negative mammographic results, and breast tissue with BI-RADS category 3 or 4 density were evaluated with bilateral whole-breast US for occult cystic and solid masses, areas of architectural distortion, and acoustic shadowing. Suggestive findings were compared with tissue diagnoses from US-guided core biopsy specimens. US was initially performed by a US or a mammography technologist. The average time to perform the examination was approximately 10 minutes. Abnormal findings were corroborated by a fellowship-trained breast-imaging radiologist., Results: In the 1,862 women examined with bilateral whole-breast US, 57 biopsies were recommended in 56 patients; follow-up data were available in 51 of the 56 patients. Six breast cancers were detected (cancer detection rate, 0.3%)., Conclusion: Bilateral whole-breast US, when performed in patients with dense (BI-RADS category 3 or 4 density) breast tissue, is useful in detecting breast cancer not discovered with mammography or clinical breast examination. The 0.3% cancer detection rate compares favorably with that of screening mammography and with that in previously published studies involving bilateral whole-breast US.

Infection is too often associated with prosthetic devices. Increased susceptibility to infection at these surgical sites appears to be associated with defective local phagocytic killing. The mechanisms for neutrophil down-regulation, however, continue to be obscure. We have recently demonstrated that cytotoxic substances are released from granulocytes associated with materials. One group of releasants, the cationic human neutrophil peptide(s) (also called defensins) not only impairs the antimicrobial capacity of the granulocyte that releases it but also impairs bystander phagocytes. Because plasma or matrix proteins soon become associated with implants, we investigated the interactive effect of adding these proteins, singly and in combination, on the microbicidal effect of bystander cells. Some plasma/matrix proteins (whole plasma, albumin, fibrinogen, and fibronectin) strongly interfered with the anti-microbicidal effects generated by neutrophil-polystyrene interaction. Other proteins (vitronectin and laminin) were without effect. These results suggest that protein composition at the prosthetic implant site could have a significant effect on infectivity, depending on whether neutrophils releasants were attenuated. In the absence of attenuation, the local environment would be hostile to host defenses, permitting bacterial survival and proliferation.

Background and Purpose: Genetically engineered mice are used to study the role of single genes in cerebral ischemia, but inherent, strain-dependent differences in neuronal vulnerability may affect experimental end points. To examine this possibility, tissue injury resulting from focal ischemia and its relationship to cerebral hemodynamics were determined in 3 common mutant mouse strains., Methods: Permanent middle cerebral artery ligation was performed in male C57BL/6J, Balb/C, and 129X1/SvJ mice. Mean arterial blood pressure, blood gases, basal and postischemic cortical blood flow ([(14)C]iodoantipyrine autoradiography and laser-Doppler flowmetry), posterior communicating artery patency, and infarct size were determined., Results: Basal cortical blood flow did not differ among strains. Ten minutes after middle cerebral artery ligation, relative red cell flow in the ischemic cortex was 6% to 7% of preischemic flow in every strain. Despite similar hemodynamics, cortical infarcts in Balb/C mice were 3-fold larger than those in 129X1/SvJ and C57BL/6J mice; infarct size in the latter 2 strains was not significantly different. The posterior communicating artery was either poorly developed or absent in >90% of the Balb/C and C57BL/6J but in <50% of the 129X1/SvJ mice., Conclusions: The extent of ischemic injury differed markedly between the 3 strains. The presence and patency of posterior communicating arteries, although variable among strains, did not affect preischemic or postischemic cortical blood flow or bear any relationship to ischemic injury. Therefore, intrinsic factors, other than hemodynamic variability, may contribute to the differences in ischemic vulnerability among strains. These findings underscore the importance of selecting genetically matched wild-type controls.

Background and Purpose: Hydroxyethyl starch (HES) has beneficial effects on ischemic brain injury; however, its mechanism of action remains unclear. The present study was undertaken to test the hypothesis that HES can attenuate increases in leukocyte adherence and vascular permeability in the cerebral vasculature after global cerebral ischemia induced by asphyxia., Methods: Pial venular leukocyte adherence and permeability to sodium fluorescein were quantified in anesthetized newborn piglets by in situ fluorescence videomicroscopy through closed cranial windows during basal conditions and during 2 hours of reperfusion after global ischemia induced by 9 minutes of asphyxia. Experimental animals received HES after the asphyxial insult (10% HES 257/0.47, 600 mg/kg IV bolus 5 minutes after asphyxia, followed by 600 mg/kg per hour IV drip during reperfusion; n=9)., Results: A progressive and significant (P:<0.05) increase in adherent leukocytes was observed during the initial 2 hours of reperfusion after asphyxia compared with nonasphyxial controls. In this model, vascular injury, as determined by significant (P:<0.05) increases in fluorescein permeability at 2 hours of reperfusion, is largely dependent on adherent leukocytes. HES significantly reduced (P:<0.05) leukocyte adherence at 1 hour and 2 hours of reperfusion and reduced fluorescein permeability at 2 hours. HES did not change hematocrit or alter pial arteriolar diameter., Conclusions: These findings indicate that a vascular anti-inflammatory action may underlie the beneficial effects of HES in global cerebral ischemia secondary to asphyxia. Since this compound is well tolerated by patients, future preclinical and clinical studies may reveal improvements in functional outcome with the early introduction of this or similar agents after perinatal asphyxia or global ischemia.

The p21WAF1 protein is involved in the control of cell differentiation and proliferation. We have previously shown that p21WAF1 is upregulated in normal, proliferating hematopoietic cells undergoing differentiation. Exogenous p21WAF1 has been reported to increase colony-formation by normal hematopoietic progenitors. We examined the effects of exogenous p21WAF1 on proliferation, differentiation, gene expression and colony-formation by K562 cells using an inducible p21WAF1 expression construct. Expression of the stathmin (oncoprotein 18) gene decreased within 24 h of p21WAF1 expression; Hox B4 expression increased. Four K562 subclones were derived which differed in their response to equivalent induction of p21WAF1. All four subclones exhibited growth arrest in response to p21WAF1 in liquid culture. Three of four clones developed cytoplasmic granulation and partial morphologic differentiation after p21WAF1 induction. One clone exhibited fewer morphologic features of differentiation following p21WAF1 induction and unlike other clones, colony formation in methlycellulose was not decreased by p21WAF1 expression in this clone. This indicates that additional cell-specific factors influence cellular fate in the presence of elevated p21WAF1.