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1.
Acad Med ; 98(11): 1319-1325, 2023 11 01.
Article in English | MEDLINE | ID: mdl-37343175

ABSTRACT

PURPOSE: The increasing professionalization of medical education during the past 2 decades has ushered in an era in which formal degrees, particularly master's of health professions education (MHPE), have become important for career advancement in medical education. Although tuition costs can pose a substantial barrier for many seeking advanced degrees in health professions education, data on tuition associated with these programs are lacking. This study examines the accessibility of pertinent cost-related information available to prospective students and the variability of costs among programs worldwide. METHOD: The authors conducted an Internet-based, cross-sectional study, augmented with emails and direct contact with educators, to extract tuition-related data for MHPE programs between March 29, 2022, and September 20, 2022. Costs were converted to an annual total within each jurisdiction's currency and converted to U.S. dollars on August 18, 2022. RESULTS: Of the 121 programs included in the final cost analysis, only 56 had publicly available cost information. Excluding programs free to local students, the mean (SD) total tuition cost was $19,169 ($16,649), and the median (interquartile range) cost was $13,784 ($9,401- $22,650) (n = 109). North America had the highest mean (SD) tuition for local students ($26,751 [$22,538]), followed by Australia and New Zealand ($19,778 [$10,514]) and Europe ($14,872 [$7,731]), whereas Africa had the lowest ($2,598 [$1,650]). The region with the highest mean (SD) tuition for international students was North America ($38,217 [$19,500]), followed by Australia and New Zealand ($36,891 [$10,397]) and Europe ($22,677 [$10,010]), whereas Africa had the lowest ($3,237 [$1,189]). CONCLUSIONS: There is substantial variability in the geographic distribution of MHPE programs and marked differences in tuition. Incomplete program websites and limited responsiveness from many programs contributed to a lack of transparency regarding potential financial implications. Greater efforts are necessary to ensure equitable access to health professions education.


Subject(s)
Education, Medical , Humans , Cross-Sectional Studies , 3-Methoxy-4-hydroxyphenylethanol , Students , Health Occupations/education
2.
Vaccine ; 40(10): 1385-1389, 2022 03 01.
Article in English | MEDLINE | ID: mdl-35144848

ABSTRACT

Adjuvant activity of the Toll receptor 9 agonist CpG 1826 was compared when given subcutaneously (s.c.) together with ovalbumin (s.c.[CpG + Ova]), or when given by either s.c. or intradermally (i.d.) routes two days prior to s.c. ovalbumin. Frequencies of CD8 + effector (TEFF) and central memory (TCM) T cells along with total IgG, IgG2c, and IgG1 titres were measured to ascertain how timing and location of CpG conditioning influenced vaccination outcome. Prior treatment with CpG enhanced TEFF, TCM, as well as total IgG responses. TEFF and TCM responses were greatest when CpG was given intradermally and prior to s.c. ovalbumin, conditions that eliminated the fraction of TCM 'non-responders' observed after s.c.[CpG + Ova] vaccination. IgG responses were polarized toward IgG2c after early s.c. CpG but toward IgG1 after early i.d. CpG. Separating CpG adjuvant and antigen application in time and space can improve vaccination outcome.


Subject(s)
Adjuvants, Immunologic , Vaccines , Animals , Antigens , Immunoglobulin G , Mice , Mice, Inbred C57BL , Oligodeoxyribonucleotides , Ovalbumin , Vaccination
3.
Mol Cancer Res ; 19(12): 2096-2109, 2021 12.
Article in English | MEDLINE | ID: mdl-34556524

ABSTRACT

A rate-limiting step for circulating tumor cells to colonize distant organ sites is their ability to locate a microenvironmental niche that supports their survival and growth. This can be achieved by features intrinsic to the tumor cells and/or by the conditioning of a "premetastatic" niche. To determine if pulmonary inflammation promotes the latter, we initiated models for inflammatory asthma, hypersensitivity pneumonitis, or bleomycin-induced sterile inflammation before introducing tumor cells with low metastatic potential into the circulation. All types of inflammation increased the end-stage metastatic burden of the lungs 14 days after tumor cell inoculation without overtly affecting tumor extravasation. Instead, the number and size of early micrometastatic lesions found within the interstitial tissues 96 hours after tumor cell inoculation were increased in the inflamed lungs, coincident with increased tumor cell survival and the presence of nearby inflammation-induced monocyte-derived macrophages (MoDM; CD11b+CD11c+). Remarkably, the adoptive transfer of these MoDM was sufficient to increase lung metastasis in the absence of inflammation. These inflammation-induced MoDM secrete a number of growth factors and cytokines, one of which is hepatocyte growth factor (HGF), that augmented tumor cell survival under conditions of stress in vitro. Importantly, blocking HGF signaling with the cMET inhibitor capmatinib abolished inflammation-induced early micrometastatic lesion formation in vivo. These findings indicate that inflammation-induced MoDM and HGF in particular increase the efficiency of early metastatic colonization in the lung by locally preconditioning the microenvironment. IMPLICATIONS: Inflammation preconditions the distant site microenvironment to increase the metastatic potential of tumor cells that arrive there.


Subject(s)
Hepatocyte Growth Factor/metabolism , Lung/pathology , Macrophages/metabolism , Animals , Humans , Mice , Neoplasm Metastasis , Tumor Microenvironment
4.
Front Immunol ; 11: 516, 2020.
Article in English | MEDLINE | ID: mdl-32373108

ABSTRACT

Background:Staphylococcus epidermidis is the most common nosocomial infection and the predominant pathogen in late-onset sepsis in preterm infants. Infection and inflammation are linked to neurological and developmental sequelae and bacterial infections increase the vulnerability of the brain to hypoxia-ischemia (HI). We thus tested the hypothesis that S. epidermidis exacerbates HI neuropathology in neonatal mice. Methods: Male and female C57Bl/6 mice were injected intraperitoneally with sterile saline or 3.5 × 107 colony-forming units of S. epidermidis on postnatal day (PND) 4 and then subjected to HI on PND5 (24 h after injection) or PND9 (5 d after injection) by left carotid artery ligation and exposure to 10% O2. White and gray matter injury was assessed on PND14-16. In an additional group of animals, the plasma, brain, and liver were collected on PND5 or PND9 after infection to evaluate cytokine and chemokine profiles, C5a levels and C5 signaling. Results: HI induced 24 h after injection of S. epidermidis resulted in greater gray and white matter injury compared to saline injected controls in males, but not in females. Specifically, males demonstrated increased gray matter injury in the cortex and striatum, and white matter loss in the subcortical region, hippocampal fimbria and striatum. In contrast, there was no potentiation of brain injury when HI occurred 5 d after infection in either sex. In the plasma, S. epidermidis-injected mice demonstrated increased levels of pro- and anti-inflammatory cytokines and chemokines and a reduction of C5a at 24 h, but not 5 d after infection. Brain CCL2 levels were increased in both sexes 24 h after infection, but increased only in males at 5 d post infection. Conclusion: Ongoing S. epidermidis infection combined with neonatal HI increases the vulnerability of the developing brain in male but not in female mice. These sex-dependent effects were to a large extent independent of expression of systemic cytokines or brain CCL2 expression. Overall, we provide new insights into how systemic S. epidermidis infection affects the developing brain and show that the time interval between infection and HI is a critical sensitizing factor in males.


Subject(s)
Brain Injuries/immunology , Brain/pathology , Chemokine CCL2/metabolism , Hypoxia-Ischemia, Brain/immunology , Sex Factors , Staphylococcal Infections/immunology , Staphylococcus epidermidis/physiology , Animals , Animals, Newborn , Brain Injuries/microbiology , Cells, Cultured , Chemokine CCL2/genetics , Cross Infection , Female , Hypoxia-Ischemia, Brain/microbiology , Immunization , Male , Mice , Mice, Inbred C57BL , Pregnancy , Prenatal Exposure Delayed Effects , Signal Transduction , Up-Regulation
6.
ASAIO J ; 66(2): 132-138, 2020 02.
Article in English | MEDLINE | ID: mdl-30913099

ABSTRACT

At fixed speed, the spontaneous increase in pump flow accompanying exercise in patients with continuous flow left ventricular assist devices (cfLVADs) is slight in comparison to normal physiologic response, limiting exercise capacity. We systematically exercised 14 patients implanted with an isolated HeartWare HVAD undergoing routine right heart catheterization at baseline and at maximal safe pump speed. In addition to hemodynamics, mixed venous oxygen saturation (SvO2), echocardiography and noninvasive mean arterial pressure, and heart rate were measured. Significantly greater pump flows were achieved with maximum pump speed compared with baseline speed at rest (mean ± standard deviation [SD]: 5.0 ± 0.7 vs. 4.6 ± 0.8 L/min) and peak exercise (6.7 ± 1.0 vs. 5.9 ± 0.9 L/min, p = 0.001). Pulmonary capillary wedge pressure was significantly reduced with maximum pump speed compared to baseline pump speed at rest (10 ± 4 vs. 15 ± 5 mmHg, p < 0.001) and peak exercise (27 ± 8 vs. 30 ± 8 mmHg, p = 0.002). Mixed venous oxygen saturation decreased with exercise (p < 0.001) but was unaffected by changes in pump speed. In summary, although higher pump speeds synergistically augment the increase in pump flow associated with exercise and blunt the exercise-induced rise in left heart filling pressures, elevated filling pressures and markedly diminished SvO2 persist at maximal safe pump speed, suggesting that physiologic flow increases are not met by isolated cfLVADs in the supported failing heart.


Subject(s)
Exercise/physiology , Heart Failure/physiopathology , Heart-Assist Devices , Hemodynamics/physiology , Female , Humans , Male
7.
Int J Surg Pathol ; 28(4): 367-370, 2020 Jun.
Article in English | MEDLINE | ID: mdl-31847634

ABSTRACT

Counting intraepithelial lymphocytes (IELs) is a key part of the assessment of duodenal biopsies. Immunohistochemistry (IHC) for CD3 can aid identification of lymphocytes in this context, but it is not evident that counts on hematoxylin and eosin (H&E) and CD3 are comparable. This study aimed to compare the IEL counts in duodenal biopsies using H&E stains and CD3 IHC, and to examine the interobserver variability. Thirty-five paired H&E and CD3 sections were reviewed by 6 pathologists who counted the number of IELs per 100 enterocytes. The counts were categorized into groups: normal (<25 lymphocytes), mildly raised (25-40 lymphocytes), and markedly raised (>40 lymphocytes). CD3 IHC was associated with significantly higher IEL counts than H&E. Four cases with normal H&E counts had raised counts with CD3. There was moderate agreement between observers for both H&E and CD3. Lack of concordance between CD3 and H&E IEL counts suggests that counts derived from the 2 methods may not be comparable to each other and should not be considered equivalent. There was no significant improvement in interobserver variability with CD3 IHC.


Subject(s)
CD3 Complex/analysis , Intraepithelial Lymphocytes/metabolism , Lymphocyte Count/methods , Adolescent , Adult , Aged , Aged, 80 and over , Biopsy , CD3 Complex/metabolism , Celiac Disease/diagnosis , Celiac Disease/pathology , Child , Child, Preschool , Coloring Agents/chemistry , Duodenum/cytology , Duodenum/pathology , Eosine Yellowish-(YS)/chemistry , Female , Hematoxylin/chemistry , Humans , Immunohistochemistry/methods , Intestinal Mucosa/cytology , Intestinal Mucosa/pathology , Intraepithelial Lymphocytes/immunology , Male , Middle Aged , Observer Variation , Staining and Labeling/methods , Young Adult
8.
Article in English | MEDLINE | ID: mdl-31818825

ABSTRACT

Infection is correlated with increased risk of neurodevelopmental sequelae in preterm infants. In modeling neonatal brain injury, Toll-like receptor agonists have often been used to mimic infections and induce inflammation. Using the most common cause of bacteremia in preterm infants, Staphylococcus epidermidis, we present a more clinically relevant neonatal mouse model that addresses the combined effects of bacterial infection together with subsequent hypoxic-ischemic brain insult. Currently, there is no neuroprotective treatment for the preterm population. Hence, we tested the neuroprotective effects of vancomycin with and without adjunct therapy using the anti-inflammatory agent pentoxifylline. We characterized the effects of S. epidermidis infection on the inflammatory response in the periphery and the brain, as well as the physiological changes in the central nervous system that might affect neurodevelopmental outcomes. Intraperitoneal injection of postnatal day 4 mice with a live clinical isolate of S. epidermidis led to bacteremia and induction of proinflammatory cytokines in the blood, as well as transient elevations of neutrophil and monocyte chemotactic cytokines and caspase 3 activity in the brain. When hypoxia-ischemia was induced postinfection, more severe brain damage was observed in infected animals than in saline-injected controls. This infection-induced inflammation and potentiated brain injury was inoculum dose dependent and was alleviated by the antibiotic vancomycin. Pentoxifylline did not provide any additional neuroprotective effect. Thus, we show for the first time that live S. epidermidis potentiates hypoxic-ischemic preterm brain injury and that peripheral inhibition of inflammation with antibiotics, such as vancomycin, reduces the extent of brain injury.


Subject(s)
Hypoxia-Ischemia, Brain/microbiology , Hypoxia-Ischemia, Brain/prevention & control , Staphylococcus epidermidis/drug effects , Staphylococcus epidermidis/pathogenicity , Vancomycin/therapeutic use , Animals , Animals, Newborn , Blood Glucose/drug effects , Brain Injuries , Female , Infant, Premature , Male , Mice , Mice, Inbred C57BL , Sepsis/microbiology , Sepsis/prevention & control
9.
J Immunol ; 203(9): 2443-2450, 2019 11 01.
Article in English | MEDLINE | ID: mdl-31578270

ABSTRACT

Skin tissue resident memory T cells (TRM) provide superior protection to a second infection. In this study, we evaluated the use of topical CpG oligodeoxynucleotide (ODN) as adjuvant to generate skin TRM in mice. Topical or s.c. CpG ODN adjuvant administration at the time of a s.c. Ag injection led to an accumulation of CD103- CD8 T cells in the epidermis. However, only mice with CpG ODN administered topically had significant numbers of CD103+ Ag-specific CD8 T cells persisting in the local epidermal skin, enhanced circulating memory cells in the blood, and showed protection from intradermal challenge with melanoma cells. Generation of Ag-specific CD8 T cells was dependent on TLR9 expression on hematopoietic cells and partially dependent on receptor expression on stromal cells. Topical challenge of immunized mice at a distal site led to significant expansion of Ag-specific T cells in the blood and accumulation in the challenged skin. We demonstrate that local and systemic T cell memory can be generated with topical CpG ODN at the time of s.c. immunization, suggesting a new method of enhancing current vaccine formulations to generate tissue TRM.


Subject(s)
Adjuvants, Immunologic/administration & dosage , Immunologic Memory , Oligodeoxyribonucleotides/administration & dosage , Skin/immunology , T-Lymphocytes/physiology , Vaccination , Animals , Cell Line, Tumor , Immunity, Innate , Injections, Subcutaneous , Mice , Mice, Inbred C57BL , Ovalbumin/immunology , Toll-Like Receptor 9/physiology
12.
Pharm Pract (Granada) ; 17(1): 1397, 2019.
Article in English | MEDLINE | ID: mdl-31015879

ABSTRACT

BACKGROUND: Pain remains one of the most common and debilitating symptoms of advanced cancer. To date, there is a lack of studies on pain and its treatment among Malaysian palliative care patients. OBJECTIVE: This study aimed to explore the prevalence of pain and its treatment outcomes among adult cancer patients admitted to a palliative care unit in Sabah, Malaysia. METHODS: Of 327 patients screened (01/09/15-31/12/17), 151 patients with assessed self-reported pain scores based on the numerical rating scale of 0-10 (current, worst and least pain within the past 24 hours) upon admission (baseline), 24, 48 and 72 hours post-admission and discharge were included. Pain severity and pain score reductions were analysed among those who experienced pain upon admission or in the past 24 hours. Treatment adequacy was measured by the Pain Management Index (PMI) among discharged patients. The PMI was constructed upon worst scores categorised as 0 (no pain), 1 (1-4, mild pain), 2 (5-6, moderate pain), or 3 (7-10, severe pain) which is then subtracted from the most potent level of prescribed analgesic drug scored as 0 (no analgesia), 1 (non-opioid), 2 (weak opioid) or 3 (strong opioid). PMI≥0 indicated adequate treatment. RESULTS: Upon admission, 61.1% [95%CI 0.54:0.69] of 151 patients presented with pain. Of 123 patients who experienced pain upon admission or in the past 24 hours, 82.1% had moderate to severe worst pain. Throughout patients' ward stay until discharge, there was an increased prescribing of analgesics and adjuvants compared to baseline, excluding weak opioids, with strong opioids as the mainstay treatment. For all pain score types (current, worst and least pain within the past 24 hours), means decreased at each time point (24, 48 and 72 hours post-admission and discharge) from baseline, with a significant decrease at 24 hours post-admission (p<0.001). Upon discharge (n=100), treatment adequacy significantly improved (PMI≥0 100% versus 68% upon admission, p<0.001). CONCLUSIONS: Accounting for pain's dynamic nature, there was a high prevalence of pain among cancer patients in the palliative care unit. Continuous efforts incorporating comprehensive pain assessments, evidence-based treatments and patient education are necessary to provide adequate pain relief and end-of-life comfort care.

13.
J Glob Infect Dis ; 11(1): 2-6, 2019.
Article in English | MEDLINE | ID: mdl-30814828

ABSTRACT

INTRODUCTION: Conventionally, a combination of four separate drugs (ethambutol, isoniazid, rifampicin, and pyrazinamide [EHRZ]) is the first-line pharmacotherapy for pulmonary tuberculosis (TB). In recent years, fixed-dose combination (FDC) formulation, where a single tablet contains the active ingredients of four aforementioned drugs, is gaining popularity due to its ease of administration. OBJECTIVE: To compare the real-world effectiveness of EHRZ and FDC treatment groups on a cohort registry by investigating the sputum conversion rate and treatment outcomes of both groups. METHODS: A total of 11,489 patients' data were extracted from the Sabah TB registry between January 2012 and June 2016, including EHRZ (n = 4188) and FDC (n = 7301) patients. Then, 1:1 propensity score matching was adopted to reduce the baseline bias. Caliper matching was conducted with maximum tolerance score set at 0.001. Confounders included in the propensity score matching were gender, nationality, diabetes, HIV status, smoking status, and chest X-ray status. Successful matching provided 4188 matched pairs (n = 8376) for final analysis. RESULTS: In this matched cohort of 4188 pairs, the 2-month sputum conversion rate of FDC group was significantly higher than the EHRZ group (96.3% vs. 94.3%; P < 0.001) whereas 6-month sputum conversion of both groups showed no significant difference. Treatment outcomes such as noncompliance rate, failure rate, and success rate have no significant difference (P > 0.05) in both the treatment groups. There was an incidental finding of reduced death rate among FDC group compared to the EHRZ group (0.2% vs. 0.5%; P = 0.034). CONCLUSION: The FDC formulation has better sputum conversion rate at 2 months compared to conventional EHRZ regime as separate-drug formulation. It was also observed that FDC has a slight protective effect against all-cause death among TB patients. This protective effect of FDC, however, still needs to be proven further.

14.
Pharm. pract. (Granada, Internet) ; 17(1): 0-0, ene.-mar. 2019. tab, graf
Article in English | IBECS | ID: ibc-184615

ABSTRACT

Background: Pain remains one of the most common and debilitating symptoms of advanced cancer. To date, there is a lack of studies on pain and its treatment among Malaysian palliative care patients. Objective: This study aimed to explore the prevalence of pain and its treatment outcomes among adult cancer patients admitted to a palliative care unit in Sabah, Malaysia. Methods: Of 327 patients screened (01/09/15-31/12/17), 151 patients with assessed self-reported pain scores based on the numerical rating scale of 0-10 (current, worst and least pain within the past 24 hours) upon admission (baseline), 24, 48 and 72 hours post-admission and discharge were included. Pain severity and pain score reductions were analysed among those who experienced pain upon admission or in the past 24 hours. Treatment adequacy was measured by the Pain Management Index (PMI) among discharged patients. The PMI was constructed upon worst scores categorised as 0 (no pain), 1 (1-4, mild pain), 2 (5-6, moderate pain), or 3 (7-10, severe pain) which is then subtracted from the most potent level of prescribed analgesic drug scored as 0 (no analgesia), 1 (non-opioid), 2 (weak opioid) or 3 (strong opioid). PMI≥0 indicated adequate treatment. Results: Upon admission, 61.1% [95%CI 0.54:0.69] of 151 patients presented with pain. Of 123 patients who experienced pain upon admission or in the past 24 hours, 82.1% had moderate to severe worst pain. Throughout patients' ward stay until discharge, there was an increased prescribing of analgesics and adjuvants compared to baseline, excluding weak opioids, with strong opioids as the mainstay treatment. For all pain score types (current, worst and least pain within the past 24 hours), means decreased at each time point (24, 48 and 72 hours post-admission and discharge) from baseline, with a significant decrease at 24 hours post-admission (p<0.001). Upon discharge (n=100), treatment adequacy significantly improved (PMI≥0 100% versus 68% upon admission, p<0.001). Conclusions: Accounting for pain's dynamic nature, there was a high prevalence of pain among cancer patients in the palliative care unit. Continuous efforts incorporating comprehensive pain assessments, evidence-based treatments and patient education are necessary to provide adequate pain relief and end-of-life comfort care


No disponible


Subject(s)
Humans , Pain Management/methods , Cancer Pain/drug therapy , Hospice Care/methods , Analgesia/methods , Malaysia/epidemiology , Neoplasms/complications , Analgesics, Opioid/therapeutic use , Analgesics/therapeutic use , Prospective Studies
15.
J Chem Neuroanat ; 96: 79-85, 2019 03.
Article in English | MEDLINE | ID: mdl-30586607

ABSTRACT

The developing brain is very susceptible to environmental insults, and very immature infants often suffer from long-term neurological syndromes associated with white matter injuries such as periventricular leukomalacia. Infection and inflammation are important risk factors for neonatal brain white matter injuries, but the evaluation of white matter injury in animal models, especially the quantification of myelinated axons, has long been problematic due to the lack of ideal measurement methods. Here, we present an automated segmentation method, which we call MyelinQ, for the quantification of myelinated white matter in immunohistochemical DAB-stained sections of the neonatal mouse brain. Using MyelinQ, we show that a viral infection mimic agent, the Toll-like receptor 3 ligand Poly I:C, causes significant hypomyelination of white matter in the cortical and hippocampal fimbria regions, but not in the striatal caudoputamen region. We showed that MyelinQ can reliably produce results that are comparable to a method used in our previous publications. However, in comparison to the conventional method, MyelinQ has the advantages of being automated, objective and accurate. MyelinQ can analyze white matter in various specific brain regions and therefore provides a useful platform for the quantification of myelin and the evaluation of white matter injuries in animal models. MyelinQ and its code together with instructions for use can be found at: https://github.com/parham-ap/myelinq.


Subject(s)
Algorithms , Brain/pathology , Image Processing, Computer-Assisted/methods , White Matter/pathology , Animals , Animals, Newborn , Immunohistochemistry/methods , Inflammation/pathology , Mice , Mice, Inbred C57BL , Nerve Fibers, Myelinated
16.
Front Neurol ; 9: 159, 2018.
Article in English | MEDLINE | ID: mdl-29615958

ABSTRACT

BACKGROUND: Periventricular leukomalacia (PVL) is the most common form of preterm brain injury affecting the cerebral white matter. This type of injury involves a multiphase process and is induced by many factors, including hypoxia-ischemia (HI) and infection. Previous studies have suggested that lymphocytes play a significant role in the pathogenesis of brain injury, and the aim of this study was to determine the contribution of lymphocyte subsets to preterm brain injury. METHODS: Immunohistochemistry on brain sections from neonatal mice was performed to evaluate the extent of brain injury in wild-type and T cell and B cell-deficient neonatal mice (Rag1-/- mice) using a mouse model of HI-induced preterm brain injury. Flow cytometry was performed to determine the presence of different types of immune cells in mouse brains following HI. In addition, immunostaining for CD3 T cells and CD20 B cells was performed on postmortem preterm human infant brains with PVL. RESULTS: Mature lymphocyte-deficient Rag1-/- mice showed protection from white matter loss compared to wild type mice as indicated by myelin basic protein immunostaining of mouse brains. CD3+ T cells and CD20+ B cells were observed in the postmortem preterm infant brains with PVL. Flow cytometry analysis of mouse brains after HI-induced injury showed increased frequency of CD3+ T, αßT and B cells at 7 days after HI in the ipsilateral (injured) hemisphere compared to the contralateral (control, uninjured) hemisphere. CONCLUSION: Lymphocytes were found in the injured brain after injury in both mice and humans, and lack of mature lymphocytes protected neonatal mice from HI-induced brain white matter injury. This finding provides insight into the pathology of perinatal brain injury and suggests new avenues for the development of therapeutic strategies.

17.
ESC Heart Fail ; 5(4): 695-702, 2018 08.
Article in English | MEDLINE | ID: mdl-29573567

ABSTRACT

AIMS: Both ventricular assist device (VAD) and pulmonary vasodilator therapy have been shown in uncontrolled studies to improve pulmonary hypertension secondary to advanced left heart failure (Group 2 PH). This study aimed to compare haemodynamic benefits and survival in patients with fixed Group 2 PH treated with continuous-flow VAD to intensive medical therapy. METHODS AND RESULTS: Ninety-five patients listed for heart transplantation with sequential right heart catheters were studied, 24 patients having fixed Group 2 PH (as defined by cardiac index < 2.8 L/min/m2 , pulmonary capillary wedge pressure > 15 mmHg, and transpulmonary gradient ≥ 15 mmHg or pulmonary vascular resistance > 3.0 WU, unresponsive to vasodilator challenge). Ten patients received VAD therapy, and 14 patients received standard heart failure therapy with or without sildenafil, nitrates, or endothelin receptor antagonists. At repeat right heart catheterization, patients treated with VAD therapy demonstrated significant improvement in both transpulmonary gradient (19 vs. 12 mmHg, P = 0.046) and pulmonary vascular resistance (6.5 vs. 2.9 WU, P = 0.003) compared with baseline, while those treated with medical therapy did not (20.9 vs. 20.3 mmHg and 6.5 vs. 6.4 WU, P = NS for both). Patients who received VAD therapy were significantly more likely to achieve normalized transpulmonary gradient (8/10 vs. 4/14, P = 0.013) and were more likely to be listed for orthotopic heart transplantation (7/10 vs. 4/14, P < 0.05). There were no significant differences between groups in terms of all-cause mortality. CONCLUSIONS: Continuous-flow VAD therapy more effectively reverses fixed Group 2 PH compared with medical therapy alone and may allow a higher rate of listing for orthotopic heart transplantation.


Subject(s)
Cardiac Catheterization/methods , Heart Failure/complications , Heart-Assist Devices , Hypertension, Pulmonary/therapy , Pulmonary Artery/physiopathology , Vascular Resistance/physiology , Vasodilator Agents/therapeutic use , Female , Follow-Up Studies , Heart Failure/physiopathology , Heart Failure/therapy , Humans , Hypertension, Pulmonary/etiology , Hypertension, Pulmonary/physiopathology , Male , Middle Aged , Pulmonary Wedge Pressure/physiology , Retrospective Studies , Stroke Volume , Treatment Outcome
18.
Innate Immun ; 23(6): 524-536, 2017 08.
Article in English | MEDLINE | ID: mdl-28714327

ABSTRACT

Preterm infants are highly susceptible to late-onset sepsis (LOS) and necrotizing enterocolitis (NEC), but disease pathogenesis and specific diagnostic markers are lacking. Circulating cell-free DNA (cfDNA) and immune cell-derived proteins are involved in multiple immune diseases in adults but have not been investigated in preterm neonates. We explored the relation of circulating neutrophil-associated proteins and cfDNA to LOS and/or NEC. Using a clinically relevant preterm pig model of spontaneous LOS and NEC development, we investigated neutrophil-associated proteins and cfDNA in plasma, together with cytokines in gut tissues. The changes in cfDNA levels were further studied in preterm pigs and neonatal mice with induced sepsis, and in preterm infants with or without LOS and/or NEC. Fifteen of 114 preterm pigs spontaneously developed both LOS and NEC, and they showed increased intestinal levels of IL-6 and IL-1ß and plasma levels of cfDNA, neutrophil-associated proteins, and proteins involved in platelet-neutrophil interaction during systemic inflammation. The abundance of neutrophil-associated proteins highly correlated with cfDNA levels. Further, Staphylococcus epidermidis challenge of neonatal mice and preterm pigs increased plasma cfDNA levels and bacterial accumulation in the spleen. In infants, plasma cfDNA levels were elevated at LOS diagnosis and 1-6 d before NEC. In conclusion, elevated levels of plasma cfDNA and neutrophil proteins are associated with LOS and NEC diagnosis.


Subject(s)
Biomarkers/metabolism , Cell-Free Nucleic Acids/blood , Enterocolitis, Necrotizing/diagnosis , Neutrophils/metabolism , Sepsis/diagnosis , Staphylococcal Infections/diagnosis , Staphylococcus epidermidis/immunology , Animals , Animals, Newborn , Case-Control Studies , Cytokines/metabolism , Disease Models, Animal , Humans , Infant , Infant, Newborn , Infant, Premature , Mice , Mice, Inbred C57BL , Neutrophils/immunology , Retrospective Studies , Swine
19.
Front Immunol ; 8: 1772, 2017.
Article in English | MEDLINE | ID: mdl-29312305

ABSTRACT

Immunization is key to preventing infectious diseases, a leading cause of death early in life. However, due to age-specific immunity, vaccines often demonstrate reduced efficacy in newborns and young infants as compared to adults. Here, we combined in vitro and in vivo approaches to identify adjuvant candidates for early life immunization. We employed newborn and adult bone marrow-derived dendritic cells (BMDCs) to perform a screening of pattern recognition receptor agonists and found that the stimulator of interferon genes ligand 2'3'-cGAMP (hereafter cGAMP) induces a comparable expression of surface maturation markers in newborn and adult BMDCs. Then, we utilized the trivalent recombinant hemagglutinin (rHA) influenza vaccine, Flublok, as a model antigen to investigate the role of cGAMP in adult and early life immunization. cGAMP adjuvantation alone could increase rHA-specific antibody titers in adult but not newborn mice. Remarkably, as compared to alum or cGAMP alone, immunization with cGAMP formulated with alum (Alhydrogel) enhanced newborn rHA-specific IgG2a/c titers ~400-fold, an antibody subclass associated with the development of IFNγ-driven type 1 immunity in vivo and endowed with higher effector functions, by 42 days of life. Highlighting the amenability for successful vaccine formulation and delivery, we next confirmed that cGAMP adsorbs onto alum in vitro. Accordingly, immunization early in life with (cGAMP+alum) promoted IFNγ production by CD4+ T cells and increased the proportions and absolute numbers of CD4+ CXCR5+ PD-1+ T follicular helper and germinal center (GC) GL-7+ CD138+ B cells, suggesting an enhancement of the GC reaction. Adjuvantation effects were apparently specific for IgG2a/c isotype switching without effect on antibody affinity maturation, as there was no effect on rHA-specific IgG avidity. Overall, our studies suggest that cGAMP when formulated with alum may represent an effective adjuvantation system to foster humoral and cellular aspects of type 1 immunity for early life immunization.

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