Hemodynamic Effects of Noninvasive Ventilation in Patients with Venocapillary Pulmonary Hypertension

Background: The hemodynamic effects of noninvasive ventilation with positive pressure in patients with pulmonary hypertension without left ventricular dysfunction are not clearly established. Objectives: Analyze the impact of increasing airway pressure with continuous positive airway pressure on hemodynamic parameters and, in particular, on cardiac output in patients with variable degrees of pulmonary hypertension. Methods: The study included 38 patients with pulmonary hypertension caused by mitral stenosis without left ventricular dysfunction or other significant valvulopathy. The hemodynamic state of these patients was analyzed in three conditions: baseline, after continuous positive pressure of 7 cmH2O and, finally, after pressure of 14 cmH2O. Results: The population was composed of predominantly young and female individuals with significant elevation in pulmonary arterial pressure (mean systolic pressure of 57 mmHg). Of all variables analyzed, only the right atrial pressure changed across the analyzed moments (from the baseline condition to the pressure of 14 cmH2O there was a change from 8 ± 4 mmHg to 11 ± 3 mmHg, respectively, p = 0.031). Even though there was no variation in mean cardiac output, increased values in pulmonary artery pressure were associated with increased cardiac output. There was no harmful effect or other clinical instability associated with use application of airway pressure. Conclusion: In patients with venocapillary pulmonary hypertension without left ventricular dysfunction, cardiac output response was directly associated with the degree of pulmonary hypertension. The application of noninvasive ventilation did not cause complications directly related to the ventilation systems.

Anatomy and histology of Embolyntha batesi MacLahlan, 1877 (Embiidina)

The Embioptera are rather generalized insects whose internal anatomy is simple and not subject to great modifications. For this reason these insects form an ideal group for elementary anatomical and histological studies (fig. 2). The digestive tract is a long, simple tube without convolutions or diverticulae from the buccal cavity to the rectum. The buccal structures are of the chewing type. The oesophagus and ingluvia are differentiated only by slight dilation of their walls. In nymphs and females the proventriculus is very distinct due to folds which flatten as the structure becomes packed with food. The enteron is the largest in such forms and in both sexes limited caudally by the Malpighian tubules. The proctodeus has six large rectal papillae. The nervous system is complete with only the fifth abdominal segment lacking a ganglion in the metathorax includes the ganglion of the first abdominal segment. The brain exhibits very clear structure in histological sections. The tracheal system includes two pairs of thoracic spiracles and eight abdominal pairs. Only th metathoracic spiracle has an air expiration function; all others serve for inspiration. Various structures in the spiracles protect the atrium. The circulatory system includes a long, simple dorsal vessel which extends forward from the ninth abdominal segment into the cranium. It opens anteriorly near the circumoesophageal connectives. The dorsal vessel has a pair of ostia and valves corresponding to each abdominal and thoracic segment. It lacks the diverticulae or folds commonly found in more highly evolved insects. The excretory system is represented by Malphighian tubules, pericardial cells, and fat-body. The number and disposition of Malpighian tubules is variable within the order. The pericardial cells are localized around the entire dorsal vessel up to the opening of the aorta in the head. The fat-bodies form compact layers in the dorsal and ventral regions of the body. In males they are more developed in the abdominal region. The mandibles, maxillae, and salivary glands are of a simple type with very few cytological modifications. Only the salivary glands which extend into the mesothoracic region show appreciable specialization. The reproductive system is bi-sixual and shows considerable sexual dimorphism. Males have five pair of testes with a metameric disposition, two distinct ducts, two epidymis, and the ejaculatory organs. The accessory glands vary in number and size and open in the anterior portion of the ejaculatory duct. The female reproductive organs are of the panoistic type. The system includes five pairs of ovarioles, two long paired oviducts a small, unpaired oviduct and the spermatheca which opens in the vagina. Reproduction usually involves a union of male and female gametes, and eggs are usually laid in clusters attached to a substrate.

Pulmonary biology of anti-interleukin 5 antibodies

Interleukin 5 (IL-5) is a critical cytokine for the maturation of eosinophil precursors to eosinophils in the bone marrow and those eosinophils then accumulate in the lungs during asthma. We have studied anti IL-5 antibodies on allergic responses in mice, guinea pigs and monkeys and are extending this experiment into humans with a humanized antibody. In a monkey model of pulmonary inflammation and airway hyperreactivity, we found that the TRFK-5 antibody blocked both responses for three months following a single dose of 0.3 mg/kg, i.v. This antibody also blocked lung eosinophilia in mice by inhibiting release from the bone marrow. To facilitate multiple dosing and to reduce immunogenicity in humans, we prepared Sch 55700, a humanized antibody against IL-5. Sch 55700 was also active against lung eosinophilia in allergic monkeys and mice and against pulmonary eosinophilia and airway hyperresponsiveness in guinea pigs. Furthermore, as opposed to steroids, Sch 55700 did not cause immunosuppression in guinea pigs. Studies with this antibody in humans will be critical to establishing the therapeutic potential of IL-5 inhibition.

IL-5 and IL-5 receptor in asthma

Eosinophils, along with mast cells are key cells involved in the innate immune response against parasitic infection whereas the adaptive immune response is largely dependent on lymphocytes. In chronic parasitic disease and in chronic allergic disease, IL-5 is predominantly a T cell derived cytokine which is particularly important for the terminal differentiation, activation and survival of committed eosinophil precursors. The human IL-5 gene is located on chromosome 5 in a gene cluster that contains the evolutionary related IL-4 family of cytokine genes. The human IL-5 receptor complex is a heterodimer consisting of a unique a subunit (predominantly expressed on eosinophils) and a beta subunit which is shared between the receptors for IL-3 & GM-CSF (more widely expressed). The a subunit is required for ligand-specific binding whereas association with the beta subunit results in increased binding affinity. The alternative splicing of the alphaIL-5R gene which contains 14 exons can yield several alphaIL-5R isoforms including a membrane-anchored isoform (alphaIL-5Rm) and a soluble isoform (alphaIL-5Rs). Cytokines such as IL-5 produce specific and non-specific cellular responses through specific cell membrane receptor mediated activation of intracellular signal transduction pathways which, to a large part, regulate gene expression. The major intracellular signal transduction mechanism is activation of non-receptor associated tyrosine kinases including JAK and MAP kinases which can then transduce signals via a novel family of transcriptional factors named signal transducers and activators of transcription (STATS). JAK2, STAT1 and STAT 5 appear to be particularly important in IL-5 mediated eosinophil responses. Asthma is characterized by episodic airways obstruction, increased bronchial responsiveness, and airway inflammation. Several studies have shown an association between the number of activated T cells and eosinophils in the airways and abnormalities in FEV1, airway reactivity and clinical severity in asthma. It has now been well documented that IL-5 is highly expressed in the bronchial mucosa of atopic and intrinsic asthmatics and that the increased IL-5 mRNA present in airway tissues is predominantly T cell derived. Immunocytochemical staining of bronchial biopsy sections has confirmed that IL-5 mRNA transcripts are translated into protein in asthmatic subjects. Furthermore, the number of activated CD 4 + T cells and IL-5 mRNA positive cells are increased in asthmatic airways following antigen challenge and studies that have examined IL-5 expression in asthmatic subjects before and after steroids have shown significantly decreased expression following oral corticosteroid treatment in steroid-sensitive asthma but not in steroid resistant and chronic severe steroid dependent asthma. The link between T cell derived IL-5 and eosinophil activation in asthmatic airways is further strengthened by the demonstration that there is an increased number of alphaIL-5R mRNA positive cells in the bronchial biopsies of atopic and non-atopic asthmatic subjects and that the eosinophil is the predominant site of this increased alphaIL-5R mRNA expression. We have also shown that the subset of activated eosinophils that expressed mRNA for membrane bound alpha IL5r inversely correlated with FEV1, whereas the subset of activated eosinophils that expressed mRNA for soluble alphaIL5r directly correlated with FEV1. Hence, not only does this data suggest that the presence of eosinophils expressing alphaIL-5R mRNA contribute towards the pathogenesis of bronchial asthma, but also that the eosinophil phenotype with respect to alphaIL-5R isoform expression is of central importance. Finally, there are several animal, and more recently in vitro lung explant, models of allergen induced eosinophilia, late airway responses(LARS), and bronchial hyperresponsiveness(BHR) - all of which support a link between IL-5 and airway eosinophila and bronchial hyperresponsiveness. The most direct demonstration of T cell involvement in LARS is the finding that these physiological responses can be transferred by CD4+ but not CD8+ T cells in rats. The importance of IL-5 in animal models of allergen induced bronchial hyperresponsiveness has been further demonstrated by a number of studies which have indicated that IL-5 administration is able to induce late phase responses and BHR and that anti-IL-5 antibody can block allergen induced late phase responses and BHR. In summary, activated T lymphocytes, IL5 production and eosinophil activation are particularly important in the asthmatic response. Human studies in asthma and studies in allergic animal models have clearly emphasised the unique role of IL-5 in linking T lymphocytes and adaptive immunity, the eosinophil effector cell, and the asthma phenotype. The central role of activated lymphocytes and eosinophils in asthma would argue for the likely therapeutic success of strategies to block T cell and eosinophil activation (eg steroids). Importantly, more targeted therapies may avoid the complications associated with steroids. Such therapies could target key T cell activation proteins and cytokines by various means including blocking antibodies (eg anti-CD4, anti-CD40, anti-IL-5 etc), antisense oligonucleotides to their specific mRNAs, and/or selective inhibition of the promoter sites for these genes. Another option would be to target key eosinophil activation mechanisms including the aIL5r. As always, the risk to benefit ratio of such strategies await the results of well conducted clinical trials.

Mechanisms of cell accumulation induced by Mycobacterium bovis BCG

Mycobacteria, specially Mycobacterium tuberculosis are among the micro-organisms that are increasing dramatically the number of infections with death, all over the world. A great number of animal experimental models have been proposed to investigate the mechanisms involved in the host response against these intracellular parasites. Studies of airway infection in guinea-pigs and rabbits, as well as, in mice intravenously infected with BCG have made an important contribution to our understanding of the virulence, pathogenesis and the immunology of mycobacterial infections. Although, there are few models to study the mechanisms of the initial inflammatory process induced by the first contact with the Mycobacteria, and the relevance of the acute generation of inflammatory mediators, cytokines and leukocyte infiltration to the development of the mycobacterial infection. In this work we reviewed our results obtained with a model of M. bovis BCG-induced pleurisy in mice, describing the mechanisms involved in the leukocyte influx induced by BCG at 24 hr. Different mechanisms appear to be related with the influx of neutrophils, eosinophils and mononuclear cells and distinct inflammatory mediators, cytokines and adhesion molecules are involved in the BCG-induced cell accumulation.

Nitric oxide paradox in asthma

Asthma results from allergen-driven intrapulmonary Th2 response, and is characterized by intermittent airway obstruction, airway hyperreactivity (AHR), and airway inflammation. Accumulating evidence indicates that inflammatory diseases of the respiratory tract are commonly associated with elevated production of nitric oxide (NO). It has been shown that exhaled NO may be derived from constitutive NO synthase (NOS) such as endothelial (NOS 3) and neural (NOS 1) in normal airways, while increased levels of NO in asthma appear to be derived from inducible NOS2 expressed in the inflamed airways. Nevertheless, the functional role of NO and NOS isoforms in the regulation of AHR and airway inflammation in human or experimental models of asthma is still highly controversial. In the present commentary we will discuss the role of lipopolysaccharides contamination of allergens as key element in the controversy related to the regulation of NOS2 activity in experimental asthma.

The role of interferon-gamma on immune and allergic responses

Allergic diseases have been closely related to Th2 immune responses, which are characterized by high levels of interleukin (IL) IL-4, IL-5, IL-9 and IL-13. These cytokines orchestrate the recruitment and activation of different effector cells, such as eosinophils and mast cells. These cells along with Th2 cytokines are key players on the development of chronic allergic inflammatory disorders, usually characterized by airway hyperresponsiveness, reversible airway obstruction, and airway inflammation. Accumulating evidences have shown that altering cytokine-producing profile of Th2 cells by inducing Th1 responses may be protective against Th2-related diseases such as asthma and allergy. Interferon-gamma (IFN-gamma), the principal Th1 effector cytokine, has shown to be crucial for the resolution of allergic-related immunopathologies. In fact, reduced production of this cytokine has been correlated with severe asthma. In this review, we will discuss the role of IFN-gamma during the generation of immune responses and its influence on allergic inflammation models, emphasizing its biologic properties during the different aspects of allergic responses.

Local anaesthetic medication for the treatment of asthma

It is presumed that drugs able to prevent bronchial spasm and/or inflammation may have therapeutic potential to control asthma symptoms. The local anaesthetic lidocaine has recently received increased attention as an alternative form of treatment for asthmatic patients. This paper reviews the major findings on the topic and summarizes the putative mechanisms underlying the airway effects of local anaesthetic agents. We think that lidocaine extends the spectrum of options in asthma therapy, probably by counteracting both spasmogenic and inflammatory stimuli in the bronchial airways. The possibility of development of new anti-asthma compounds based on the synthesis of lidocaine derivatives is also on the horizon.

Macrophage elastase (MMP-12): a pro-inflammatory mediator?

As many metalloproteinases (MMPs), macrophage elastase (MMP-12) is able to degrade extracellular matrix components such as elastin and is involved in tissue remodeling processes. Studies using animal models of acute and chronic pulmonary inflammatory diseases, such as pulmonary fibrosis and chronic obstrutive pulmonary disease (COPD), have given evidences that MMP-12 is an important mediator of the pathogenesis of these diseases. However, as very few data regarding the direct involvement of MMP-12 in inflammatory process in the airways were available, we have instilled a recombinant form of human MMP-12 (rhMMP-12) in mouse airways. Hence, we have demonstrated that this instillation induced a severe inflammatory cell recruitment characterized by an early accumulation of neutrophils correlated with an increase in proinflammatory cytokines and in gelatinases and then by a relatively stable recruitment of macrophages in the lungs over a period of ten days. Another recent study suggests that resident alveolar macrophages and recruited neutrophils are not involved in the delayed macrophage recruitment. However, epithelial cells could be one of the main targets of rhMMP-12 in our model. We have also reported that a corticoid, dexamethasone, phosphodiesterase 4 inhibitor, rolipram and a non-selective MMP inhibitor, marimastat could reverse some of these inflammatory events. These data indicate that our rhMMP-12 model could mimic some of the inflammatory features observed in COPD patients and could be used for the pharmacological evaluation of new anti-inflammatory treatment. In this review, data demonstrating the involvement of MMP-12 in the pathogenesis of pulmonary fibrosis and COPD as well as our data showing a pro-inflammatory role for MMP-12 in mouse airways will be summarized.

Clonal multidrug-resistant Corynebacterium striatum within a nosocomial environment, Rio de Janeiro, Brazil

Corynebacterium striatum is a potentially pathogenic microorganism with the ability to produce outbreaks of nosocomial infections. Here, we document a nosocomial outbreak caused by multidrug-resistant (MDR) C. striatum in Rio de Janeiro, Brazil. C. striatum identification was confirmed by 16S rRNA and rpoB gene sequencing. Fifteen C. striatum strains were isolated from adults (half of whom were 50 years of age and older). C. striatum was mostly isolated in pure culture from tracheal aspirates of patients undergoing endotracheal intubation procedures. The analysis by pulsed-field gel electrophoresis (PFGE) indicated the presence of four PFGE profiles, including two related clones of MDR strains (PFGE I and II). The data demonstrated the predominance of PFGE type I, comprising 11 MDR isolates that were mostly isolated from intensive care units and surgical wards. A potential causal link between death and MDR C. striatum (PFGE types I and II) infection was observed in five cases.

Influenza A virus infection of healthy piglets in an abattoir in Brazil: animal-human interface and risk for interspecies transmission

Asymptomatic influenza virus infections in pigs are frequent and the lack of measures for controlling viral spread facilitates the circulation of different virus strains between pigs. The goal of this study was to demonstrate the circulation of influenza A virus strains among asymptomatic piglets in an abattoir in Brazil and discuss the potential public health impacts. Tracheal samples (n = 330) were collected from asymptomatic animals by a veterinarian that also performed visual lung tissue examinations. No slaughtered animals presented with any noticeable macroscopic signs of influenza infection following examination of lung tissues. Samples were then analysed by reverse transcription-polymerase chain reaction that resulted in the identification of 30 (9%) influenza A positive samples. The presence of asymptomatic pig infections suggested that these animals could facilitate virus dissemination and act as a source of infection for the herd, thereby enabling the emergence of influenza outbreaks associated with significant economic losses. Furthermore, the continuous exposure of the farm and abattoir workers to the virus increases the risk for interspecies transmission. Monitoring measures of swine influenza virus infections and vaccination and monitoring of employees for influenza infection should also be considered. In addition regulatory agencies should consider the public health ramifications regarding the potential zoonotic viral transmission between humans and pigs.

Modified method for bronchial suture by Ramirez Gama compared to separate stitches suture: experimental study

OBJECTIVE: To experimentally compare two classic techniques described for manual suture of the bronchial stump.METHODS: We used organs of pigs, with isolated trachea and lungs, preserved by refrigeration. We dissected 30 bronchi, which were divided into three groups of ten bronchi each, of 3mm, 5mm, and 7mm, respectively. In each, we performed the suture with simple, separated, extramucosal stitches in five other bronchi, and the technique proposed by Ramirez and modified by Santos et al in the other five. Once the sutures were finished, the anastomoses were tested using compressed air ventilation, applying an endotracheal pressure of 20mmHg.RESULTS: the Ramirez Gama suture was more effective in the bronchi of 3, 5 and 7 mm, and there was no air leak even after subjecting them to a tracheal pressure of 20mmHg. The simple interrupted sutures were less effective, with extravasation in six of the 15 tested bronchi, especially in the angles of the sutures. These figures were not significant (p = 0.08).CONCLUSION: manual sutures of the bronchial stumps were more effective when the modified Ramirez Gama suture was used in the caliber bronchi arms when tested with increased endotracheal pressure.

Helicopter emergency medical rescue for the traumatized: experience in the metropolitan region of Campinas, Brazil

OBJECTIVE: To analyze the profile of patients served by the air medical rescue system in the Metropolitan Region of Campinas, evaluating: triage and mobilization criteria; response time; on-site care and transport time; invasive procedures performed in the Pre-Hospital Care (PHC); severity of patients; morbidity and mortality.METHODS: We conducted a prospective, descriptive study in which we analyzed medical records of patients rescued between July 2010 and December 2012. During this period, 242 victims were taken to the HC-Unicamp. Of the 242 patients, 22 were excluded from the study.RESULTS: of the 220 cases evaluated, 173 (78.6%) were male, with a mean age of 32 years. Blunt trauma was the most prevalent (207 cases - 94.1%), motorcycle accidents being the most common mechanisms of injury (66 cases - 30%), followed by motor vehicle collisions (51 cases - 23.2%). The average response time was 10 ± 4 minutes and the averaged total pre-hospital time was 42 ± 11 minutes. The mean values of the trauma indices were: RTS = 6.2 ± 2.2; ISS = 19.2 ± 12.6; and TRISS = 0.78 ± 0.3. Tracheal intubation in the pre-hospital environment was performed in 77 cases (35%); 43 patients (19.5%) had RTS of 7.84 and ISSd"9, being classified as over-triaged. Of all patients admitted, the mortality was 15.9% (35 cases).CONCLUSION: studies of air medical rescue in Brazil are required due to the investments made in the pre-hospital care in a country without an organized trauma system. The high rate of over-triage found highlights the need to improve the triage and mobilization criteria.

Comparative analysis between identified injuries of victims of fall from height and other mechanisms of closed trauma

OBJECTIVE: To analyze the lesions diagnosed in victims of falls, comparing them with those diagnosed in other mechanisms of blunt trauma.METHODS: We conducted a retrospective study of trauma protocol charts (prospectively collected) from 2008 to 2010, including victims of trauma over 13 years of age admitted to the emergency room. The severity of injuries was stratified by the Abbreviated Injury Scale (AIS) and Injury Severity Score (ISS). Variables were compared between the group of victims of falls from height (Group 1) and the other victims of blunt trauma (Group 2). We used the Student t, chi-square and Fisher tests for comparison between groups, considering the value of p <0.05 as significant.RESULTS: The series comprised 4,532 cases of blunt trauma, of which 555 (12.2%) were victims of falls from height. Severe lesions (AISe"3) were observed in the extremities (17.5%), in the cephalic segment (8.4%), chest (5.5%) and the abdomen (2.9%). Victims of Group 1 had significantly higher mean age, AIS in extremities / pelvis, AIS in the thoracic segment and ISS (p <0.05). The group 1 had significantly (p <0.05) higher incidence of tracheal intubation on admission, pneumothorax, hemothorax, rib fractures, chest drainage, spinal trauma, pelvic fractures, complex pelvic fractures and fractures to the upper limbs.CONCLUSION: Victims of fall from height had greater anatomic injury severity, greater frequency and severity of lesions in the thoracic segment and extremities.

Importance of flexible bronchoscopy in decannulation of tracheostomy patients

OBJECTIVE: To evaluate the importance of flexible bronchoscopy in tracheostomy patients in the process of decannulation to assess the incidence and types of laryngotracheal injury and compare the presence of such lesions with clinical criteria used for decannulation. METHODS: We studied 51 tracheostomized patients aged between 19 and 87 years, with tracheal stent for a mean of 46 ± 28 days and with clinical criteria for decannulation. They were submitted to tracheostomy tube occlusion tolerance testfor 24 hours, and then to flexible bronchoscopy. We described and classified the diagnosed laryngotracheal changes. We compared the clinical criteria for decannulation indication with the bronchoscopy-diagnosed laryngotracheal injuries that contraindicated decannulation. We identified the factors that could interfere in decannulation and evaluated the importance of bronchoscopy as part of the process. RESULTS: Forty (80.4%) patients had laryngotracheal alterations. Of the 40 patients considered clinically fit to decannulation, eight (20%) (p = 0.0007) presented with laryngotracheal injuries at bronchoscopy that contraindicated the procedure. The most frequent laryngeal alteration was vocal cords lesion, in 15 (29%) individuals, and granuloma, the most prevalent tracheal lesion, in 14 (27.5%) patients. CONCLUSION: flexible bronchoscopy showed a large number of laryngotracheal injuries, the most frequent being the vocal cords injury in the larynx and the granuloma in the trachea, which contributed to increase the decannulation procedure safety.