Morphological alterations of exogenous surfactant inhibited by meconium can be prevented by dextran

BACKGROUND: Surfactant dysfunction due to inhibition is involved in the pathophysiology of meconium aspiration syndrome. Dextran addition has been shown to reverse exogenous surfactant inactivation by meconium, but the precise mechanisms and the morphological correlate of this effect are yet unknown. Morphological surfactant analysis by transmission electron microscopy (TEM) and stereology allows the differentiation of active (large aggregates = LA) and inactive (small aggregates = SA) subtypes. METHODS: To determine the in vitro effects of meconium and dextran addition on the morphology of a modified porcine natural surfactant (Curosurf), Curosurf samples were either incubated alone or together with meconium or with meconium and dextran, fixed and processed for TEM. Volume fractions of surfactant subtypes [lamellar body-like forms (LBL), multilamellar vesicles (MV), unilamellar vesicles (UV)] were determined stereologically. RESULTS: All preparations contained LBL and MV (corresponding to LA) as well as UV (corresponding to SA). The volume fraction of UV increased with addition of meconium and decreased with further addition of dextran. Correspondingly, the UV/(LBL+MV) ratio (resembling the SA/LA ratio) increased when meconium was added and decreased when dextran was added to the surfactant-meconium mixture. CONCLUSION: Meconium causes alterations in the ultrastructural composition of Curosurf that can be visualized and analyzed by TEM and stereology. These alterations resemble an increase in the SA/LA ratio and are paralleled by an increase in minimum surface tension. Dextran prevents these effects and may therefore be a useful additive to exogenous surfactant preparations to preserve their structural and functional integrity, thereby improving their resistance to inactivation.

Examining the gateway to the limbic system with diffusion tensor imaging: the perforant pathway in dementia

Current treatments for Alzheimer's disease (AD) are only able to slow the progression of mental deterioration, making early and reliable diagnosis an essential part of any promising therapeutic strategy. In the initial stages of AD, the first neuropathological alterations occur in the perforant pathway (PP), a large neuronal fiber tract located at the entrance to the limbic system. However, to date, there is no sensitive diagnostic tool for performing in vivo assessments of this structure. In the present bimodal magnetic resonance imaging (MRI) study, we examined 10 elderly controls, 10 subjects suffering from mild cognitive impairment (MCI), and 10 AD patients in order to evaluate the sensitivity of diffusion tensor imaging (DTI), a new MRI technique, for detecting changes in the PP. Furthermore, the diagnostic explanatory power of DTI data of the PP should be compared to high-resolution MRI volumetry and intervoxel coherences (COH) of the hippocampus and the entorhinal cortex, two limbic regions also involved in the pathophysiology of early AD. DTI revealed a marked decrease in COH values in the PP region of MCI (right side: 26%, left side: 29%, as compared to controls) and AD patients (right side: 37%, left side: 43%, as compared to controls). Reductions in COH values of the PP region were significantly correlated with cognitive impairment. DTI data of the PP zone were the only parameter differing significantly between control subjects and MCI patients, while the volumetric measures and the COH values of the hippocampus and the entorhinal cortex did not. DTI of medial temporal brain regions is a promising non-invasive tool for the in vivo diagnosis of the early/preclinical stages of AD.

Coronary artery disease, nitric oxide and oxidative stress: the "Yin-Yang" effect--a Chinese concept for a worldwide pandemic

Prevention of coronary artery disease (CAD) and reduction of its mortality and morbidity remains a major public health challenge throughout the "Western world". Recent evidence supports the concept that the impairment of endothelial function, a hallmark of insulin resistance states, is an upstream event in the pathophysiology of insulin resistance and its main corollaries: atherosclerosis and myocardial infarction. Atherosclerosis is currently thought to be the consequence of a subtle imbalance between pro- and anti-oxidants that produces favourable conditions for lesion progression towards acute thrombotic complications and clinical events. Over the last decade, a remarkable burst of evidence has accumulated, offering the new perspective that bioavailable nitric oxide (NO) plays a pivotal role throughout the CAD-spectrum, from its genesis to the outcome after acute events. Vascular NO is a critical modulator of coronary blood flow by inhibiting smooth muscle contraction and platelet aggregation. It also acts in angiogenesis and cytoprotection. Defective endothelial nitric oxide synthase (eNOS) driven NO synthesis causes development of major cardiovascular risk factors (insulin resistance, arterial hypertension and dyslipidaemia) in mice, and characterises CAD-prone insulin-resistant humans. On the other hand, stimulation of inducible nitric oxide synthase (iNOS) and NO overproduction causes metabolic insulin resistance and characterises atherosclerosis, heart failure and cardiogenic shock in humans, suggesting a "Yin-Yang" effect of NO in the cardiovascular homeostasis. Here, we will present a concise overview of the evidence for this novel concept, providing the conceptual framework for developing a potential therapeutic strategy to prevent and treat CAD.

Central hypersensitivity in chronic pain: mechanisms and clinical implications

The available literature consistently shows increased pain sensitivity after sensory stimulation of healthy tissues in patients who have various chronic pain conditions. This indicates a state of hypersensitivity of the CNS that amplifies the nociceptive input arising from damaged tissues. Experimental data indicate that central hypersensitivity is probably induced primarily by nociceptive input arising from a diseased tissue. In patients, imbalance of descending modulatory systems connected with psychologic distress may play a role. There is experimental support in animal studies for the persistence of central hypersensitivity after complete resolution of tissue damage. This is particularly true for neuropathic pain conditions, whereby potentially irreversible plasticity changes of the CNS have been documented in animal studies. Whether such changes are present in musculoskeletal pain states is at present uncertain. Despite the likely importance of central hypersensitivity in the pathophysiology of chronic pain, this mechanism should not be used to justify the lack of understanding on the anatomic origin of the pain complaints in several pain syndromes, which is mostly due to limitations of the available diagnostic tools. Treatment strategies for central hypersensitivity in patients have been investigated mostly in neuropathic pain states. Possible therapy modalities for central hypersensitivity in chronic pain of musculoskeletal origin are largely unexplored. The limited evidence available and everyday practice show, at best, modest efficacy of the available treatment modalities for central hypersensitivity. The gap between basic knowledge and clinical benefits remains large and should stimulate further intensive research.

Strategies to prevent neuronal damage in paediatric bacterial meningitis

PURPOSE OF REVIEW: The mortality of bacterial meningitis can reach 30%, and up to 50% of survivors suffer from persisting neurological deficits as a consequence of the disease. The incidence of neurological sequelae of bacterial meningitis has not improved over the last decade. Adjunctive therapeutic options are limited, and ongoing research into the pathophysiology of brain damage in bacterial meningitis aims at providing the scientific basis for future development of more efficient adjunctive options. RECENT FINDINGS: In a population with good access to health care, dexamethasone given before or at the time of initiation of antibiotic therapy acts beneficially in paediatric pneumococcal meningitis, but not in meningococcal meningitis. In experimental animal models, brain-derived neurotrophic factor protected against brain injury and improved hearing while melatonin, which has antioxidant properties among other effects, reduced neuronal death. Transgene technology can be used to provide new insights into the pathophysiology of the disease and to identify potential therapeutic targets. SUMMARY: Although dexamethasone improves outcome of bacterial meningitis under defined circumstances, the morbidity of bacterial meningitis still remains unacceptably high. Experimental models may help to identify new therapeutic strategies to further improve the neurological outcome in young children suffering from bacterial meningitis.

The deadly broomstick: an unusual missile injury to the neck

A 51-year-old man was struck by the tip of a broomstick weighing 1000 g at the left side of the neck, upon which he collapsed. Intense but delayed cardiopulmonary resuscitation restored the circulation roughly 30 minutes after the incident. Upon admittance to a nearby hospital, an extensive hypoxic cerebral damage was diagnosed. Death due to the severe cerebral damage occurred 5 hours after the incident. An autopsy demonstrated a severe subcutaneous traumatization of the left side of the neck, with a hemorrhage compressing the carotid bifurcation. A prolonged excitation due to this ongoing compression of the baroreceptors in the carotid sinus was assumed to have led to a cardiac arrest. In this case report, the authors discuss the underlying pathophysiology of this potentially lethal and rare reflexogenic incident also known as the Hering reflex and discuss possible therapeutic measures.

Hematopoietic and endothelial progenitor cell trafficking in patients with myeloproliferative diseases

BACKGROUND AND OBJECTIVES. The presence of circulating hematopoietic progenitor cells in patients with myeloproliferative diseases (MPD) has been described. However, the exact nature of such progenitor cells has not been specified until now. The aim of this work was to investigate the presence of endothelial precursor cells in the blood of patients with MPD and to assess the role of the endothelial cell lineage in the pathophysiology of this disease. DESIGN AND METHODS. Endothelial progenitor cell marker expression (CD34, prominin (CD133), kinase insert domain receptor (KDR) or vascular endothelial growth factor receptor 2 (VEGFR2), and von Willebrand factor) was assessed in the blood of 53 patients with MPD by quantitative polymerase chain reaction. Clonogenic stem cell assays were performed with progenitor cells and monocytes to assess differentiation towards the endothelial cell lineage. The patients' were divided according to whether they had essential thrombocythemia (ET, n=17), polycythemia vera (PV, n=21) or chronic idiopathic myelofibrosis (CIMF, n=15) and their data compared with data from normal controls (n=16) and patients with secondary thrombo- or erythrocytosis (n=17). RESULTS. Trafficking of CD34-positive cells was increased above the physiological level in 4/17 patients with ET, 5/21 patients with PV and 13/15 patients with CIMF. A subset of patients with CIMF co-expressed the markers CD34, prominin (CD133) and KDR, suggesting the presence of endothelial precursors among the circulating progenitor cells. Clonogenic stem cell assays confirmed differentiation towards both the hematopoietic and the endothelial cell lineage in 5/10 patients with CIMF. Furthermore, the molecular markers trisomy 8 and JAK2 V617F were found in the grown endothelial cells of patients positive for trisomy 8 or JAK2 V617F in the peripheral blood, confirming the common clonal origin of both hematopoietic and endothelial cell lineages. INTERPRETATION AND CONCLUSIONS. Endothelial precursor cells are increased in the blood of a subset of patients with CIMF, and peripheral endothelial cells bear the same molecular markers as hematopoietic cells, suggesting a primary role of pathological endothelial cells in this disease.

[Sun-tanned and still not healthy!]

We describe a case of a 10 years old girl, which presented to the emergency room with non-specific gastro-intestinal symptoms, fatigue and low blood pressure. The clinical signs and laboratory value supported the diagnosis of Addison crisis with hypovolaemic shock. The pathophysiology and the therapy of this entity are discussed. Importantly, in children the aetiology may differ depending on age and sex. Based on the family history of autoimmune disorders, in our patient presenting with autoimmune adrenalitis and celiac disease, the diagnosis of an autoimmune polyendocrinopathy was made. A therapy of mineralcorticoids and glucocorticoids was initiated and a special gluten-free diet was prescribed. On this treatment our patient recovered promptly.

Is the metabolic syndrome a new childhood disease?

Overweight and obesity in children and adolescents have become a major public health problem in recent years throughout the world. The medical consequences of obesity may manifest as an increase in the prevalence of the metabolic syndrome in children and adolescents putting them at increased risk for future cardiovascular diseases. Obesity can cause insulin resistance and might disturb glucose homeostasis eventually leading to type 2 diabetes in susceptible patients. Insulin resistance is also involved in the pathogenesis of dyslipidemia in obese children characteristically presenting as hypertriglyceridemia and low HDL cholesterol. Even elevated blood pressure might be present in obese kids. Here we present a 12-year-old boy diagnosed with the metabolic syndrome. The diagnostic criteria of the metabolic syndrome in children and adolescents are discussed. Thoughts about pathophysiology and therapeutic options are offered.

Snake C-type lectin-like proteins and platelet receptors

Snake venoms are complex mixtures of biologically active proteins and peptides. Many affect haemostasis by activating or inhibiting coagulant factors or platelets, or by disrupting endothelium. Snake venom components are classified into various families, such as serine proteases, metalloproteinases, C-type lectin-like proteins, disintegrins and phospholipases. Snake venom C-type lectin-like proteins have a typical fold resembling that in classic C-type lectins such as the selectins and mannose-binding proteins. Many snake venom C-type lectin-like proteins have now been characterized, as heterodimeric structures with alpha and beta subunits that often form large molecules by multimerization. They activate platelets by binding to VWF or specific receptors such as GPIb, alpha2beta1 and GPVI. Simple heterodimeric GPIb-binding molecules mainly inhibit platelet functions, whereas multimeric ones activate platelets. A series of tetrameric snake venom C-type lectin-like proteins activates platelets by binding to GPVI while another series affects platelet function via integrin alpha2beta1. Some act by inducing VWF to bind to GPIb. Many structures of these proteins, often complexed with their ligands, have been determined. Structure-activity studies show that these proteins are quite complex despite similar backbone folding. Snake C-type lectin-like proteins often interact with more than one platelet receptor and have complex mechanisms of action.

The 2002 European registry of cardiac catheter interventions

OBJECTIVE: The tradition of yearly reports on cardiac catheter interventions in Europe has been initiated in 1992. This 11th report presents aggregated data on cardiac catheter procedures in 30 European countries in the year 2002. DESIGN AND SETTING: A detailed questionnaire addressing summary data of all cardiac interventions was mailed to presidents or delegates of the national societies of cardiology in Europe. The questionnaire was distributed to all institutions with cardiac catheterisation programs. All questionnaires were compiled in a national summary data sheet, then entered into a central database and subsequently analysed. MAIN OUTCOME MEASURES: Coronary angiography, PTCA, and stenting in absolute numbers and per million inhabitants in the participating countries and the whole of Europe. RESULTS: Overall, 1,901,932 coronary angiograms were reported. The population-adjusted rate of coronary angiograms amounted to an absolute mean of 3358 per 10(6) inhabitants, an increase of 7% compared with 2001. A total of 686,869 PTCA procedures were reported. The mean European number of PTCAs per 10(6) inhabitants increased by 10% from 1103 in 2001 to 1213 in 2002. Procedures with stenting increased by 17% from 508,999 to 593,906. The stenting rate was 86% compared with 82% in 2001. CONCLUSIONS: In pace with epidemiological demand and the need to catch-up from underuse in certain countries, a continuous and considerable growth of coronary interventions can be observed. It will take years to find out whether the announced change of paradigm in the treatment of multivessel disease in the wake of drug-eluting stents will come true.

European Working Group on Clinical Cell Analysis: Consensus protocol for the flow cytometric characterisation of platelet function

An increased or disturbed activation and aggregation of platelets plays a major role in the pathophysiology of thrombosis and haemostasis and is related to cardiovascular disease processes. In addition to qualitative disturbances of platelet function, changes in thrombopoiesis or an increased elimination of platelets, (e. g., in autoimmune thrombocytopenia), are also of major clinical relevance. Flow cytometry is increasingly used for the specific characterisation of phenotypic alterations of platelets which are related to cellular activation, haemostatic function and to maturation of precursor cells. These new techniques also allow the study of the in vitro response of platelets to stimuli and the modification thereof under platelet-targeted therapy as well as the characterisation of platelet-specific antibodies. In this protocol, specific flow cytometric techniques for platelet analysis are recommended based on a description of the current state of flow cytometric methodology. These recommendations are an attempt to promote the use of these new techniques which are at present broadly evaluated for diagnostic purposes. Furthermore, the definition of the still open questions primarily related to the technical details of the method should help to promote the multi-center evaluation of procedures with the goal to finally develop standardized operation procedures as the basis of interlaboratory reproducibility when applied to diagnostic testing.

Patent foramen ovale closure: a new therapy for migraine

Migraine is a recurrent disabling disorder predominantly affecting middle-aged women. Migraine occurs with or without aura symptoms. Several studies have shown an increased prevalence of right-to-left shunts (RLSs) in migraine with aura. The overwhelming majority of these shunts were due to a patent foramen ovale (PFO). Furthermore, migraine with aura is more prevalent in clinical entities associated with a RLS, e.g. cryptogenic stroke, decompression illness in divers, or in patients with hereditary hemorrhagic teleangiectasia and pulmonary arteriovenous fistulas. Retrospective studies have consistently shown that shunt closure was associated with a significant reduction in migraine frequency. Its beneficial effect seemed to exceed the efficacy of conventional migraine therapy. Several randomized clinical trials to prospectively assess the benefit of shunt closure in migraine patients have been initiated. The only one completed, the MIST trial (Migraine Intervention with STARFLEX Technology), showed a significant reduction of migraine with aura after device implantation, compared with controls. However, the benefit of PFO closure was more modest than expected. This review recapitulates the current data regarding PFO closure and migraine with aura and summarizes in brief the current knowledge regarding migraine pathophysiology and the link to a RLS.

Isolated mediotegmental lesion causing narcolepsy and rapid eye movement sleep behaviour disorder: a case evidencing a common pathway in narcolepsy and rapid eye movement sleep behaviour disorder

Narcolepsy is usually an idiopathic disorder, often with a genetic predisposition. Symptomatic cases have been described repeatedly, often as a consequence of hypothalamic lesions. Conversely, REM (rapid eye movement) sleep behaviour disorder (RBD) is usually a secondary disorder, often due to degenerative brain stem disorders or narcolepsy. The case of a hitherto healthy man is presented, who simultaneously developed narcolepsy and RBD as the result of an acute focal inflammatory lesion in the dorsomedial pontine tegmentum in the presence of normal cerebrospinal fluid hypocretin-1 levels and in the absence of human lymphocyte antigen haplotypes typically associated with narcolepsy and RBD (DQB1*0602, DQB1*05). This first observation of symptomatic narcolepsy with RBD underlines the importance of the mediotegmental pontine area in the pathophysiology of both disorders, even in the absence of a detectable hypocretin deficiency and a genetic predisposition.

Reduced hippocampal anisotropy related to anteriorization of alpha EEG in schizophrenia

Dysfunctions of the hippocampus have been suggested to be related to schizophrenia, and reduced connectivity with other brain regions may be a key for the pathophysiology. The aim of this study was to investigate the effect of white matter anomalies in the hippocampus, as a sign of altered connectivity, on the brain electrical activity. We investigated seven first episode schizophrenic patients and seven age, gender and education-matched controls with diffusion tensor imaging and resting EEG. Fractional anisotropy was computed based on diffusion tensor imaging data for the right and left hippocampus for both groups. No group differences were found in hippocampal fractional anisotropy, EEG spectral power and topography. However a significant correlation was found between more anterior alpha activity and lower fractional anisotropy of both hippocampi in schizophrenics, but not in controls. More anterior alpha activity has been described in schizophrenia. We conclude that this feature might depict a group of schizophrenic patients with reduced hippocampal connectivity.