Intra-arterial administration of cell-based biological agents for ischemic stroke therapy

Introduction: Ischemic stroke is becoming a primary cause of disability and death worldwide. To date, therapeutic options remain limited focusing on mechanical thrombolysis or administration of thrombolytic agents. However, these therapies do not promote neuroprotection and neuro-restoration of the ischemic area of the brain.

Areas covered: This review highlights the option of minimal invasive, intra-arterial, administration of biological agents for stroke therapy. The authors provide an update of all available studies, discuss issues that influence outcomes and describe future perspectives which aim to improve clinical outcomes. New therapeutic options based on cellular and molecular interactions following an ischemic brain event, will be highlighted.

Expert opinion: Intra-arterial administration of biological agents during trans-catheter thrombolysis or thrombectomy could limit neuronal cell death and facilitate regeneration or neurogenesis following ischemic brain injury. Despite the initial progress, further meticulous studies are needed in order to establish the clinical use of stem cell-induced neuroprotection and neuroregeneration.     

Leadership Development in UK Medical Training: Pedagogical Theory and Practice

Phenomenon: The central role of clinical leadership in achieving the vision of quality and productivity could be attained by investing in its development in postgraduate medical education. Approach: A critical review of selected literature is presented. Findings: The author identifies some of the main theoretical constructs related to leadership; the pedagogical underpinning of medical leadership programs; their learning objectives; and the mixture of methods, individual and collective, to achieve them. Insights: How to best develop leadership through medical education remains an open debate. Experiential learning, reflective practice, action learning, and mentoring could provide the foundations of leadership development. Application of the aforementioned should be cautious due to limitations of the concept of leadership as currently promoted and lack of robust evaluation methodologies.     

Soluble transferrin receptors and tissue oxygenation in non anaemic cystic fibrosis patients.

BACKGROUND: Chronic pulmonary disease and progressive tissue hypoxia are major causes of morbidity and mortality in cystic fibrosis (CF). Normally the body adapts to tissue hypoxia by increasing the red cell mass and decreasing the Hb-O(2) affinity. These adaptations are commonly observed in patients with cyanotic heart disease and individuals living at high altitude. However, patients with CF not only have an impaired erythroid response to hypoxia, but also are frequently anaemic. METHODS: In order to evaluate erythroid marrow activity and tissue oxygenation in 37 patients with CF we measured: the haematological and blood chemistry parameters; including red cell indices, ferritin, erythropoietin (Epo) and soluble transferrin receptors (sTfR) levels; arterial blood gases, P(50) and oxygen release to the tissues (O(2)(R)) and the 2,3-BPG levels. RESULTS: The main results showed that a) patients with CF have a mild degree of tissue hypoxia which is expressed by the moderately decreased of P(50) and O(2)(R) values and the relative increase of Epo level, b) 2,3-BPG synthesis in patients with CF is normal and c) sTfR levels are significantly increased (3-fold normal) in patients with CF compared to normal controls. CONCLUSIONS: The above observations indicate that erythroid marrow activity in patients with CF is increased.     

Quantifying osteoblast and osteocyte apoptosis: challenges and rewards.

Since the initial demonstration of the phenomenon in murine and human bone sections approximately 10 yr ago, appreciation of the biologic significance of osteoblast apoptosis has contributed greatly not only to understanding the regulation of osteoblast number during physiologic bone remodeling, but also the pathogenesis of metabolic bone diseases and the pharmacology of some of the drugs used for their treatment. It is now appreciated that all major regulators of bone metabolism including bone morphogenetic proteins (BMPs), Wnts, other growth factors and cytokines, integrins, estrogens, androgens, glucocorticoids, PTH and PTH-related protein (PTHrP), immobilization, and the oxidative stress associated with aging contribute to the regulation of osteoblast and osteocyte life span by modulating apoptosis. Moreover, osteocyte apoptosis has emerged as an important regulator of remodeling on the bone surface and a critical determinant of bone strength, independently of bone mass. The detection of apoptotic osteoblasts in bone sections remains challenging because apoptosis represents only a tiny fraction of the life span of osteoblasts, not unlike a 6-mo-long terminal illness in the life of a 75-yr-old human. Importantly, the phenomenon is 50 times less common in human bone biopsies because human osteoblasts live longer and are fewer in number. Be that as it may, well-controlled assays of apoptosis can yield accurate and reproducible estimates of the prevalence of the event, particularly in rodents where there is an abundance of osteoblasts for inspection. In this perspective, we focus on the biological significance of the phenomenon for understanding basic bone biology and the pathogenesis and treatment of metabolic bone diseases and discuss limitations of existing techniques for quantifying osteoblast apoptosis in human biopsies and their methodologic pitfalls.     

Upregulation of CD40, CD80, CD83 or CD86 on alveolar macrophages after lung transplantation.

BACKGROUND: Alveolar macrophages (AMs) are known to be poor antigen-presenting cells, and lack the accessory molecules such as CD40, CD80 or CD86 to activate T cells. The question raised is about the potential changes in phenotypes after lung transplantation, particularly during acute rejection episodes. METHODS: The present study analyzed the phenotype of AMs longitudinally in 45 lung transplant patients, between August 1997 and April 2002, with a follow-up period of 27.2 +/- 2.5 (mean +/- SEM) months. There were 7.7 +/- 0.6 bronchoalveolar lavage (BAL) assessments performed per patient (i.e., 345 BALs), simultaneously with transbronchial biopsies. Transplantation was soon followed by a progressive upregulation of CD40 on 49.7 +/- 8% of AMs during the first month, and this marker remained elevated at 60 +/- 8% after 5 years. RESULTS: Both CD86 and CD80, as well as CD83, a marker of dendritic cells, were enhanced for most AMs during Grade A2 and A3 rejection episodes. A correlation was found between expression of CD83 and CD86, but not between CD1a and CD86. Immunohistology confirmed that CD40-positive cells in the alveoli corresponded to AMs and to some dendritic cells in the basal layers of the airways. In vitro studies showed that harvested AMs with these enhanced accessory molecules remained poor stimulators of allogeneic cells, a phenomenon that may be related to the ongoing immunosuppressive treatments. CONCLUSIONS: AM phenotypes showed marked changes during early or late acute rejection episodes, acquiring CD80, CD83 and CD86, while CD40 expression was further enhanced. This finding may provide clues on how to monitor the tolerance of transplanted lungs and may also provide new insights into the pathophysiology of lung transplantation.     

Late left ventricular diastolic flow propagation velocity determined by color M-mode Doppler in the assessment of diastolic dysfunction.

BACKGROUND: Early color M-mode Doppler flow propagation (Ep) through the left ventricle (LV) has been proposed as a useful noninvasive index for assessing LV relaxation, whereas data concerning late velocity propagation (Ap) is lacking. METHODS: We studied 51 patients with delayed relaxation (group I) and 50 with pseudonormal filling pattern (group II). Another 51 aged-matched healthy persons served as the control group. RESULTS: Patients showed increased left atrial dimensions, atrial wave of the pulmonary vein flow, and Ap, and reduced LV ejection fraction, Ep, and Ep/Ap ratio compared with the control group. Patients in group II revealed increased left atrial dimensions (P =.001), atrial wave of the pulmonary vein flow (P <.001), and Ep/Ap ratio (P <.001), and reduced LV ejection fraction and Ap (P <.001) compared with group I. Regression analysis showed that the strongest independent variable distinguishing normal from pseudonormal filling pattern was the Ep/Ap ratio. CONCLUSION: Ap evaluation offers a new diagnostic diastolic index, especially in the field of the pseudonormal pattern where the separation from normal is difficult.     

Pulmonary aspergilloma

Pulmonary aspergillomas usually arise from colonization of Aspergillus in preexisting lung cavities. Between 1972 and 1988, 18 patients underwent thoracotomy for treatment of pulmonary aspergilloma in our institution. Eight patients had simple aspergilloma and ten had complex aspergilloma. Hemoptysis was the most frequent complication. Tuberculosis was the most common underlying lung disease. Patients presenting with complex aspergilloma usually had associated factors potentially reducing their immune competence. Patients with simple aspergilloma tolerated surgery quite well and the outcome was satisfactory. By contrast operative mortality was 30% (3 deaths) in patients with complex aspergilloma and complications occurred in 8 patients (80%). Treatment of pulmonary aspergilloma must be individualized to take into account the patient's overall health and the risks attendant with each treatment modality.     

Ontogeny of intrinsic innervation in the human kidney

We aimed to define, for the first time, the ontogeny of intrarenal innervation and to assess the distribution and nature of parenchymal nerves in the human fetal kidney. Our material consisted of routinely-processed renal tissue sections from 17 human fetuses, six of 20–24 gestational weeks (gw) and 11 of 25–40 gw, and three adults. We used immunohistochemistry with antibodies to the pan-neural markers neuron-specific enolase (NSE), neurofilaments (NF), PGP9.5, S100, and the adrenergic marker tyrosine hydroxylase (TH). NSE-, NF-, S100-, and PGP9.5-positive nerves, associated with arterial and venous vasculature, were identified in the renal cortex from 20 gw onwards, and their density appeared to increase with gestation, reaching adult levels at 28 gw. Most of the intrarenal nerves were TH-positive. Nerve fibers extended from the corticomedullary region to the outer cortex, reaching the renal capsule in the 3rd trimester. In detail, NSE-, NF-, S100-, PGP9.5-, and TH-immunoreactive fibers were observed in close apposition to the renal artery and its branches, occasionally reaching the afferent and efferent arteriole (3rd trimester). Nerve fibers were detected in close apposition to the juxtaglomerular apparatus in the 2nd and 3rd trimesters. In the renal medulla, NSE-, PGP9.5-, S100-, and TH-positive nerve fibers were detected close to tubular cells as early as 20 gw. However, their density gradually decreased during the 3rd trimester, and they were not observed in the medulla of the adult kidney. In conclusion, the human fetal kidney appears richly innervated during the 2nd and 3rd trimesters. There is a progressive increase in the density of parenchymal nerve fibers towards term from the corticomedullary region to the cortex. Most intrarenal nerves are adrenergic and have a predominant perivascular distribution, implying that renal innervation plays an important functional role during intrauterine life.     

Clostridium difficile vaccine and serum immunoglobulin G antibody response to toxin A

There is a strong association between serum antibody responses to toxin A and protection against Clostridium difficile diarrhea. A parenteral C. difficile toxoid vaccine induced very-high-level responses to anti-toxin A immunoglobulin G (IgG) in the sera of healthy volunteers. After vaccination, the concentrations of anti-toxin A IgG in the sera of all 30 recipients exceeded the concentrations that were associated with protection in previous clinical studies. Furthermore, the median concentration of serum anti-toxin A IgG in the test group was 50-fold higher than the previous threshold. These findings support the feasibility of using a vaccine to protect high-risk individuals against C. difficile-associated diarrhea and colitis.