Borrelia lonestari infection after a bite by an Amblyomma americanum tick

Erythematous rashes that are suggestive of early Lyme disease have been associated with the bite of Amblyomma americanum ticks, particularly in the southern United States. However, Borrelia burgdorferi, the causative agent of Lyme disease, has not been cultured from skin biopsy specimens from these patients, and diagnostic serum antibodies usually have not been found. Borrelia lonestari sp nov, an uncultured spirochete, has been detected in A. americanum ticks by DNA amplification techniques, but its role in human illness is unknown. We observed erythema migrans in a patient with an attached A. americanum tick. DNA amplification of the flagellin gene flaB produced B. lonestari sequences from the skin of the patient that were identical to those found in the attached tick. B. lonestari is a probable cause of erythema migrans in humans.     

Pathophysiological role of Toll-like receptor 5 engagement by bacterial flagellin in colonic inflammation

Commensal and enteroinvasive microbes in the human gut release bacterial flagellin, a specific microbial ligand of Toll-like receptor 5 (TLR5). However, the pathophysiological role of bacterial flagellin in gastrointestinal inflammation has not been determined. Here we evaluated the role of bacterial flagellin using native human colonic mucosa and the mouse colitis model of dextran sulfate sodium (DSS). We demonstrate that, in intact human colonic mucosa, the flagellin/TLR5 response occurs only after exposure to the basolateral, not the apical, surface, implying a basolaterally polarized TLR5 response in human colonic mucosa. In this context, flagellin exposure to injured colonic mucosa due to DSS administration in mice resulted in a TLR5-associated response evaluated by in vivo activation of mitogen-activated protein kinase/extracellular signal-related kinase 1/2 (MEK1/2) and elevated IL-6, TNF-alpha, and keratinocyte-derived chemokine production, whereas intact colonic mucosa did not respond to flagellin. Moreover, flagellin exposure to injured mouse colon in vivo, but not to intact colon, also significantly aggravated colonic inflammation, increased mouse mortality, and enhanced histopathological damage in the colonic mucosa. However, the TLR2-specific agonist, peptidoglycan or lipoteichoic acid, did not cause an inflammatory response in intact or DSS-injured mouse colon. Furthermore, intracolonic flagellin administration in mice causes severe apoptosis in colonic epithelium disrupted by DSS administration. These data suggest that intracolonic flagellin via TLR5 engagement is able to elicit inflammatory responses in disrupted colon, whereas the normal colon is not responsive to bacterial flagellin. These results demonstrate that bacterial flagellin plays an important role in the development and progress of colitis.     

Evasion of Toll-like receptor 5 by flagellated bacteria

Toll-like receptor 5 (TLR5) recognizes an evolutionarily conserved site on bacterial flagellin that is required for flagellar filament assembly and motility. The alpha and epsilon Proteobacteria, including the important human pathogens Campylobacter jejuni, Helicobacter pylori, and Bartonella bacilliformis, require flagellar motility to efficiently infect mammalian hosts. In this study, we demonstrate that these bacteria make flagellin molecules that are not recognized by TLR5. We map the site responsible for TLR5 evasion to amino acids 89-96 of the N-terminal D1 domain, which is centrally positioned within the previously defined TLR5 recognition site. Salmonella flagellin is strongly recognized by TLR5, but mutating residues 89-96 to the corresponding H. pylori flaA sequence abolishes TLR5 recognition and also destroys bacterial motility. To preserve bacterial motility, alpha and epsilon Proteobacteria possess compensatory amino acid changes in other regions of the flagellin molecule, and we engineer a mutant form of Salmonella flagellin that evades TLR5 but retains motility. These results suggest that TLR5 evasion is critical for the survival of this subset of bacteria at mucosal sites in animals and raise the intriguing possibility that flagellin receptors provided the selective force to drive the evolution of these unique subclasses of bacterial flagellins.     

Helicobacter pylori flagellin evades toll-like receptor 5-mediated innate immunity

Helicobacter pylori colonizes the human stomach for decades unless pharmacologically eradicated. We hypothesized that this flagellated pathogen escapes immune clearance, in part, by avoiding detection by the flagellin receptor Toll-like receptor 5 (TLR5). In contrast to other gram-negative microbes, H. pylori did not release flagellin. Furthermore, recombinant H. pylori flagellin (FlaA) was significantly less potent (1000-fold) than Salmonella typhimurium flagellin in activating TLR5-mediated interleukin (IL)-8 secretion. TLR5 can mediate flagellin-induced IL-8 secretion via p38 mitogen-activated protein kinase signaling; however, compared with potent induction by S. typhimurium flagellin, H. pylori FlaA-dependent p38 activation was substantially attenuated. In addition, disruption of H. pylori flaA decreased motility but had no effect on H. pylori-induced IL-8 secretion, which indicates that H. pylori flagellin plays no role in activating epithelial orchestration of inflammation. We conclude that H. pylori evades TLR5-mediated detection, which may contribute to its long-term persistence in individual hosts.     

Chlamydia pneumoniae, strain TWAR, infection in patients with chronic obstructive pulmonary disease.

TWAR, the only known serovar of Chlamydia pneumoniae, is a newly described bacterium that has been identified as a cause of both epidemics and endemic cases of pneumonia. The role of TWAR infection in patients with chronic obstructive pulmonary disease (COPD) is not known. We conducted a prospective study to establish whether TWAR infection is a common cause of acute exacerbations of COPD. We studied two groups of patients: 44 patients admitted to the hospital with acute exacerbations of COPD, and 65 stable clinic patients with COPD. We found that evidence of acute TWAR infection was infrequent in patients with exacerbations (5%). In contrast, the majority of patients from both groups had serologic evidence of previous TWAR infection (77%). This was not significantly greater than the prevalence found in a small group of patients of similar age and sex without lung disease from the same institution (73%). TWAR was not isolated from the oropharyngeal specimens obtained from 97 subjects, suggesting that it does not colonize the respiratory tract of patients with COPD. This study shows that at the time of low incidence in the community, acute TWAR infection is uncommon in patients with acute exacerbations of COPD. The majority of patients with COPD have, however, been infected with TWAR in the past. The clinical manifestations of these infections are not known and should be the focus of further studies.     

慢性阻塞性肺疾病稳定期下呼吸道细菌定植状况

慢性阻塞性肺疾病（COPD）是严重危害人类健康的一种疾病,感染是COPD发病和加剧的重要因素之一,稳定期患者下呼吸道存在细菌定植,主要是嗜血杆菌属、肺炎链球菌和卡他莫拉菌,细菌定植的存在与气道炎症、肺功能的降低有关,并且当细菌负荷量超过阈值时就会产生足够严重的炎症反应,从而诱发加重期的临床症状,使疾病迅速进展。     

Permissive hypercapnia

There has been increasing recognition that mechanical ventilation can cause acute parenchymal lung injury (ventilator-induced lung injury, or VILI) in addition to the more widely recognized forms of barotrauma. Furthermore, in patients with acute lung injury, this type of injury may cause considerable morbidity and mortality. Subsequently, the goals of mechanical ventilation have been altered to avoid this outcome. In patients with relatively normal lungs who are receiving mechanical ventilation because of neuromuscular dysfunction or impaired conscious level or for short-term postoperative support, maintaining normal blood-gas tensions without risk of VILI is usually easy. In patients with acute asthma, chronic obstructive pulmonary disease, or acute lung injury, however, accepting abnormal blood-gas tensions, particularly an elevated PaCO2 (permissive hypercapnia), to improve survival and reduce complications is frequently necessary. Extensive experience has shown that ventilated patients usually tolerate moderate hypercapnia and frequently some degree of hypoxemia in the absence of shock, anemia, severe cardiac disease, or other contraindications.     

Sickle acute lung injury: role of prevention and early aggressive intervention strategies on outcome

Acute chest syndrome in sickle cell disease is a form of acute lung injury that may progress to acute respiratory distress syndrome and death. Despite recent advances in diagnosis and treatment that have resulted in improved survival in sickle cell disease, acute chest syndrome remains the most common cause of death in this population. The current standards of treatment for acute chest syndrome have been reviewed. Biomedical re-search forms the basis for sound clinical decision making and implementation of interventions that target prevention, diagnosis, and effective treatment options. Although current clinical trials are ongoing to address several new potential therapeutic options,more research using preventative and interventional strategies in sickle acute lung injury is warranted.     

肠道菌群失衡在急性胰腺炎肠黏膜屏障损伤中的作用

急性胰腺炎(acute pancreatitis,AP)是临床常见的急腹症,其发病率呈逐年增高趋势.AP病情进展迅速,15％～20％的患者发展为重症急性胰腺炎(severe acute pancreatitis,SAP),病死率高达20％～30％.SAP常可导致肠道功能障碍,包括肠黏膜屏障损伤和肠道动力障碍,引起肠道细...     

Death from ischemic heart disease in young Finns aged 15 to 24 years

The epidemiology and autopsy findings of death from ischemic heart disease were studied among 7,998 Finns who died at age 15 to 24 years between 1961 and 1971 (9,150,000 person-years). In 34 of this group, ischemic heart disease was indicated as the cause of death in the death certificate. Eight cases were excluded, six because of questionable evidence of ischemic disease and two because of the presence of another severe underlying disease. With 26 accepted deaths, the incidence of death from ischemic heart disease was 0.51/100,000 man-years and 0.04/100,000 woman-years, respectively. The World Health Organization criteria for acute ischemic heart disease were met in 21 cases (81 percent); in the remaining 5 cases, death had occurred suddenly with no other known cause. In 24 of 25 cases with a known time of onset of the fatal attack, death occurred within 24 hours of onset. The acute symptoms appeared during or immediately after physical exertion hi 13 subjects (65 percent); in 5 of these the exercise was approximately maximal. Eight of 20 subjects with available data had a history of previous chest pain or arrhythmia. Autopsy was performed in 19 cases (73 percent). A stenosing process in the coronary arteries was found in 17 patients (89 percent). Among 15 to 19 year olds the stenosis was generally ostial and non-sclerotic; ostial stenosis was found in half of this group. After age 20, atherosclerosis was the major cause of coronary stenosis. The role and etiology of sclerotic and nonsclerotic coronary processes as a cause of acute ischemic heart disease in young persons are discussed.     

Epidemiology, etiology, and prevention of lung cancer

Over the past century, lung cancer has gone from an obscure disease to the leading cause of cancer death worldwide. Initially an epidemic disease among men in industrialized nations, lung cancer now has become the leading cancer killer in both sexes in the United States and an increasingly common disease of both sexes in developing countries. Lung cancer incidence largely mirrors smoking prevalence, with a latency period of several decades. Other important risk factors for the development of lung cancer include environmental exposure to tobacco smoke, radon, occupational carcinogens, and pre-existing nonmalignant lung disease. Studies in molecular biology have elucidated the role that genetic factors play in modifying an individual's risk for lung cancer. Although chemopreventive agents may be developed to prevent lung cancer, prevention of smoking initiation and promotion of smoking cessation are currently the best weapons to fight lung cancer. No other malignancy has been shown to have such a strong epidemiologic relation between a preventable behavior and incidence of disease. Despite this knowledge, more than 20% of all Americans smoke, and tobacco use is exploding in developing countries. Based on current and projected smoking patterns, it is anticipated that lung cancer will remain the leading cause of cancer death in the world for decades to come.     

The value of serial serum angiotensin converting enzyme determinations in hospitalized patients with lung disease

Abnormal serum angiotensin converting enzyme (ACE) activity has been reported in various human lung disorders and in laboratory animals with acute lung injuries. To test the value of serum ACE activity as an indicator of lung damage and its assistance in diagnosis or prognosis, 328 serum samples were obtained from 108 hospitalized patients with lung disease and 26 normal subjects. When patients were clinically grouped by disease entity, only the sarcoidosis group showed elevated mean serum ACE. Significantly increased serum ACE was found in 17 patients with various lung diseases (15% of hospitalized patients) 12 of whom also had concomitant liver disease. It is hypothesized that the liver may play a role in the normal metabolism of ACE being released by lung endothelial injury. Significantly low levels were seen in many acute and chronic lung injuries; specifically the groups with chronic obstructive lung disease, lung cancer, acute pneumonia, aspiration pneumonitis, gram-negative sepsis, acute myocardial infarction, and congestive heart failure. Serial measures of ACE in 71 patients with lung injuries showed that significantly decreasing levels over successive days were associated with a very high mortality. A single ACE measurement did not predict the presence or extent of lung injury, or aid in diagnosis or prognosis, but serial levels are of value prognostically.     

Future directions in early cystic fibrosis lung disease research: an NHLBI workshop report

Since the 1989 discovery that mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), there has been substantial progress toward understanding the molecular basis for CF lung disease, leading to the discovery and development of new therapeutic approaches. However, the earliest impact of the loss of CFTR function on airway physiology and structure and its relationship to initial infection and inflammation are poorly understood. Universal newborn screening for CF in the United States represents an unprecedented opportunity for investigating CF clinical manifestations very early in life. Recently developed animal models with pulmonary phenotypic manifestations also provide a window into the early consequences of this genetic disorder. For these reasons, the National Heart, Lung, and Blood Institute (NHLBI) convened a working group of extramural experts, entitled "Future Research Directions in Early CF Lung Disease" on September 21-22, 2010, to identify future research directions of great promise in CF. The priority areas identified included (1) exploring pathogenic mechanisms of early CF lung disease; (2) leveraging newborn screening to elucidate the natural history of early lung disease; (3) developing a spectrum of biomarkers of early lung disease that reflects CF pathophysiology, clinical outcome, and response to treatment; (4) exploring the role of genetics/genomics (e.g., modifier genes, gene-environmental interactions, and epigenetics) in early CF pathogenesis; (5) defining early microbiological events in CF lung disease; and (6) elucidating the initial airway inflammatory, remodeling, and repair mechanisms in CF lung disease.     

Interstitial lung disease in patients with ataxia-telangiectasia

Ataxia-telangiectasia (A-T) is an autosomal-recessive multiorgan disease characterized by progressive neurologic deterioration in which the most common causes of death are diseases of the respiratory system and cancers. The aim of this retrospective study was to delineate the clinical, radiographic, and pathologic manifestations of the chronic progressive interstitial lung disease seen in patients with A-T. The medical records of 97 patients with A-T and chronic lung disease were reviewed. Interstitial lung disease (ILD) was specifically diagnosed in 25 of 97 patients. None of these patients had evidence of an infectious process preceding the onset of their lung disease, and none had lasting clinical improvement after treatment with antibiotics. Although many medications were used to treat their ILD, only treatment with systemic corticosteroids early in the course of their illness was associated with clinical and radiographic improvement. Nineteen of these 25 patients with ILD died within 24 months of the onset of their ILD, and of 7 patients treated with corticosteroids, 5 are still alive. Recognition of interstitial lung disease in patients with A-T and its early treatment could reduce or eliminate pulmonary disease as a leading cause of death for these patients.     

One hundred years of lung cancer

A hundred years ago, lung cancer was a reportable disease, and it is now the commonest cause of death from cancer in both men and women in the developed world, and before long, will reach that level in the developing world as well. The disease has no particular symptoms or signs for its detection at an early stage. Most patients therefore present with advanced stage IIIB or IV disease. Screening tests began in the 1950s with annual chest x-ray films and sputum cytology but they resulted in no improvement in overall mortality compared with control subjects. The same question is now being asked of spiral low-dose computed tomographic scanning. There have been big refinements in the staging classification of lung cancer and advances in stage identification using minimally invasive technology. Postsurgical mortality has declined from the early days of the 1950s but 5-year cure rates have only barely improved. The addition of chemotherapy to radical radiotherapy, together with novel radiotherapy techniques, is gradually improving the outcome for locally advanced, inoperable non-small cell lung cancer. Chemotherapy offers modest survival improvement for patients with non-small cell lung cancer, the modern agents being better tolerated resulting in an improved quality of life. The management of small cell lung cancer, which appeared so promising at the beginning of the 1970s, has hit a plateau with very little advance in outcome over the last 15 years. The most important and cost-effective management for lung cancer is smoking cessation, but for those with the disease, novel agents and treatment approaches are urgently needed.     

New pulmonary infiltrates in a 19 year-old with sickle cell crisis.

OBJECTIVE: Sickle cell anemia (SCA) is the most common inherited blood disorder. Sickle cell crisis is characterized by episodes of pain, chronic hemolytic anemia and severe infections, usually beginning in early childhood. Sickle cell disease primarily affects those of African descent and Hispanics of Caribbean ancestry, but the trait has also been found in those with Middle Eastern, Indian, Latin American, Native American, and Mediterranean heritage. Recent studies indicate that more than 12,500 people in England have sickle cell disorders. The acute chest syndrome is the leading cause of death and the second most common cause of hospitalization among patients with sickle cell disease. The acute chest syndrome (ACS) is characterized by chest pain with dyspnea and recent radiological abnormalities. Since its cause is largely unknown, rapid recognition and early institution of therapy is paramount as with timely and appropriate intervention majority of these patients survive. The treatment of ACS rests on controlled hydration, antibiotic therapy, oxygen therapy, controlled analgesic therapy, blood transfusion and exchange transfusion. A better understanding of the disease and a close collaborative approach between a primary care physician and a specialist may be the key to improve the quality of care rendered. METHODS: Research studies, review articles, and published scientific meeting abstracts were reviewed.