This paper describes achievements of faculty in federal funding, publication, and other areas following their participation in the Visiting Professorship (VP) Program. Achievements of participants were compared to those of matched peers and showed marked improvement following their VP experiences.
Scientific workforce diversity is critical to ensuring the realization of our national research goals and minority-serving institutions play a vital role in preparing undergraduate students for science careers. This paper summarizes the outcomes of supporting career training and research practices by faculty from teaching-intensive, minority-serving institutions. Support of these faculty members is predicted to lead to: 1) increases in the numbers of refereed publications, 2) increases in federal grant funding, and 3) a positive impact on professional activities and curricular practices at their home institutions that support student training. The results presented show increased productivity is evident as early as 1 yr following completion of the program, with participants being more independently productive than their matched peers in key areas that serve as measures of academic success. These outcomes are consistent with the goals of the Visiting Professorship Program to enhance scientific practices impacting undergraduate student training. Furthermore, the outcomes demonstrate the benefits of training support for research activities at minority-serving institutions that can lead to increased engagement of students from diverse backgrounds. The practices and results presented demonstrate a successful generalizable approach for stimulating junior faculty development and can serve as a basis for long-term faculty career development strategies that support scientific workforce diversity.
Adipose tissue is an attractive and abundant source of multipotent stem cells. Human adipose stem cells (ASCs) have shown to have therapeutic relevancy in diverse clinical applications. Nevertheless, expansion of ASCs is often necessary before performing clinical studies. Standard in vitro cell-culture techniques use animal-derived reagents that should be avoided in clinical use because of safety issues. Therefore, xeno- and serum-free (XF/SF) reagents are highly desirable for enhancing the safety and quality of the transplanted ASCs.
In the current study, animal component-free isolation and cell-expansion protocols were developed for ASCs. StemPro MSC SFM XF medium with either CELLstart™ CTS™ coating or Coating Matrix Kit were tested for their ability to support XF/SF growth. Basic stem-cell characteristics such as immunophenotype (CD3, CD11a, CD14, CD19, CD34, CD45RO, CD54, CD73, CD80, CD86, CD90, CD105, HLA-DR), proliferation, and differentiation potential were assessed in XF/SF conditions and compared with human serum (HS) or traditionally used fetal bovine serum (FBS) cultures.
ASCs cultured in XF/SF conditions had significantly higher proliferation rates compared with HS/FBS cultures. Characteristic immunophenotypes of ASCs were maintained in every condition; however, cells expanded in XF/SF conditions showed significantly lower expression of CD54 (intercellular adhesion molecule 1, ICAM-1) at low passage number. Further, multilineage differentiation potential of ASCs was maintained in every culture condition.
Our findings demonstrated that the novel XF/SF conditions maintained the basic stem cell features of ASCs and the animal-free workflow followed in this study has great potential in clinical cell therapies.
Adipose stem cells; Xeno-free; Serum-free; Human serum; Fetal bovine serum; Multipotentiality; Proliferation rate; Immunophenotype; Flow cytometry; Cell therapy
This paper describes practices designed to improve graduate student training outcomes in the sciences. It describes work to increase student diversity in the graduate ranks and documents the success of trainees. The practices designed to achieve these outcomes are broadly applicable to all graduate training programs and students.
In this paper, we examine the impact of implementing three systemic practices on the diversity and institutional culture in biomedical and public health PhD training at Brown University. We hypothesized that these practices, designed as part of the National Institutes of Health–funded Initiative to Maximize Student Development (IMSD) program in the Division of Biology and Medicine, would have a positive effect on underrepresented minority (URM) recruitment and retention and objective measures of student success. These practices include: 1) develop strategic partnerships with selected undergraduate institutions; 2) provide a personalized education program of student support and skill-based modules to supplement discipline-based course work; and 3) transform institutional culture by engaging faculty in supporting diversity-related goals and practices. Data comparing URM numbers and key academic milestones before and after implementation of IMSD practices support the initial hypothesis and effectiveness of these practices at Brown. Program components are broadly applicable as best practices for others seeking to improve URM recruitment and achievements of graduate students traditionally underrepresented in the sciences.
A comparison of growth data (fish length) with latitude shows that southern juvenile mackerel attain a greater length than those originating from further north before growth ceases during their first winter. A similar significant relationship was found between the growth in the first year (derived from the otolith inner winter ring) and latitude for adult mackerel spawning between 44°N (Bay of Biscay) and 54°N (west of Ireland). These observations are consistent with spatial segregation of the spawning migration; the further north that the fish were hatched, the further north they will tend to spawn. No such relationship was found in mackerel spawning at more northerly latitudes, possibly as a consequence of increased spatial mixing in a more energetic regime with stronger currents. This study provides previously lacking support for spawning segregation behaviour among North East Atlantic mackerel – an important step towards understanding the migratory behaviour of mackerel and hence the spatiotemporal distribution dynamics around spawning time.
To identify factors associated with frequent severe vaso-occlusive pain crises in a contemporary pediatric cohort of sickle cell anemia (SCA)enrolled in a prospective study of pulmonary hypertension and the hypoxic response in sickle cell disease (SCD).
Clinical and laboratory characteristics of children with SCA who had ≥3 severe pain crises requiring health care in the preceding year were compared with subjects with <3 such episodes.
Seventy-five children (20%) reported ≥3 severe pain episodes in the preceding year, and 232 (61%) had none. Frequent pain episodes were associated with older age (OR 1.2; 95% CI 1.1–1.3; P<0.0001), α-thalassemia trait (OR 3.5; 1.6–6.7; P=0.002), higher median hemoglobin (OR 1.7; 95% CI: 1.2–2.4; P<0.003) and lower lactate dehydrogenase (LDH) concentration (OR 1.82; 95% CI: 1.07–3.11; P = 0.027). Children with high pain frequency also had an increased iron burden (serum ferritin 480 vs. 198 μg/L; P=0.006) and higher median tricuspid regurgitation jet velocity (2.41 vs. 2.31 m/s; P=0.001). Neither hydroxy urea use nor fetal hemoglobin levels were significantly different according to severe pain history.
In our cohort of children with SCA increasing age was associated with higher frequency of severe pain episodes as were α-thalassemia, iron overload, higher hemoglobin and lower LDH concentration and higher tricuspid regurgitation velocity.
Sickle cell anemia; vaso-occlusive crisis; pain
Expression of the Rac-guanine nucleotide exchange factor (RacGEF), P-Rex1 is a key determinant of progression to metastasis in a number of human cancers. In accordance with this proposed role in cancer cell invasion and metastasis, we find that ectopic expression of P-Rex1 in an immortalised human fibroblast cell line is sufficient to drive multiple migratory and invasive phenotypes. The invasive phenotype is greatly enhanced by the presence of a gradient of serum or platelet-derived growth factor, and is dependent upon the expression of functional PDGF receptor β. Consistently, the invasiveness of WM852 melanoma cells, which endogenously express P-Rex1 and PDGFRβ, is opposed by siRNA of either of these proteins. Furthermore, the current model of P-Rex1 activation is advanced through demonstration of P-Rex1 and PDGFRβ as components of the same macromolecular complex. These data suggest that P-Rex1 has an influence on physiological migratory processes, such as invasion of cancer cells, both through effects upon classical Rac1-driven motility and a novel association with RTK signalling complexes.
It has been suggested that observed spatial variation in mackerel fisheries, extending over several hundreds of kilometers, is reflective of climate-driven changes in mackerel migration patterns. Previous studies have been unable to clearly demonstrate this link. In this paper we demonstrate correlation between temperature and mackerel migration/distribution as proxied by mackerel catch data from both scientific bottom trawl surveys and commercial fisheries. We show that mackerel aggregate and migrate distances of up to 500 km along the continental shelf edge from mid-November to early March. The path of this migration coincides with the location of the relatively warm shelf edge current and, as a consequence of this affinity, mackerel are guided towards the main spawning area in the south. Using a simulated time series of temperature of the shelf edge current we show that variations in the timing of the migration are significantly correlated to temperature fluctuations within the current. The proposed proxies for mackerel distribution were found to be significantly correlated. However, the correlations were weak and only significant during periods without substantial legislative or technical developments. Substantial caution should therefore be exercised when using such data as proxies for mackerel distribution. Our results include a new temperature record for the shelf edge current obtained by embedding the available hydrographic observations within a statistical model needed to understand the migration through large parts of the life of adult mackerel and for the management of this major international fishery.
The immunomodulatory properties of mesenchymal stem cells (MSCs) make them attractive therapeutic agents for a wide range of diseases. However, the highly demanding cell doses used in MSC clinical trials (up to millions of cells/kg patient) currently require labor intensive methods and incur high reagent costs. Moreover, the use of xenogenic (xeno) serum-containing media represents a risk of contamination and raises safety concerns. Bioreactor systems in combination with novel xeno-free medium formulations represent a viable alternative to reproducibly achieve a safe and reliable MSC doses relevant for cell therapy. The main goal of the present study was to develop a complete xeno-free microcarrier-based culture system for the efficient expansion of human MSC from two different sources, human bone marrow (BM), and adipose tissue. After 14 days of culture in spinner flasks, BM MSC reached a maximum cell density of (2.0±0.2)×105 cells·mL−1 (18±1-fold increase), whereas adipose tissue-derived stem cells expanded to (1.4±0.5)×105 cells·mL−1 (14±7-fold increase). After the expansion, MSC expressed the characteristic markers CD73, CD90, and CD105, whereas negative for CD80 and human leukocyte antigen (HLA)-DR. Expanded cells maintained the ability to differentiate robustly into osteoblast, adipocyte, and chondroblast lineages upon directed differentiation. These results demonstrated the feasibility of expanding human MSC in a scalable microcarrier-based stirred culture system under xeno-free conditions and represent an important step forward for the implementation of a Good Manufacturing Practices–compliant large-scale production system of MSC for cellular therapy.
Malignant peritoneal mesothelioma is a rare malignancy of the serosal membranes that is difficult to diagnose and carries a poor prognosis. Progression of presenting symptoms is slow and nonspecific. Diffuse peritoneal seeding by the neoplasm can present silently so that physical abnormalities may not be detected until the disease is far advanced. Standard laboratory and radiographic studies can also be inconclusive. We report a case of an adolescent female whose clinical presentation and initial response to management were consistent with inflammatory bowel disease (IBD) but who was ultimately diagnosed with malignant peritoneal mesothelioma.
malignant mesothelioma; peritoneum; inflammatory bowel disease; child
More than 60 percent of newborns with severe congenital heart disease develop perioperative brain injuries. Known risk factors include: preoperative hypoxemia, cardiopulmonary bypass characteristics, and postoperative hypotension. Infection is an established risk factor for white matter injury in premature newborns. In this study, we examined term infants with congenital heart disease requiring surgical repair to determine whether infection is associated with white matter injury. Acquired infection was specified by site (bloodstream, pneumonia, or surgical site infection) according to strict definitions. Infection was present in 23/127. Pre and post-operative imaging was evaluated for acquired injury by a pediatric neuroradiologist. Overall, there was no difference in newly acquired postoperative white matter injury in infants with infection (30 percent), compared to those without (31 percent). When stratified by anatomy, infants with transposition of the great arteries and bloodstream infection had an estimated doubling of risk of white matter injury that was not significant, whereas those with single ventricle anatomy had no apparent added risk. When considering only infants without stroke, the estimated association was higher, and became significant after adjusting for duration of inotrope therapy. In this study, nosocomial infection was not associated with white matter injury. Nonetheless, when controlling for risk factors, there was an association between bloodstream infection and white matter injury in selected sub-populations. Infection prevention may have the potential to mitigate long-term neurologic impairment as a consequence of white matter injury, which underscores the importance of attention to infection control for these patients.
Heart defects, congenital; Sepsis; Magnetic resonance imaging; Leukomalacia, periventricular; Pneumonia, ventilator acquired
Metastases are the major cause of death from melanoma, a skin cancer which has the fastest rising incidence of any malignancy in the Western world. Molecular pathways that drive melanoblast migration in development are believed to underpin the movement and ultimately the metastasis of melanoma. Here we show that mice lacking P-Rex1, a Rac-specific Rho GTPase guanine nucleotide exchange factor (GEF), have a melanoblast migration defect during development evidenced by a white belly. Moreover, these P-Rex1−/− mice are resistant to metastasis when crossed to a murine model of melanoma. Mechanistically, this is associated with P-Rex1 driving invasion in a Rac-dependent manner. P-Rex1 is elevated in the great majority of human melanoma cell lines as well as tumor tissue. We conclude that P-Rex1 plays an important role in melanoblast migration and cancer progression to metastasis in mice and humans.
Allogeneic hematopoietic stem cell transplantation is often performed for patients with acute lymphoblastic leukemia (ALL) whose disease has relapsed after chemotherapy treatment. However, graft versus leukemia (GVL) effects in ALL are generally weak and the mechanisms of this weakness are unknown. These studies tested the hypothesis that ALL cells that have survived conventional chemotherapy in vivo acquire relative resistance to the allogeneic GVL effect. C57BL/6 mice were injected with murine pre-B ALL lines driven by human mutations and then were treated with combination chemotherapy. ALL cells surviving therapy were analyzed in vitro and in vivo for acquisition of resistance to chemotherapy, radiation, cytolytic T cells, NK cells, LAK cells and cytokines. In vivo drug treatment did lead to leukemia population with more rapid proliferation and also decreased sensitivity to vincristine, doxorubicin and radiation. However, drug treatment did not produce ALL populations that were less sensitive to GVL effects in vitro or in vivo.
graft versus leukemia effect; allogeneic hematopoietic stem cell transplantation; acute lymphoblastic leukemia; chemotherapy; cancer immunology; graft versus host disease
These experiments explored mechanisms of control of acute lymphoblastic leukemia following allogeneic hematopoietic stem cell transplantation using a murine model of MHC-matched, minor histocompatibility antigen mismatched transplantation. The central hypothesis examined was that addition of active vaccination against leukemia cells would substantially increase the effectiveness of allogeneic donor lymphocyte infusion against ALL present in the host after transplant. While vaccination did increase the magnitude of type I T cell responses against leukemia cells associated with donor lymphocyte infusion, it did not lead to substantial improvement in long term survival. Analysis of immunological mechanisms of leukemia progression demonstrated that the failure of vaccination was not due to antigen loss in leukemia cells. However, analysis of survival provided surprising findings that, in addition to very modest type I T cell responses, a B cell response that produced antibodies that bind leukemia cells was found in long term survivors. The risk of death from leukemia was significantly lower in recipients that had higher levels of such antibodies. These studies raise the hypothesis that stimulation of B cell responses after transplant may provide a novel way to enhance allogeneic graft versus leukemia effects associated with transplantation.
To report the clinical outcomes (early death, late death, and rate of reintervention) and performance of the Contegra conduit as a right ventricle outflow tract implant and to determine the risk factors for early reintervention.
Forty-nine Contegra conduits were implanted between January 2002 and June 2009. Data collection was retrospective. The mean age and follow-up duration of Contegra recipients was 3.5 ± 4.6 years and 4.2 ± 2.0 years, respectively.
There were three deaths (two early, one late), giving a survival rate of 93.9%. The rate of conduit-related reintervention was 19.6% and was most often due to distal conduit stenosis. Age at implantation of <3 months, receipt of a conduit of 12–16 mm diameter, and a diagnosis of truncus arteriosus were each significant contributors to the rate of reintervention.
The Contegra is a cost-effective and readily available solution. However, there is a limited range of larger calibers, which means that the homograft conduit (>22 mm) remains the first choice of implant in older children. The rates of reintervention are significantly higher with a diagnosis of truncus arteriosus, age at implantation of <3 months, and implantation of conduits sized 12–16 mm.
Contegra; outcome; pulmonary; reintervention; risk factor
Pulmonary hypertension (PH) is associated with adverse outcomes in adults with sickle cell disease (SCD) but its importance in children is less clear. We define the incidence and etiologies of PH in pediatric patients with SCD. Children with SCD (n = 310) and matched controls (n = 54) were prospectively enrolled under basal conditions. Participants underwent echocardiography, pulse oximetry, 6-minute walk, and hematologic testing. Echocardiographic measures were compared between SCD and control subjects before and after adjusting for hemoglobin. Correlation of echocardiographic and clinical parameters was performed. Tricuspid regurgitation velocity (TRV) was elevated compared to controls (2.28 vs. 2.10 m/s, p <0.0001). Increased TRV was associated with left ventricular diastolic diameter, hemoglobin, and estimated left atrial pressure. TRV remained elevated when controlled for left ventricular diameter and left atrial pressure. An echocardiography-derived pulmonary resistance was not significantly different between SCD and control patients, although it was elevated in the SCD subgroup with elevated TRV. When controlled for hemoglobin, TRV was no longer statistically different, but pulmonary insufficiency velocity, septal wall thickness and estimated pulmonary resistance were statistically higher. TRV, pulmonary insufficiency end diastolic velocity, and markers of increased cardiac output correlated with indicators of adverse functional status including history of acute chest syndrome, stroke, transfusions, and 6-minute walk. In conclusion, children with SCD have mildly increased TRV that correlated with increased cardiac output and left ventricular filling pressures. Hemoglobin adjusted analysis also suggests contribution of primary vascular changes.
Pulmonary hypertension; Tricuspid regurgitation; Pulmonary vascular resistance; Sickle cell
Laccase, a multicopper oxidase, catalyses the four electron reduction of oxygen to water. Upon adsorption to an electrode surface, laccase is known to reduce oxygen at overpotentials lower than the best noble metal electrocatalysts usually employed. While the electrocatalytic activity of laccase is well established on carbon electrodes, laccase does not typically adsorb to better defined noble metal surfaces in an orientation that allows for efficient electrocatalysis. In this work, we utilized anthracene-2-methanethiol (AMT) to modify the surface of Au electrodes and examined the electrocatalytic activity of adsorbed laccase. AMT facilitated the adsorption of laccase, and the onset of electrocatalytic oxygen reduction was observed as high as 1.13 VRHE. We observed linear Tafel behavior with a 144 mV/dec slope, consistent with an outer sphere single electron transfer from the electrode to a Cu site in the enzyme as the rate determining step of the oxygen reduction mechanism.
biofuel cell; multicopper oxidase; Tafel slope; electrochemistry; voltammetry
The genetic bases of the highly variable degrees of anaemia and haemolysis in persons with Hb SS are not fully known, but several studies have indicated that G6PD deficiency is not a factor. The G6PD202A and G6PD376G alleles and α-thalassaemia were determined by molecular genetic testing in 261 children and adolescents with Hb SS in a multicentre study. G6PD202A,376G (G6PD A-) was defined as hemizygosity for both alleles in males and homozygosity in females. Among the participants 41% were receiving hydroxycarbamide.
The prevalence of G6PD202A,376G was 13.6% in males and 3.3% in females with an overall prevalence of 8.7%. G6PD202A,376G was associated with a 10 g/l decrease in haemoglobin concentration (P=0.008) but not with increased haemolysis as measured by lactate dehydrogenase, bilirubin, aspartate-aminotransferase, reticulocyte count or a haemolytic component derived from these markers (P>0.09). Similar results were found within a sub-group of children who were not receiving hydroxycarbamide. By comparison, single and double α-globin deletions were associated with progressively higher haemoglobin concentrations (P=0.005 for trend), progressively lower values for haemolytic component (P=0.007), and increased severe pain episodes (P<0.001).
In conclusion, G6PD202A,376G may be associated with lower haemoglobin concentration in sickle cell anaemia by a mechanism other than increased haemolysis.
sickle cell anaemia; G6PD; haemolysis; alpha-thalassaemia; haemoglobin concentration
Kingella kingae, a HACEK (Haemophilus parainfluenzae, Aggregatibacter actinomycetemcomitans, Aggregatibacter aphrophilus, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae) organism, is a common resident of the upper airway in children; it has been associated with endocarditis in children with pre-existing heart conditions. This case report describes K. kingae endocarditis leading to valvular damage in a previously healthy 18-month-old child. Our patient developed a K. kingae bacteremia that was later complicated by meningitis, septic embolic stroke, and endocarditis of the mitral valve, leading to perforation of the posterolateral leaflet. The patient was initially treated conservatively with cefotaxime but, subsequently, required a mitral valve repair with a pericardial patch and annuloplasty. This report draws attention to the need for clinicians to be aware of the potentially serious complications of K. kingae infection in young children. If K. kingae infection is suspected then therapy should be initiated promptly with a β-lactam, followed by early echocardiographic assessment. This case also highlights the lack of specific guidelines available for K. kingae endocarditis.
Endocarditis; Kingella kingae; mitral regurgitation; pediatric
Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection in infants. Preterm birth, in addition to several demographic and environmental factors, increases the risk for development of severe RSV infection. The purpose of this study was to describe differences in risk factors and protective factors between preterm birth (up to 35 weeks’ gestational age) and term infants hospitalized for RSV lower respiratory tract infection in the Russian Federation during the 2008–2009 RSV season.
Infants up to two years of age hospitalized for a lower respiratory tract infection in Moscow, St Petersburg, and Tomsk were tested for RSV. Patient data, including risk factors and protective factors for RSV, were captured at admission. Differences in these factors were compared between preterm and term patients.
A total of 519 infants hospitalized for lower respiratory tract infection were included in the study. Of these, 197 infants (182 term and 15 preterm) tested positive for RSV. Of all hospitalizations, 51.7% (15/29) of preterm infants versus 37.1% (182/490) of term infants had confirmed RSV (P = 0.118). Among the RSV-positive patients, preterm infants were more likely to have a lower weight at admission (P = 0.050), be of multiple gestation (P < 0.001), have more siblings (P = 0.013), and have more siblings under the age of eight years (P < 0.007) compared with term patients. The preterm infants were less likely to be breastfed (P < 0.001) and more likely to have older mothers (P = 0.050).
Compared with term infants, RSV was a more prevalent cause of hospitalization for lower respiratory tract infection in preterm infants. Of infants hospitalized for RSV, preterm infants were more likely to have additional risk factors for severe RSV. These findings suggest that preterm infants may be exposed to a combination of more strongly interrelated risk factors for severe RSV than term infants.
respiratory syncytial virus; prematurity; protective risk factors; Russian Federation
Respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infections among infants and young children, and is responsible for an estimated four million deaths per year globally. A monthly injection of palivizumab has been used for prophylaxis of serious RSV infections among high-risk children in 71 countries since 1998 and approval for use in the Russian Federation was obtained in February 2010. A recommendation for RSV prophylaxis in the Russian Federation would require knowledge of the prevalence and seasonality of RSV in that country.
In a prospective, multicenter, epidemiological study of the prevalence, seasonality, and peak occurrence of RSV infection, children aged ≤2 years hospitalized for lower respiratory tract infections in three regions of the Russian Federation, from September 2008 through April 2009, were screened and tested for RSV using rapid immunochromatography of nasopharyngeal lavage. For subjects who were tested positive, hospitalization data were collected.
Of 519 children aged ≤2 years enrolled from September 11, 2008 through April 26, 2009, 197 tested positive for RSV (38.0%, 95% CI: 33.8, 42.3). The onset of the 2008–2009 RSV season in the Russian Federation occurred in late October 2008, similar to what is observed in other northern temperate zones. Peak activity occurred in early April 2009, when 62% of children enrolled tested positive for RSV.
The prevalence of serious RSV infections in the Russian Federation is similar to the prevalence previously identified in other temperate zones of the northern hemisphere. The seasonality of disease shifted towards early spring, with peak activity later in the season, within a range reported in other countries. These data provide further evidence of serious RSV infection in children in the Russian Federation, as well as guidance for timing of seasonal RSV prophylaxis, especially among individuals at high risk for serious RSV infection.
RSV; prophylaxis; prevalence; seasonality; palivizumab
During transcatheter occlusion of a patent ductus arteriosus, one potential complication is that the coil can embolize into one of the branch pulmonary arteries or the aorta. It is often possible to remove this coil percutaneously, but at times, surgical intervention is required. The present report describes a case in which the coil migrated to the left pulmonary artery and repeated attempts to retrieve the coil were unsuccessful. A left thoracotomy was performed, the coil was removed and the patent ductus arteriosus was ligated.
Cardiac catheterization; Congenital heart disease (CHD); Pediatric; Pulmonary embolism; Thoracotomy
Annual influenza vaccination is routinely recommended for pediatric solid organ transplant recipients. However, there are limited data defining the immune response to the inactivated vaccine in this population.
This prospective study compared the humoral and cell-mediated immune responses to the trivalent subvirion influenza vaccine in pediatric liver transplant recipients with those in their healthy siblings. All subjects received inactivated influenza vaccine. Hemagglutination inhibition and interferon-γ (IFN-γ) enzyme-linked immunosorbent spot assays for New Caledonia and Shanghai strains were performed at baseline, after each vaccine dose, and 3 months after the series. Seroconversion was defined as a 4-fold increase in antibody titers; seroprotection was defined as an antibody titer ≥1:40. An increase in the number of T cells secreting IFN-γ was considered to be a positive enzyme-linked immunosorbent spot response.
After 1 dose of vaccine, transplant recipients achieved rates of antibody seroprotection and seroconversion that were similar to those achieved by their healthy siblings. However, for both influenza strains, IFN-γ responses by enzyme-linked immunosorbent spot were significantly attenuated in transplant recipients after 2 doses of vaccine. No cases of influenza or vaccine-related serious adverse events were documented in the study.
The diminished cell-mediated immune response to influenza vaccination that was observed in pediatric liver transplant recipients suggests that the current vaccine strategy may not provide optimal protection. Because of concerns regarding potential emergence of more virulent influenza strains, further studies are warranted to determine if IFN-γ responses are predictive of efficacy and to identify the optimal vaccination strategy to protect populations with a high risk of infection.
Molinate has been widely used as a pre emergent herbicide in the rice fields of California’s Central Valley. In rat studies, the metabolite molinate sulfoxide is suspected of causing testicular toxicity after exposure to molinate. The sulfoxide is generated in the liver and can circulate in the blood, eventually reaching the testis. Man qualitatively produces the same molinate metabolites as the rat. To extrapolate the reproductive risk to man, the present study outlines the development of a preliminary PBPK (Physiologically-based Pharmacokinetic) model, validation in the rat and extrapolation to man.
The preliminary seven-compartment PBPK model for molinate was constructed for the adult, male Sprague-Dawley rat that employed both flow-limited (blood, kidney, liver, rapid-perfused tissues and slowly perfused tissues) and diffusion-limited (fat) rate equations. The systemic circulation connects the various compartments. The simulations predict the molinate blood concentrations of the rat blood and testes compartment favorably with the profiles obtained from 10 and 100 mg/kg po or 1.5 and 15 mg/kg iv doses. Human physiological parameters were substituted into the oral dosed model and the simulations closely predicted the molinate blood concentration obtained from 5.06 mg oral dose. A sensitivity analysis determined for an oral dose that peak blood molinate concentrations were most responsive to the blood flows to kidney and fat compartments while testicular molinate sulfoxide concentrations depended on molinate sulfoxide partition coefficients for the testes compartment and the Km for glutathione conjugation of molinate sulfoxide in the liver compartment.
PBPK; Molinate; Rat; Testicular toxicity
Pulmonary hypertension and left ventricular diastolic dysfunction are complications of sickle cell disease. Pulmonary hypertension is associated with hemolysis and hypoxia, but other unidentified factors are likely involved in pathogenesis as well.
Design and Methods
Plasma concentrations of three angiogenic markers (fibroblast growth factor, platelet derived growth factor–BB [PDGF-BB], vascular endothelial growth factor [VEGF]) and seven inflammatory markers implicated in pulmonary hypertension in other settings were determined by Bio-Plex suspension array in 237 children and adolescents with sickle cell disease at steady state and 43 controls. Tricuspid regurgitation velocity (which reflects systolic pulmonary artery pressure), mitral valve E/Edti ratio (which reflects left ventricular diastolic dysfunction), and a hemolytic component derived from four markers of hemolysis and hemoglobin oxygen saturation were also determined.
Plasma concentrations of interleukin-8, interleukin-10 and VEGF were elevated in the patients with sickle cell disease compared to controls (P≤0.003). By logistic regression, greater values for PDGF-BB (P = 0.009), interleukin-6 (P = 0.019) and the hemolytic component (P = 0.026) were independently associated with increased odds of elevated tricuspid regurgitation velocity while higher VEGF concentrations were associated with decreased odds (P = 0.005) among the patients with sickle cell disease. These findings, which are consistent with reports that PDGF-BB stimulates and VEGF inhibits vascular smooth muscle cell proliferation, did not apply to E/Etdi.
Circulating concentrations of angiogenic and pro-Inflammatory markers are altered in sickle cell disease children and adolescents with elevated tricuspid regurgitation velocity, a subgroup that may be at risk for developing worsening pulmonary hypertension. Further studies to understand the molecular changes in these children are indicated.