Special article: Smallpox: Its history and reemergence as a weapon of biological warfare

Smallpox is an extremely contagious viral infection caused by the orthopoxvirus variola virus. A disease that once was “conquered,” smallpox has appeared on the scene again as a potential weapon of biological warfare. Along with anthrax, smallpox is considered one of the 2 most threatening diseases associated with bioterrorism, and an overwhelming amount of evidence indicates that contraband samples of the virus are stored in several laboratories throughout the world. Medical personnel form the nation's first line of defense. This review focuses on the history of smallpox, with an emphasis on the individuals who helped eradicate it, and presents recent developments as they relate to biological warfare. Copyright © 2001 by W.B. Saunders Company     

Phytoestrogens: a review of recent findings

Phytoestrogens have been investigated at the epidemiological, clinical and molecular levels to determine their potential health benefits. The two major groups of phytoestrogens, isoflavones and lignans, are abundant in soy products and flax respectively, but are also present in a variety of other foods. It is thought that these estrogen-like compounds may protect against chronic diseases, such as hormone-dependent cancers, cardiovascular disease and osteoporosis. Furthermore, phytoestrogens are used as a natural alternative to hormone replacement therapy and to reduce menopausal symptoms. Phytoestrogens have been shown to induce both estrogenic and anti-estrogenic effects but their biological relevance and potency have not been well characterized. In children, consumption of soy-based formulas and soy milk can lead to high levels of exposure to phytoestrogens with only limited data available concerning potential benefits or adverse effects. Phytoestrogens are considered good candidates for use in natural therapies and as chemopreventive agents in adults. Safe and efficacious levels have yet to be established.     

Abnormal immune function in vivo in a murine model of lysosomal storage disease

Lysosomal storage diseases are a class of inborn errors of metabolism that lead to widespread disease in multiple tissues. The murine model of mucopolysaccharidosis type VII (MPS VII) closely parallels the human syndrome and has been extensively used to investigate the natural history and therapeutic strategies for lysosomal storage diseases in general. Here we demonstrate a previously undescribed immune defect in the MPS VII mouse. Although the normal populations of cells are present in lymph nodes of these mice, MPS VII mice show a blunted T cell proliferative response and decreased antibody production after immunization with antigens. One mechanism of this defect is ineffective processing of protein antigens, as responses to peptide antigens are normal. This phenotype is presumably caused by the lysosomal disorder, as the defect can be corrected in vivo by direct enzyme replacement therapy. These findings have implications for the use of this animal model, and may have clinical significance for other, more-common lysosomal storage diseases.     

Risky behavior in teens with cystic fibrosis or sickle cell disease: a multicenter study

OBJECTIVE: To determine the prevalence and age of onset of common risky behaviors such as smoking and sexual activity in teens with cystic fibrosis and those with sickle cell disease and to compare their behaviors with those of adolescents in the general population. DESIGN: Survey. SETTING: All five major pediatric tertiary care centers in North Carolina (study participants with sickle cell disease or cystic fibrosis) and North Carolina public schools (comparison population). PARTICIPANTS: Three hundred twenty-one adolescents with cystic fibrosis or sickle cell disease aged 12 to 19 years (mean age, 15.6 years; 49% female). Demographically matched comparison teens for each group were selected from 2760 in-school adolescents (mean age, 16.0 years; 51% female). MAIN OUTCOMES MEASURES: Prevalence of tobacco and marijuana use, alcohol use, sexual intercourse, sexually transmitted diseases, seat belt use, weapon carrying, and age of onset of these behaviors. RESULTS: Chronically ill teens reported significantly less lifetime and current use of tobacco, marijuana, and alcohol; less sexual intercourse; less weapon carrying, less drunk driving, and more seat belt use than their peers. Nonetheless, 21% of the teens with cystic fibrosis and 30% of those with sickle cell disease had smoked; sexual intercourse was reported by 28% and 51%, respectively. Age of onset of these behaviors was frequently older for the chronically ill teens. CONCLUSION: Teens with cystic fibrosis or sickle cell disease took more potentially damaging health risks than might be expected, although the prevalence was lower than reported by their peers. Future longitudinal studies should examine the relationships between chronic illness, physical and psychosocial maturation, and risky behavior. Screening for psychosocial issues, including risky behaviors, should be incorporated into the routine health care of chronically ill teens.     

What’s new in surfactant?

Surfactant therapy has significantly changed clinical practice in neonatology over the last 25 years. Recent trials in infants with respiratory distress syndrome (RDS) have not shown superiority of any natural surfactant over another. Advancements in the development of synthetic surfactants are promising, yet to date none has been shown to be superior to natural preparations. Ideally, surfactant would be administered without requiring mechanical ventilation. An increasing number of studies investigate the roles of alternative modes of administration and the use of nasal continuous positive airway pressure to minimise the need for mechanical ventilation. Whether children with other lung diseases benefit from surfactant therapy is less clear. Evidence suggests that infants with meconium aspiration syndrome and children with acute lung injury/acute respiratory distress syndrome may benefit, while no positive effect of surfactant is seen in infants with congenital diaphragmatic hernia. However, more research is needed to establish potential beneficial effects of surfactant administration in children with lung diseases other than RDS. Furthermore, genetic disorders of surfactant metabolism have recently been linked to respiratory diseases of formerly unknown origin. It is important to consider these disorders in the differential diagnosis of unexplained respiratory distress although no established treatment is yet available besides lung transplantation for the most severe cases. Conclusion: Research around surfactant is evolving and recent developments include further evolution of synthetic surfactants, evaluation of surfactant as a therapeutic option in lung diseases other than RDS and the discovery of genetic disorders of surfactant metabolism. Ongoing research is essential to continue to improve therapeutic prospects for children with serious respiratory disease involving disturbances in surfactant. Funding: Jasper Been is supported by a Profileringsfonds grant from the Maastricht University Hospital.     

Managing paediatric musculoskeletal diseases with biological agents

The introduction of biological agents (BA) has markedly improved the outcome for children with musculoskeletal (MSK) diseases over the past two decades. Several BA have been developed, which alone or in combination with other immunomodulators, such as disease-modifying anti-rheumatic drugs (DMARD), have resulted in disease remission as an achievable target. Their use has also led to the reduction of reliance of steroid treatment and its undesirable side effects. The widest range of BA has been used for managing juvenile idiopathic arthritis (JIA), which is the most common rheumatic disease in childhood. However, they have also been successfully used in refractory cases of juvenile systemic lupus erythematosus (JSLE), juvenile dermatomyositis (JDM) and autoinflammatory syndromes. The efficacy of BA has been demonstrated in several clinical trials. It is important to highlight that BA biologics are costly and also have the potential for toxicity. They have been associated with adverse events such as serious infections, malignancy, hepatotoxicity, and demyelination. This article summarizes the clinical experience of the available BA, discusses the known risks and side effects and aims to offer the reader a general overview of their use in the management of paediatric musculoskeletal disease.     

Vacunas multivalentes frente a enfermedad meningocócica: ¿dentro o fuera de nuestras agendas?

The development of tetravalent vaccines against Invasive Meningococcal Disease (IMD) has been driven mainly due to the increase of the prevalence and geographic expansion of several serogroups considered unusual, but also because of the need for vaccines that offer broad spectrum protection in a devastating disease such as IMD. These changes in serogroups considered usual (B and C) have been detected for both serogroup Y and W, which has led to the multivalent vaccines being used by a number of countries with different strategies that will be discussed in the article. Epidemiological data in Spain, currently do not justify its use in immunization schedules, but there is a potential risk for the introduction of virulent clones of those uncommon serogroups (Y and W), and this would lead us to open a discussion of their potential use, particularly in the adolescent/pre-teen population as a target group for intervention.     

Stem cells as a therapeutic avenue for active and long-term complications of Necrotizing Enterocolitis

Necrotizing enterocolitis (NEC) is a devastating neonatal intestinal disease associated with significant morbidity and mortality. Although decades of research have been dedicated to understanding the pathogenesis of NEC and developing therapies, it remains the leading cause of death among neonatal gastrointestinal diseases. Mesenchymal stem cells (MSCs) have garnered significant interest recently as potential therapeutic agents for the treatment of NEC. They have been shown to rescue intestinal injury and reduce the incidence and severity of NEC in various preclinical animal studies. MSCs and MSC-derived organoids and tissue engineered small intestine (TESI) have shown potential for the treatment of long-term sequela of NEC such as short bowel syndrome, neurodevelopmental delay, and chronic lung disease. Although the advances made in the use of MSCs are promising, further research is needed prior to the widespread use of these cells for the treatment of NEC.     

Therapeutic potentials of bovine colostrums

Colostrum is the first milk produced by mammals for their young ones. This transfers the passive immunity gained by the mother to the baby. The bovine colostrum (BC) can be obtained in large quantity and has properties similar to human colostrum. It has been used for various disorders of the body. It has properties to stimulate immune system, contains growth factors and many bioactive substances needed for the body to combat with wear and tear. The BC has been used for various gastrointestinal disorders, respiratory tract infection, rheumatoid arthritis, healing injured tissues of body etc. There are not much double blind placebo-controlled trials to prove its efficacy, though a lot of experience about its good effects in various disorders is available in the literature. The dosage and duration of therapy need to be worked up. The BC has potential to treat as well to prevent certain diseases in the body. In future this will prove to be a very useful product to treat and control diseases in a natural way.     

Murine Mucopolysaccharidosis VII: Impact of Therapies on the Phenotype, Clinical Course, and Pathology in a Model of a Lysosomal Storage Disease

The mucopolysaccharidoses are a group of lysosomal storage diseases caused by deficiency of an enzyme required for the normal degradation of glycosaminoglycans. Patients with mucopolysaccharidosis typically have widespread lysosomal storage, skeletal and central nervous system disease, and hepatosplenomegaly. Some patients with mucopolysaccharidosis may benefit from enzyme replacement therapy or bone marrow transplantation. Animal models of mucopolysaccharidosis have proven valuable for the evaluation of the effectiveness of potential treatments for patients with lysosomal storage disease. A murine model of MPS VII (Sly syndrome) has proven particularly useful because of its well-defined genetics and its well-characterized clinical, pathologic, and biochemical alterations, which resemble those seen in patients with mucopolysaccharidosis. Correction of these alterations forms the basis for evaluation of the effectiveness of novel treatments. A wide range of therapies have been tested using this model, including enzyme replacement therapy, bone marrow, stem cell, and neural progenitor cell transplantation, and a variety of viral-mediated gene therapies. The inferences drawn from these therapeutic studies using the murine MPS VII model are likely generalizable to other lysosomal storage diseases. Received March 10, 2001; accepted April 5, 2001.     

Adjunct pharmacotherapy in acute lung disease in children

Mechanical ventilation, while accepted as standard therapy for critically ill infants and children with respiratory failure, has significant morbidity and mortality. While recent emphasis on low tidal volume ventilation and low airway pressures may result in decreased lung stretch and limit lung disease, adjunctive therapies have been tried to reduce the stressors of mechanical ventilation. Therapies included inhaled nitric oxide, heliox and surfactant. There are compelling physiological reasons why these drugs may be of benefit in these patients. However, our understanding of their role is hindered by studies with small numbers of patients and its use in diseases with varied pulmonary pathology. Studies have shown potential for benefit of inhaled nitric oxide in newborns with hypoxemic respiratory failure and pulmonary hypertension, surfactant in respiratory distress syndrome in preterm neonates and heliox in severe upper airway obstruction. However, the use in other respiratory conditions has led to mixed results and hence paucity of firm recommendations.     

Biomarkers in lysosomal storage diseases: a review

A biomarker is generally an analyte that indicates the presence or extent of a biological process, which is itself directly linked to the clinical manifestations and outcome of a particular disease. An ideal biomarker provides indirect but ongoing and specific determinations of disease activity. These characteristics emphasize the value of surrogate biomarkers for non-invasive and detailed monitoring to demonstrate the efficacy of orphan drugs in clinical trials. The emergence of novel laboratory methods has facilitated the search for biomarkers in lysosomal storage diseases (LSDs), by allowing the systematic identification of molecules whose expression is altered as a result of the primary storage pathology. In Gaucher disease, for example, a chemokine, CCL18, has been identified as a biomarker for clinical development that reflects disease severity and response to treatment.
Conclusion: New methods for the identification of novel biomarkers have the potential to provide mechanistic insights into the molecular pathogenesis of LSDs, including Fabry disease and Gaucher disease.     

Biomarkers in lysosomal storage diseases: a review

A biomarker is generally an analyte that indicates the presence or extent of a biological process, which is itself directly linked to the clinical manifestations and outcome of a particular disease. An ideal biomarker provides indirect but ongoing and specific determinations of disease activity. These characteristics emphasize the value of surrogate biomarkers for non-invasive and detailed monitoring to demonstrate the efficacy of orphan drugs in clinical trials. The emergence of novel laboratory methods has facilitated the search for biomarkers in lysosomal storage diseases (LSDs), by allowing the systematic identification of molecules whose expression is altered as a result of the primary storage pathology. In Gaucher disease, for example, a chemokine, CCL18, has been identified as a biomarker for clinical development that reflects disease severity and response to treatment. Conclusion: New methods for the identification of novel biomarkers have the potential to provide mechanistic insights into the molecular pathogenesis of LSDs, including Fabry disease and Gaucher disease.     

Aggressive fibromatosis in children: a changing approach

Desmoid tumor, also known as aggressive fibromatosis (AF), is a rare monoclonal, fibroblastic proliferation arising in musculoaponeurotic structures. AF is a tumor of intermediate malignancy, with a strong potential for local invasiveness and recurrence. The treatment of choice for these tumors has been changing all the time and may involve surgery, radiotherapy and/or systemic approaches. Surgery generally used to be considered the mainstay of treatment for AF, its goal preferably being a microscopically complete resection with histologically free margins. Mutilating surgery or procedures causing significant loss of function and/or chronic symptoms should be avoided. Involvement of surgical margins is probably associated with an increased risk of local recurrence. Postoperative radiotherapy could be used in cases with positive margins after surgery, or to avoid mutilating surgery in cases of inoperable or inaccessible disease. Postoperative radiotherapy has been reported to raise local disease control to a level similar to that of complete resection, but is associated with a relatively high rate of complications. Systemic treatment may be indicated in case of locally-advanced disease. Several risk factors for local recurrence have been investigated and include: young age, large size, presentation as recurrence, girdles or intra-abdominal location, involved surgical margins, and β-catenin-activating mutations. Recently collected data prompted the suggestion that these tumors warrant a wait-and-see strategy (clinical-radiological observation, without any treatment), since their natural history is often characterized by lengthy periods of stability or even regression, considering to treat only patients with progressing or symptomatic disease.     

Management of infectious agents of bioterrorism

Biological weapons are weapons of mass destruction derived from bacteria, viruses, fungi, or plants. While biological weapons have been in use for centuries during military conflict, their release on a civilian population as a tool of terrorism (bioterrorism) is a relatively new phenomenon. In recent decades, several events involving biological weapons (eg, the anthrax episode of 2001 and mounting concerns about the intentional reappearance of smallpox) have provided strong evidence that the covert release of a biological weapon could occur in the near future. Without prompt recognition of a bioweapons release, disease can spread rapidly among unsuspecting children and adults. There is therefore a compelling need for clinicians to acquaint themselves with biological weapons and the diseases they produce in order to identify sentinel cases. This review provides an overview of the biological weapons, their manifestations, and the pediatric emergency physician’s role in recognition and management (including protection of self and other health care workers).     

Fluticasone propionate in the treatment of airway inflammations (asthma and rhinitis)

Inflammation is the pathogenetic basis of many airway diseases like asthma and rhinitis. This provides the rationale for a therapy with antiinflammatory drugs like inhaled corticosteroids (ICS), which are able to suppress the underlying pathologic processes, ensuring an effective control of the disease and improving patients's quality of life. Within ICS, fluticasone is endowed of a potent antiinflammatory activity, due to its high affinity for the the glucocorticoid receptor (allowing the use of 50% of the dose of other ICS) and of a negligible oral bioavailability (<1%), indicating a low potential for systemic exposure. Due to its high therapeutical index, fluticasone can be used in the management of severe asthma or other airway diseases at doses devoid of relevant unwanted systemic effects. Scientific literature has broadly demonstrated its efficacy and safety, even at high doses and in the long term use.     

Cyclosporine treatment of fulminant colitis

Improved treatment of individuals with severe inflammatory bowel disease with potent immunosuppressive medications such as 6-mercaptopurine has been previously demonstrated. Unfortunately, the use of this medication in individuals with fulminant disease is often limited by its very slow onset of action. This has suggested a potential role for alternative immunosuppressive agents in selected patients with inflammatory bowel disease. We now describe the course of two adolescents with fulminant colitis who were being considered for colectomy and who were treated with oral cyclosporine. Each appeared to have a prompt response to this medication, and both entered into a complete clinical remission. A mild increase in serum creatinine and hirsutism were the only side effects noted. These observations suggest the need for controlled trials to define the potential role and long-term toxicity of cyclosporine in individuals with severe inflammatory bowel disease.     

Discriminant analysis for the diagnosis of childhood celiac disease

A new statistical approach to the analysis of laboratory data has been introduced to optimize the use of absorption tests and gliadin antibody measurement for the diagnosis of childhood celiac disease. Serum antigliadin antibodies, as well as blood xylose, iron, and tryglycerides after oral load, were evaluated in 40 celiac children and 43 age-matched patients affected by other gastrointestinal diseases. Each test evaluated individually gave a considerable rate of false-positive and false-negative results. Discriminant coefficients produced for each test were used to compute a score that allowed correct classification of 99% of patients; 2.3% of false-positive and no false-negative results were recorded. This approach improves significantly the overall sensitivity and specificity for celiac disease of these laboratory tests and we propose its use for screening patients to be submitted to jejunal biopsy.     

儿童糖皮质激素性骨质疏松的发病机制及诊治

目前,儿童骨质疏松症已成为影响儿童骨骼健康的重要疾病,包括原发性骨质疏松症及继发性骨质疏松症,其中糖皮质激素性骨质疏松症是儿童最常见的继发性骨质疏松症.糖皮质激素被临床广泛用于治疗各种炎性疾病和自身免疫功能紊乱性疾病,如肾病综合征、系统性红斑狼疮等.虽然糖皮质激素具有强大的抗炎、抗过敏及免疫抑制作用,但长期应用会引起多种并发症,如骨质疏松.该综述主要讨论糖皮质激素性骨质疏松症的发病机制及诊治策略,以期为临床儿科医生提供更为广泛的理论依据,并做出合理的评估和临床指导.