Showing papers in "Pediatric Pathology & Molecular Medicine in 2001"
TL;DR: Under normal conditions, the inhibitory effects of the lipid prevail, but the collectins may provide focal activation and stimulate immune cells at sites where they are needed, however, in some types of lung disease or after certain insults or exposures, the balance between these inhibitory and stimulatory influences may be disrupted and result in inflammatory injury.
Abstract: Although the lung is protected by classic innate and adaptive immune mechanisms, another unique local immunoregulatory system involving pulmonary surfactant is described in this review. Normal surfactant inhibits many immune cell functions including proliferation resulting from various stimuli and production of reactive oxidants, inflammatory mediators, and some cell surface markers. The predominant surfactant lipids appear to be responsible for these suppressive effects. Conversely, surfactant proteins SP-A and SP-D stimulate many aspects of immune cell behavior. These proteins are collagenous lectins or collectins that bind to glycoconjugates on many pathogens, enhancing phagocytosis and killing in some cases. SP-A and SP-D stimulate chemotaxis and reactive oxidant generation, particularly in macrophages, although other cells are probably affected as well. In some cases, SP-A also stimulates the expression of cell surface markers and is involved in the stimulation of inflammatory mediators. Under normal conditions, the inhibitory effects of the lipid prevail, but the collectins may provide focal activation and stimulate immune cells at sites where they are needed. However, in some types of lung disease or after certain insults or exposures, the balance between these inhibitory and stimulatory influences may be disrupted and result in inflammatory injury.
115 citations
TL;DR: The etiology(s) of thrombin generation in SCD will be described and whether the activation of the cellular and plasmatic phases of hemostasis is causative or occurs as a result of vascular injury will be discussed.
Abstract: The protean manifestations of sickle cell disease (SCD), especially, microvessel involvement in the vasoocclusive process, is classically ascribed to the phenomena of erythrocyte sickling and enhanced red cell-endothelial adherence. Pertubations in various hemostatic systems occurs in SCD, both in steady state and during vasoocclusion, with the intravascular generation of thrombin. The etiology(s) of thrombin generation in SCD will be described. Whether the activation of the cellular and plasmatic phases of hemostasis is causative or occurs as a result of vascular injury will be discussed.
68 citations
TL;DR: Both the induction of endothelial CAM expression and subsequent endothelial adherence of Sickle erythrocytes may play significant roles in the pathophysiology of sickle-related complications, and reduction in CAM expression may provide a new approach to treatment.
Abstract: Microvascular complications in sickle cell disease occur as a result of obstruction of small vessels by deoxygenated sickle cells. Cerebrovascular complications are also common and result from obstruction of large blood vessels by thrombosis with changes in vessels that have some similarity to those found in arteriosclerotic vascular disease. Endothelial damage and activation from sickle cell-endothelial interactions may contribute to both. We find that endothelial cells have increased expression of VCAM-1, E-selectin, and ICAM-1 when exposed to sickle blood cells. The concentration-dependent, sickle-induced, adhesion molecule expression is significantly greater than that promoted by normal cells. The time course of Cell Adhesion Molecule (CAM) expression is similar to that induced by TNF-alpha and IL1. Studies after white cell enrichment and reduction suggest leukocytes are the primary mediators. CAM expression by endothelial cells appears stimulated by soluble factors. Antibody inhibition studies support TNF-alpha and IL-1, produced by sickle leukocytes, as the primary soluble factors responsible for the observed CAM expression. Both the induction of endothelial CAM expression and subsequent endothelial adherence of sickle erythrocytes may play significant roles in the pathophysiology of sickle-related complications, and reduction in CAM expression may provide a new approach to treatment.
64 citations
TL;DR: SP-A and SP-D may be important molecules in a threefold innate defense, particularly in the neonatal period between maternally acquired immunity and a fully developed adaptive immune system; the time interval between first exposure to a pathogen and generation of specific antibodies; and states of impaired immune function.
Abstract: Pulmonary surfactant protein A (SP-A) and D (SP-D), members of the collectin family, are implicated in innate host defense of the lung. Collectins consist of a collagen-like domain and a carbohydrate recognition domain. SP-A and SP-D recognize and interact with glycoconjugates on the surface of microorganisms. They protect the lung by interacting with a wide variety of potential pathogens, including viruses, bacteria, and fungi. This may result in enhanced killing and/or clearance by phagocytes. Although most extensively studied in the lung, both SP-A and SP-D, or proteins closely resembling SP-A and SP-D, are found in a number of other sites in the body and therefore may play a protective role at other sites than the lung. SP-A and SP-D protein and/or mRNA have been detected at various sites of the body: the respiratory tract, the gastrointestinal tract, the middle ear, and in the peritoneal cavity. The presence of SP-A and SP-D at these mucosal surfaces, in close contact with numerous potentially harmfu...
59 citations
TL;DR: It is concluded that Dex and cAMP additively stimulate expression of surfactant components in isolated fetal type II cells, providing a simplified culture system for investigation of surfACTant-related, and perhaps other, type II cell functions.
Abstract: We report a simplified culture system for human fetal lung type II cells that maintains surfactant expression. Type II cells isolated from explant cultures of hormone-treated lungs (18-22 wk gestation) by collagenase + trypsin digestion were cultured on plastic for 4 days in serum-free medium containing dexamethasone (Dex, 10 nM) + 8-bromo-cAMP (0.1 mM + isobutylmethylxanthine (0.1 mM) or were untreated (control). Surfactant protein (SP) mRNAs decreased markedly in control cells between days 1 and 4 of culture, but mRNA levels were high in treated cells on day) 4 (SP-A, SP-B, SP-C, SP-D; 600%, 100%, 85%, 130% of day 0 content, respectively). Dex or cAMP alone increased SP-B, SP-C, and SP-D mRNAs and together had additive effects. The greatest increase in SP-A mRNA occurred with cAMP alone. Treated cells processed pro-SP-B and pro-SP-C proteins to mature forms and had a higher rate of phosphatidylcholine (PC) synthesis (2-fold) and higher saturation of PC (approximately 34% versus 27%) than controls. Only treated cells maintained secretagogue-responsive phospholipid synthesis. By electron microscopy, the treated cells retained lamellar bodies and extensive microvilli. We conclude that Dex and cAMP additively stimulate expression of surfactant components in isolated fetal type II cells, providing a simplified culture system for investigation of surfactant-related, and perhaps other, type II cell functions.
55 citations
TL;DR: This review summarizes SP-A/lipid interaction studies regarding the lipid system used and suggests that hydrophobic-binding forces are involved in the peripherical association ofSP-A to membranes and that fluid and liquid-ordered phase coexistence in surfactant membranes might favor partition of SP-B into those membranes.
Abstract: Surfactant protein A (SP-A), an oligomeric glycoprotein, is a member of a group of proteins named collectins that contain collagen-like and Ca(2+)-dependent carbohydrate recognition domains. SP-A interacts with a broad range of amphipathic lipids (glycerophospholipids, sphingophospholipids, glycosphingolipids, lipid A, and lipoglycans) that are present in surfactant or microbial membranes. This review summarizes SP-A/lipid interaction studies regarding the lipid system used (i.e., phospholipid vesicles, phospholipid monolayers, and lipids immobilized on silica or adsorbed on a solid support). The effect of calcium, ionic strength, and pH on the binding of SP-A to lipids and the subsequent lipid aggregation process is discussed. Current evidence suggests that hydrophobic-binding forces are involved in the peripherical association of SP-A to membranes. It is also proposed that fluid and liquid-ordered phase coexistence in surfactant membranes might favor partition of SP-A into those membranes. The binding of SP-A to surfactant membranes containing hydrophobic surfactant peptides makes possible the formation of a membrane reservoir in the alveolar fluid that is protected by SP-A against inactivation and improves the rate of surfactant film formation. In addition, the interaction of SP-A with membranes might enhance the affinity of SP-A for terminal carbohydrates of glycolipids or glycoproteins on the surface of invading microorganisms.
54 citations
TL;DR: It is demonstrated that both SP-A genes are expressed in human small and large intestine, and it is speculated thatSP-A in the intestine plays a role in local host defense and inflammation.
Abstract: The human SP-A locus consists of two functional genes and one pseudogene, and SP-A is shown to play a role in local host defense and the regulation of inflammation in lung. Because the intestine, like the lung, is constantly exposed to foreign and potentially harmful substances, we investigated the hypothesis that both human SP-A genes are expressed in intestine. We demonstrate that both SP-A genes are expressed in human small and large intestine. The presence of SP-A mRNA in human intestine was detected by reverse transcription-polymerase chain reaction (RT-PCR), Northern blot analysis, and immunohistochemistry. The size of intestinal SP-A mRNA is the same as that in human lung, but the level of expression, compared with that in the lung, is very low in both the small and large intestine. Immunohistochemical analysis revealed positive reactivity for SP-A in a subgroup of epithelial cells in the intestine. Expression of both SP-A1 and SP-A2 genes was established by gene-specific PCR amplification, PCR-bas...
47 citations
TL;DR: The known clinical, pathologic, and molecular genetic aspects of pediatric PAP are discussed, and avenues for future research are considered.
Abstract: Pulmonary alveolar proteinosis (PAP) is a disorder that rapidly leads to respiratory failure, because the alveolar spaces fill with a lipid-rich, proteinaceous material that impedes gas exchange. The pathogenesis of this life-threatening process remained an enigma for decades. Recent analysis of the lung pathology and molecular genetics of affected families has provided a molecular basis for some cases of PAP-deficiency of surfactant protein SP-B. This lack result from mutations in the gene for SP-B. The common mutation, 121ins2, is present in about two-third of the patients with SP-B deficiency. Additional insights into the mechanism for this lipoproteinaceous accumulation within alveoli were contributed by serendipity in a granulocyte-macrophage colony stimulating factor (GM-CSF) knock-out mouse model developed to study basal hematopoiesis. In this model, hematopoiesis was unaffected, but the animals developed pulmonary alveolar proteinosis. Subsequently, mutations in the genes for GM-CSF or its receptor were identified as the cause for pulmonary alveolar proteinosis in some patients. In our review, we discuss the known clinical, pathologic, and molecular genetic aspects of pediatric PAP and consider avenues for future research.
47 citations
TL;DR: This review presents the knowledge available on the disposition of SP-B and SP-C in surfactant structures, the mode, extent, selectivity, and stoichiometry of their lipid-protein interactions, and the effect of the proteins on structure and dynamics of surfactants bilayers and monolayers.
Abstract: Phospholipids have the major role in pulmonary surfacant concerning its biophysical function of reducing surface tension at the alveolar air-liquid interface to facilitate respiratory mechanics. However, the presence of some specific, highly hydrophobic polypeptides is essential to modulate the physical behavior of phospholipids and to promote rapid formation of stable surface films that are able to produce surface tensions in the range of 0 dynes/cm during cyclic compression. The present review summarizes the available data on the parameters governing lipid-protein interactions of the hydrophobic surfactant proteins SP-B and SP-C with the main surfactant phospholipids. Lipid-protein interactions in surfactant have been studied in vitro using preparations reconstituted with very different methodological procedures. Conclusions concerning the role of hydrophobic surfactant proteins on the assembly of lipid-protein surfactant structures in vivo have been revised in this respect. This review presents the knowledge available on the disposition of SP-B and SP-C in surfactant structures, the mode, extent, selectivity, and stoichiometry of their lipid-protein interactions, and the effect of the proteins on structure and dynamics of surfactant bilayers and monolayers. Some considerations are given to possible concerted actions, under physiological conditions, of both proteins SP-B and SP-C.
43 citations
TL;DR: The data indicate that the coinheritance of alpha-thalassemia results in some beneficial effects and in some harmful effects, and there are trade-offs involved in this interaction in which the salutary effects are undermined by harmful ones.
Abstract: The clinical picture of sickle cell disease is heterogeneous and varies tremendously among patients and in the same patient from time to time. The level of HbF, alpha-genotype, beta-haplotype, age, sex, and the environment are important factors that modify the clinical picture of sickle cell disease. My paper focuses on the effect of alpha-globin genotype on the pathophysiology of sickle cell anemia, HbSC disease, and sickle beta-thalassemia. The data indicate that the coinheritance of alpha-thalassemia results in some beneficial effects and in some harmful effects. Thus, there are trade-offs involved in this interaction in which the salutary effects are undermined by harmful ones.
40 citations
TL;DR: Improved understanding of the influence of genes involved in modulating the complex pathophysiology of Sickle cell disease may allow prediction of the phenotype of sickle cell patients and aid in management decisions.
Abstract: Sickle hemoglobin is the product of one mutated gene, but the disease phenotype is the product of many genes. Polymorphism among the genes responsible for the pleotropic effects can be epistatic (or modifier) genes contributing to interindividual variation that characterizes sickle cell anemia patients. Modulation in the hemoglobin F levels is associated with the beta-globin gene cluster haplotypes and to gender and chromosomal sites different from chromosome 11 influencing the severity of the disease. Coexistence of alpha thalassemia with sickle cell disease produces hematologic and clinical consequences that are beneficial in some complications but deleterious in others. There is little if any modulation of the phenotype of sickle cell anemia by coexistence of G6PD deficiency. Mutations that favor blood coagulation or thrombosis may influence the phenotype of the disease. Improved understanding of the influence of genes involved in modulating the complex pathophysiology of sickle cell disease may allow prediction of the phenotype of sickle cell patients and aid in management decisions.
TL;DR: These etiologies, the evidence, and pathophysiology supporting the hypothesis that infarction of segments of ribs by the same vaso-occlusive process responsible for the acute episodes of pain (characteristic of the sickle cell diseases) is often involved in the acute chest structure are summarized.
Abstract: The acute chest syndrome is a generic term for pulmonary complications of sickle cell diseases with heterogeneous etiologies that include pneumonia, vaso-occlusion of pulmonary arterioles, rib infarction, and fat embolism syndrome. My review summarizes these etiologies, the evidence, and pathophysiology supporting the hypothesis that infarction of segments of ribs by the same vaso-occlusive process responsible for the acute episodes of pain (characteristic of the sickle cell diseases) is often involved in the acute chest structure. Inflammation associated with the infarct then causes splinting, hypoventilation, and hypoxia and further vaso-occlusion. The relationship with adult respiratory distress syndrome and fat embolism is also discussed. Use of the incentive spirometer combined with effective analgesia when chest pain is present is advocated for prevention of the pulmonary infiltrates. Newer understanding of the role of nitric oxide in regulating oxygen transport and its relationship to blood transfusions used in therapy of the acute chest syndrome are discussed.
TL;DR: It is hypothesized that the surfactants most resistant to inactivation in vitro will be the ones that are most effective in treatment of animal models of acute lung injury and are also likely to be more resistant to nonionic polymers.
Abstract: Inactivation of pulmonary surfactant may be important in acute lung injury and acute respiratory distress syndrome. Treatment of surfactant dysfunction by instilling exogenous surfactants may improve gas exchange and pulmonary mechanics. Surfactants used for treatment vary in their attributes and effects, so when various surfactants are considered for therapy, resistance to inactivation is an important consideration. Animal models of acute lung injury exist in which the relative merits of surfactants can be compared. We hypothesize that the surfactants most resistant to inactivation in vitro will be the ones that are most effective in treatment of animal models of acute lung injury. Surfactants with higher concentrations of surfactant proteins (specifically A, B, and C) are more resistant to inactivation. Nonionic polymers mimic surfactant proteins in preventing surfactant inactivation under some conditions. Adding nonionic polymers to surfactant containing minimal amounts of SP-B and SP-C markedly improv...
TL;DR: With adequate clinical and radiologic correlation, FNAB represents a technically, easily performed, cost-effective, and accurate procedure for establishing the diagnosis of skeletal osteosarcoma.
Abstract: We retrospectively reviewed our experience with fine needle aspiration biopsy (FNAB) in the diagnosis and management of skeletal osteosarcoma. The bi-institutional study sample involved 30 consecutive aspirates from 29 patients (28 primary tumors, 1 pulmonary metastasis, 1 local recurrence). There were 17 children and 12 adults. Two aspirates were unsatisfactory for diagnosis. Of the adequate primary osteosarcoma cases analyzed by FNAB, 24 of 26 were diagnosed as osteosarcoma. All pediatric cases were correctly interpreted as osteosarcoma and treated appropriately. There were 2 incomplete diagnoses. A secondary osteosarcoma arising within an otherwise clinically, radiologically, and histologically typical giant cell tumor (malignant giant cell tumor) was not diagnosed preoperatively on FNAB due to nonrepresentative sampling. Chronologically, the first patient with osteosarcoma analyzed by FNAB was diagnosed simply as "spindle cell neoplasm." No complications resulted from the procedure. With adequate clinical and radiologic correlation, FNAB represents a technically, easily performed, cost-effective, and accurate procedure for establishing the diagnosis of skeletal osteosarcoma. Immediate interpretation of aspirated material allows for therapy planning and oncologic consultation at the initial clinic visit.
TL;DR: Major developments related to characterization of molecular and cellular mechanisms underlying expression, post-translational processing, and targeting of proSP-C21 that result in production of secreted SP-C3.7 are highlighted.
Abstract: Traditional thinking about surfactant proteins has centered around their effects on the biophysical properties of surfactant phospholipids. Accumulated data now suggests that the four major surfactant proteins (SPs) are a biochemically and functionally diverse group of mammalian peptides that have function beyond modification of alveolar surface tension. Alveolar SP-C (SP-C 3 . 7 , M r 21,000) is 35 amino acid peptide isolated from lung surfactant that is synthesized and processed from a 191-197 amino acid precursor (proSP-C 21 ). Although its solubility in organic solvents and avidity for lipid membranes impart properties important for its biophysical activity, SP-C represents a structurally and functionally challenging protein for the alveolar type II cell that must synthesize and traffic the peptide through the regulated secretory pathway. Despite technical and analytical difficulties imposed by its unique structure, our current understanding of SP-C biosynthesis has evolved over the past 10 years. Rec...
TL;DR: The development of synthetic analogues of the surfacant proteins might make it possible to tailor artificial surfactants for specific therapeutic missions, for instance by enhancing resistance to inactivation by meconium, plasma proteins, or oxygen radicals or maximizing bacteriostatic effects.
Abstract: The hydrophobic proteins SP-B and SP-C are important components of natural surfactant preparations currently used in clinical practice, and physiologically active surfactants can be made from isolated SP-B and/or SP-C reconstituted with synthetic lipids. Efforts have been made to produce these polypeptides, or analogues with similar function, by organic synthesis or expression in heterologous systems. It is important to obtain proper folding of the synthetic peptides, as required for optimal interaction with the surfactant lipids. Another issue is to avoid loss of SP-C activity due to f -helix to g -sheet transition. This latter problem can be circumvented by replacing the polyvaline stretch of SP-C with a polyleucine stretch containing a few lysines. Palmitoylation of cysteines or serines at positions 5 and 6 also seems important for the properties of SP-C. SP-B, which is too big a molecule to be easily produced by organic synthesis, apparently can be replaced in an artificial surfactant by a pep...
TL;DR: It is speculated that this SP-A2 protein, like other serous secretions from airway submucosal glands, functions in local antimicrobial host defense mechanisms in the conducting airways.
Abstract: In our study, surfactant protein (SP)-A was characterized in adult human trachea and bronchi. SP-A mRNA and protein were localized to serous cells in submucosal glands by in situ hybridization and immunohistochemistry, respectively. A 2.2 kb SP-A mRNA transcript was detected in tracheal tissues by Northern blot analysis. Primer extension analysis and gene-specific reverse transcriptase-polymerase chain reaction (RT-PCR) revealed the predominance of SP-A2 mRNA. However, using nested PCR, we also detected low amounts of SP-A1 mRNA in the tracheal tissues. A ∼35 kDa SP-A immunoreactive protein was detected in the tracheal tissues by immunoblot analysis and was shown to be modified by the addition of N-linked oligosaccharides. We conclude that submucosal glands in the conducting airways produce a novel SP-A protein with a molecular weight and post-translational modification similar to the SP-A produced in the distal lung. We speculate that this SP-A2 protein, like other serous secretions from airway submucosa...
TL;DR: Molecular mechanisms involving changes in chromatin structure and/or transcription factor binding have been demonstrated for γ gene induction by butyrate may offer a new strategy for gene therapy to cure hemoglobinopathy disorders.
Abstract: The switch from embryonic to fetal then to adult hemoglobin synthesis is a unique phenomenon during early human development. Fetal hemoglobin (Hb F) is known to interfere with polymerization of Hb S in erythrocytes. Several pharmacologic agents such as 5–azacytidine, myleran, hydroxyurea, erthropoietin, and butyrates enhance fetal hemoglobin production and have been used in hemoglobinopathy patients to ameliorate severe pain episodes and reduce severe anemia. Among these, hydroxyurea is the agent of choice because of its safety and ease of administration. One of the primary cellular mechanisms involved in pharmacologic induction of Hb F synthesis is rapid regeneration of erythroid precursors following the cytoreduction phase of certain pharmacologic agents. Molecular mechanisms involving changes in chromatin structure and/or transcription factor binding have been demonstrated for γ gene induction by butyrate. Identifying the proteins involved in γ gene activation by various compounds may offer a new strat...
TL;DR: This is the first report of HSV-l or EBV myocarditis (at least in children) in which viral infection has been demonstrated in the myocardium, and CD8+ T-lymphocytes induced by herpes virus infections may play an important role in the damage to heart muscle fibers seen in fulminantMyocarditis in previously healthy children.
Abstract: We report two cases of fulminant viral myocarditis in previously healthy children. They were caused by herpes simplex virus (HSV)-1 (in a boy aged 3 years) and Epstein-Barr virus (EBV) (in a boy aged 12 months). We obtained the diagnosis of HSV-1 myocarditis by immunohistochemistry and the diagnosis of EBV myocarditis by in situ hybridization. Histologic examination of heart tissue from the two boys revealed mononuclear cell infiltration of the myocardium. Immunohistochemical staining identified these cells as CD8+ T-lymphocytes. CD8+ T-lymphocytes induced by herpes virus infections may play an important role in the damage to heart muscle fibers seen in fulminant myocarditis in previously healthy children. To our knowledge, this is the first report of HSV-1 or EBV myocarditis (at least in children) in which viral infection has been demonstrated in the myocardium.
TL;DR: Hydroxyurea made a major impact on sickle cell therapy when it was shown to decrease acute painful episodes, acute chest syndrome, and the need for blood transfusion in adults.
Abstract: During the past several decades, our understanding of the complex pathophysiology of vasoocclusion associated with sickle cell disease has improved greatly. Interaction of genes, hemoglobin molecules, red cell membrane and metabolic changes, cell-cell interactions and cell-plasma interactions, red cell adhesion to vascular endothelium, activation of coagulation, and vascular reactivity play a role in vasoocclusion.Penicillin prophylaxis of pneumococcal infections and appropriate use of blood transfusions and other supportive measures improved survival of sickle cell patients. Hydroxyurea made a major impact on sickle cell therapy when it was shown to decrease acute painful episodes, acute chest syndrome, and the need for blood transfusion in adults. Significant experience in the use of hydroxyurea has been accumulated in older children. The benefits and risks of hydroxyurea for younger children and long-term risks in all patients will be evaluated in future investigations. Other promising therapies includ...
TL;DR: A possible monosomy (Turner syndrome) was raised as a cause of the fetal death and the body measurements lagged 6 weeks behind the gestational age, confirming the sonographic evidence of severe IVCR.
Abstract: This case presents as the third pregnancy of a Hispanic woman. She underwent prenatal care complicated by an increased screening alphafetoprotein level (4.4 ngjdl), oligohydramnios, and intrauterine growth retardation (IVCR). The IVCR was severe with a 4-to-6-week lag in estimated body measurements by sonogram. Amniocentesis showed a normal 46XX karyotype. She presented at 29 weeks for a follow-up visit at which time ICtal heart tones were not heard, and fetal death in utero was diagnosed. Her past medical, family, and social history is noncontributory. She had two previous spontaneous vaginal deliveries without complications. After induction, a macerated slightly edematous female fetus was delivered (Figure I). The weight was 450 grams «5th percentile). Due to the edema that was more noticeable on the dorsum of the hands and feet, a possible monosomy (Turner syndrome) was raised as a cause of the fetal death. At autopsy, no congenital anomalies were noted. The body measurements lagged 6 weeks behind the gestational age, confirming the sonographic evidence of severe IVCR. The placenta weighted 100 grams « 5th percentile). The membranes were opaque, and numerous infarcts were noted throughout the parenchyma, occupying 50 Yo of the parenchyma. Histologically, (Figures 2-4) the infarcts were of varying ages. Large accumulations of polymorphonuclear leukocytes, forming microabcesses, were seen in an intervillous distribution. Villous necrosis was associated with the microabcesses. Gram stains were performed on multiple sections of the placenta (Figures 5 and 6) with adequate controls and revealed numerous gram-positive coccobacilli associated with the areas of necrosis and in the decidua.
TL;DR: This review focuses on the putative biological functions ofSP-A that are supported by experiments in mammals and on the structural basis of SP-A function.
Abstract: Surfactant protein A (SP-A) is a highly ordered, oligomeric glycoprotein that is secreted into the airspaces of the lung by alveolar type II cells and Clara cells of the pulmonary epithelium. Although research has shown that SP-A is both a calcium-dependent phospholipid-binding protein that affects surfactant structure and function and a lectin that opsonizes diverse microbial species, our understanding of the physiologically relevant roles of SP-A in the lung remains incomplete. My review focuses on the putative biological functions of SP-A that are supported by experiments in mammals and on the structural basis of SP-A function.
TL;DR: The risks and benefits of hematopoietic cell transplantation in patients with sickle cell disease are discussed and the outcome of 147 patients who received allografts for sicklecell disease is summarized.
Abstract: Since the genetic basis of sickle cell anemia was discovered over 50years ago, many therapies have been developed for the treatment of this disorder. Hematopoietic cell transplantation offers curative potential, but it is associated with a 5–10% risk of dying. Patients who undergo allografting but develop stable donor-host hematopoietic chimerism appear to experience a significant clinical benefit. Our paper discusses the risks and benefits of hematopoietic cell transplantation in patients with sickle cell disease and summarizes the outcome of 147 patients who received allografts for sickle cell disease. We also review the development of new approaches to establish stable mixed chimerism after transplantation for sickle cell disease.
TL;DR: The pathophysiologic background of sickling of erythrocytes in patients with sickle cell disease is discussed, and some new treatment options to prevent vasoocclusive crises or other problems in this patient population are explored.
Abstract: One of the pathogenetic mechanisms responsible for sickling of erythrocytes in patients with sickle cell disease is the decreased hydration status of the cells. In this brief review, we discuss the pathophysiologic background and explore some new treatment options to prevent vasoocclusive crises or other problems in this patient population.
TL;DR: It is concluded that a CB bank focusing on sibling-donations may be feasible, but further study is required to determine whether such a bank can colled CB units of sufficient quantity and quality to support controlled trials of sibling CB transplantation.
Abstract: Although hematopoietic stem cell transplantation has curative potential for selected patients with sickle cell disease (SCD), most patients who are eligible for transplantation do not have a suitable donor. Cord blood (CB) from a sibling could provide an alternative stem cell source that, while not as well established as marrow, may offer certain advantages for selected families. These potential advantages include low risk to the infant donor, the possibility that mismatched CB units from sibling donors may be acceptable for transplantation, prompt availability of a stored CB unit for transplant, and decreased risk of clinically significant graft-versus-host disease. When families with SCD (or other transplant-treatable condition) conceive a sibling, no comprehensive research resource exists to assist the family in collecting the new infant's CB. With support from the National Heart Lung and Blood Institute, we are developing a noncommercial research-based CB Banking Program specifically for medically ind...
TL;DR: Analysis by age groups suggested that islet cell dispersion hyperplasia persists unchanged, whereas diameters of compact islets tend to increase with age, which may be related to local tissue hypoxia and/or increased metabolic energy needs in sickle cell disease.
Abstract: Although the endocrine pancreas appears to play an important role in the pathophysiology of sickle cell disease, very little is known about the morphologic changes in this tissue. Our study was initiated to delineate the microscopic features of the endocrine pancreas in a large autopsy series of sickle cell hemoglobinopathies. From more than 650 cases archived at the Centralized Pathology Unit for Sickle Cell Disease (Mobile, AL), 224 autopsy cases were identified for review of clinical and gross autopsy findings and/or for microscopic studies, including histochemical stains (trichrome, reticulin, iron), and immunohistochemical stains (insulin, glucagon, somatostatin, and pancreatic polypeptide). The gross examinations were recorded as unremarkable in 65% of the autopsies. In childhood and adolescence (≤18 years), pancreas weights (50.76 ± 5.16SE gm) were significantly greater (p < 0.0001) than age-matched controls (30.42 ± 3.59SE gm). In adulthood, pancreas weights (108.34 ± 5.29SE gm) were not significa...
TL;DR: A boy born from a nonconsanguineous gypsy couple with intrauterine growth retardation, omphalocele, and multiple intestinal atresia from the pylorus to the rectum is described.
Abstract: Multiple intestinal atresia is a rare disorder with vascular or hereditary etiology So far, the occurrence of this malformation along with omphalocele has not been reported We describe a boy born from a nonconsanguineous gypsy couple with intrauterine growth retardation, omphalocele, and multiple intestinal atresia from the pylorus to the rectum The microscopic examination of the intestine shows multiple small lumina with a sieve-like appearance This is characteristic of the hereditary alresias and suggests development of a defect in (re) canalization during embryogenesis The association with omphalocele indicates a common developmental defect may be present
TL;DR: The histopathologic features of CMV in the livers of SA children were associated with a conspicuous inflammation absent in the NA group, and different nonspecific hepatic changes were found in SA children, including one case of peliosis hepatis.
Abstract: Liver tissue from autopsies of 29 cases of children with acquired immunodeficiency syndrome (AIDS) were collected from three major South America (SA) pediatric hospitals. The hepatopathologic findings were classified in the same fashion as in a series of 61 children with AIDS from North America (NA): inflammation, nonspecific, lymphoproliferative disorders, and giant cell transformation. By comparing both groups, we noted that the SA children were younger at time of death which was consistent with a more rapid progression of the disease. Opportunistic infections varied with a higher prevalence of cytomegalovirus (CMV) infection in SA children. The histopathologic features of CMV in the livers of SA children were associated with a conspicuous inflammation absent in the NA group. Finally, different nonspecific hepatic changes were found in SA children, including one case of peliosis hepatis.
TL;DR: A bone marrow evaluation revealed normocellular marrow with no evidence for tumor or storage disease and blood film revealed normal-appearing lymphocytes, normal red cell morphology, and several megathrombocytes suggesting a destructive thrombocytopenia.
Abstract: An ll-year-old female presented with thrombocytopenia, marked splenomegaly, and hepatomegaly. She was feeling well at the time with a normal activity level, no unusual bleeding or bruising, no bone or joint pain, and no fever or weight loss. Her past medical history was unremarkable, but her family history was significant for her [father and paternal grandmother had autosomal dominant polycystic kidney disease]. Physical examination was significant for hepatomegaly, with a liver span of approximately 12 em, and a palpable spleen 12 em below the left costal margin. The remainder of the examination was entirely normal. Laboratory evaluation revealed a WBe of 3.3, Hgb of 12.3, platelets of 70,000, and a differential of 45% segmented neutrophils, 46% lymphocytes, 7% monocytes, and 3% cosinophils. The blood film revealed normal-appearing lymphocytes, normal red cell morphology, and several megathrombocytes suggesting a destructive thrombocytopenia. Other laboratory tests included electrolytes, liver enzymes, and a urinalysis, all of which were normal. Further, a hepatitis profile, Epstein-Barr Virus antibodies, a sweat test, and platelet-associated antibodies were obtained and were negative. Beta glucosidase levels were obtained to evaluate for Gaucher's disease and were within normal limits. Last, a bone marrow evaluation revealed normocellular marrow with no evidence for tumor or storage disease.
TL;DR: Three autopsied newborns with Jarcho-Levin syndrome had multiple extraskeletical defects such as cardiovascular, urogenital, respiratory, and central nervous system malformations, which add new information to the multiple vertebral segmentation defects found in this syndrome.
Abstract: We report on pathologic examination of three autopsied newborns with Jarcho-Levin syndrome. The most important abnormalities noted were multiple extraskeletical defects such as cardiovascular, urogenital, respiratory, and central nervous system malformations. These cases add new information to the multiple vertebral segmentation defects found in this syndrome.