Identification of polymorphisms in the bovine collagenous lectins and their association with infectious diseases in cattle.

Infectious diseases are a significant issue in animal production systems, including both the dairy and beef cattle industries. Understanding and defining the genetics of infectious disease susceptibility in cattle is an important step in the mitigation of their impact. Collagenous lectins are soluble pattern recognition receptors that form an important part of the innate immune system, which serves as the first line of host defense against pathogens. Polymorphisms in the collagenous lectin genes have been shown in previous studies to contribute to infectious disease susceptibility, and in cattle, mutations in two collagenous lectin genes (MBL1 and MBL2) are associated with mastitis. To further characterize the contribution of variation in the bovine collagenous lectins to infectious disease susceptibility, we used a pooled NGS approach to identify short nucleotide variants (SNVs) in the collagenous lectins (and regulatory DNA) of cattle with (n = 80) and without (n = 40) infectious disease. Allele frequency analysis identified 74 variants that were significantly (p < 5 × 10-6) associated with infectious disease, the majority of which were clustered in a 29-kb segment upstream of the collectin locus on chromosome 28. In silico analysis of the functional effects of all the variants predicted 11 SNVs with a deleterious effect on protein structure and/or function, 148 SNVs that occurred within potential transcription factor binding sites, and 31 SNVs occurring within potential miRNA binding elements. This study provides a detailed look at the genetic variation of the bovine collagenous lectins and identifies potential genetic markers for infectious disease susceptibility.

Pathological examination and the reporting of lung cancer specimens.

The Lung Cancer Disease Site Group (DSG) of the Cancer Care Ontario Practice Guidelines Initiative first met in January of 1994. Included in the membership were three pathologists who, with the other members of the DSG, felt that a useful contribution to the work of the group would be a recommendation on standardized examination and reporting of lung cancer specimens. This review summarizes the consensus of the Lung Cancer DSG pathologists based on their review of the literature and proposes a standard synoptic report, the Primary Lung Cancer Check-Off Sheet. If generally adopted, this standard would improve the quality of reporting of clinical and pathological stage information. Such high-quality staging information is essential to define patient populations for clinical trials and for outcome analyses.

Diagnostic accuracy of transbronchial biopsy in acute farmer's lung disease.

STUDY OBJECTIVES: To evaluate whether transbronchial biopsy (TBB) is useful for the diagnosis of acute farmer's lung (FL) by calculating the likelihood ratios (LHRs) of (1) simple pathologic criteria and (2) an overall assessment of the biopsy specimens. DESIGN: Retrospective study in which a blinded analysis of 105 TBBs with adequate material from patients with parenchymal diseases (55 cases of FL matched with 50 control samples) was performed by two independent pathologists. SETTING: Respiratory clinic of a university-affiliated referral center. MEASUREMENTS: Three pathologic criteria were first studied: (1) diffuse lymphocytic infiltration (LI); (2) focal LI; and (3) granulomas. Then, an overall assessment or the TBB was done. Four diagnostic categories were considered: (1) probable FL; (2) possible FL; (3) nonspecific; and (4) alternative diagnosis. LHRs favoring the diagnosis of FL were calculated for the pathologic criteria and for each diagnostic category. RESULTS: For both the pathologic criteria and the overall assessments, the interobserver agreement was fair. As a pathologic criterion, "diffuse LI" was better than "loosely formed granuloma" to discriminate FL from control samples (LHR, 9.1 [confidence interval, 2.2 to 37.0] vs 1.8 [confidence interval, 0.5 to 6.9]). After the overall assessment, as many as 48.6% of the TBBs were read as nonspecific. The LHRs of the four diagnostic categories were as follows: (1) probable FL: 1.1 (observer 1) and 2.6 (observer 2); (2) possible FL: 2.2 and 1.7; (3) nonspecific: 0.9 and 0.6; and (4) alternative diagnosis: 0.4 and 0.0. CONCLUSION: Hematoxylin-eosin-stained TBB specimen is of limited usefulness for the diagnosis of FL and should be reserved for patients with intermediate pretest probability of FL. Diffuse LI best discriminates FL from control samples and should be specifically sought.

Hypoxia, hypocapnia and spirometry at altitude.

1. Both hypoxia and hypocapnia can cause broncho-constriction in humans, and this could have a bearing on performance at high altitude or contribute to altitude sickness. We studied the relationship between spirometry, arterial oxygen saturation and end-tidal carbon dioxide (ETCO2) concentration in a group of healthy lowland adults during a stay at high altitude, and then evaluated the response to supplementary oxygen and administration of a beta 2 agonist. 2. We collected spirometric data from 51 members of the 1994 British Mount Everest Medical Expedition at sea level (barometric pressure 101.2-101.6 kPa) and at Mount Everest Base Camp in Nepal (altitude 5300 m, barometric pressure 53-54.7 kPa) using a pocket turbine spirometer. A total of 205 spirometric measurements were made on the 51 subjects during the first 6 days after arrival at Base Camp. Further measurements were made before and after inhalation of oxygen (n = 47) or a beta 2 agonist (n = 39). ETCO2 tensions were measured on the same day as spirometric measurements in 30 of these subjects. 3. In the first 6 days after arrival at 5300 m, lower oxygen saturations were associated with lower forced expiratory volume in 1 s (FEV1; P < 0.02) and forced vital capacity (FVC; P < 0.01), but not with peak expiratory flow (PEF). Administration of supplementary oxygen for 5 min increased oxygen saturation from a mean of 81%-94%, but there was no significant change in FEV1 or FVC, whilst PEF fell by 2.3% [P < 0.001; 95% confidence intervals (CI) -4 to -0.7%]. After salbutamol administration, there was no significant change in PEF, FEV1 or FVC in 35 non-asthmatic subjects. Mean ETCO2 at Everest Base Camp was 26 mmHg, and a low ETCO2 was weakly associated with a larger drop in FVC at altitude compared with sea level (r = 0.38, P < 0.05). There was no correlation between either ETCO2 or oxygen saturation and changes in FEV1 or PEF compared with sea-level values. 4. In this study, in normal subjects who were acclimatized to hypobaric hypoxia at an altitude of 5300 m, we found no evidence of hypoxic broncho-constriction. Individuals did not have lower PEF when they were more hypoxic, and neither PEF nor FEV1 were increased by either supplementary oxygen or salbutamol. FVC fell at altitude, and there was a greater fall in FVC for subjects with lower oxygen saturations and probably lower ETCO2.

Effect of altitude on spirometric parameters and the performance of peak flow meters.

BACKGROUND: Portable peak flow meters are used in clinical practice for measurement of peak expiratory flow (PEF) at many different altitudes throughout the world. Some PEF meters are affected by gas density. This study was undertaken to establish which type of meter is best for use above sea level and to determine changes in spirometric measurements at altitude. METHODS: The variable orifice mini-Wright peak flow meter was compared with the fixed orifice Micro Medical Microplus turbine microspirometer at sea level and at Everest Base Camp (5300 m). Fifty one members of the 1994 British Mount Everest Medical Expedition were studied (age range, 19-55). RESULTS: Mean forced vital capacity (FVC) fell by 5% and PEF rose by 25.5%. However, PEF recorded with the mini-Wright peak flow meter underestimated PEF by 31%, giving readings 6.6% below sea level values. FVC was lowest in the mornings and did not improve significantly with acclimatisation. Lower PEF values were observed on morning readings and were associated with higher acute mountain sickness scores, although the latter may reflect decreased effort in those with acute mountain sickness. There was no change in forced expiratory volume in one second (FEV1) at altitude when measured with the turbine microspirometer. CONCLUSIONS: The cause of the fall in FVC at 5300 m is unknown but may be attributed to changes in lung blood volume, interstitial lung oedema, or early airways closure. Variable orifice peak flow meters grossly underestimate PEF at altitude and fixed orifice devices are therefore preferable where accurate PEF measurements are required above sea level.

Alveolar inflammation and its relation to emphysema in smokers.

The prevalent theory in the pathogenesis of emphysema proposes that increased numbers of activated neutrophils and/or alveolar macrophages produce large amounts of proteases, an activity that cannot be regulated by alpha 1-antiproteases, resulting in lung destruction. However, the cells in the lung parenchyma of smokers have not been properly identified. We characterized and quantitated the inflammatory cell load in the lungs of smokers and correlated these findings with the degree of lung destruction. Twenty-one patients, six nonsmokers and 15 smokers, undergoing lung resection were studied. Lungs or lobes were fixed and stained for light microscopy and neutrophil identification and immunohistochemically stained for identification of lymphocytes and macrophages. By point counting, we determined the extent of emphysema by the volume density of the lung parenchyma (Vvalv), and the different cell numbers per cubic millimeter in all lungs. In nonsmokers Vvalv was greater than in smokers. The number of neutrophils/mm3 of lung correlated directly with the Vvalv, (r = 0.71, p < 0.01), whereas the number of alveolar macrophages (r = -0.70) and T-lymphocytes (r = -0.78) correlated negatively with the Vvalv. The number of T-lymphocytes correlated negatively with the number of neutrophils (r = -0.58) and positively with the numbers of alveolar macrophages (r = 0.77). Our data suggest that as long as the inflammatory reaction is predominantly of neutrophils there is no destruction of the lung. However, the extent of lung destruction becomes evident, and its extent is directly related to the number of alveolar macrophages and T-lymphocytes/mm3. We conclude that the T-lymphocyte might be importantly implicated in the pathogenesis of emphysema in smokers.

Morphometry of small airways in smokers and its relationship to emphysema type and hyperresponsiveness.

Based on our previous finding, of increased small airways disease in centrilobular emphysema (CLE) when compared with panlobular emphysema (PLE), we hypothesized that smokers who develop CLE would have increased airway responsiveness associated with airway inflammation and exaggerated airway narrowing, but not smokers with PLE. We compared preoperative methacholine challenge with the morphologic and cellular inflammatory characteristics of the airways in the lungs of six nonsmokers, 10 smokers with CLE, and five smokers with PLE. The airways of the CLE group were narrower than those of the nonsmokers (KS < 0.05) and the PLE group (KS < 0.05), but perimeters were not different. A greater percentage of airways in the CLE group showed infolding of the epithelium and lumen deformity than in the PLE group and nonsmokers (p < 0.05). Airway inner wall thickening (WI) was increased in the CLE group when compared with the PLE group and nonsmokers (p < 0.05), and WI correlated significantly with PC20 in the CLE group (r = -0.64, p < 0.01) but not in the PLE group and nonsmokers. The number of T lymphocytes in the airway walls correlated with PC20 in the CLE group (r = -0.50, p < 0.05) but not in the PLE group. In conclusion, despite similar age, smoking history, and range of airflow limitation, there was a clear difference in the methacholine responsiveness between the emphysema groups, suggesting that responsiveness is not just a reaction to smoking but either a reaction developing in some smokers or an abnormality initially present in some smokers which, in combination with exposure to cigarettes, determines the development of a type of lung disease: CLE.

Pulmonary aspergillosis: pathologic and pathogenetic features.

Pulmonary aspergillosis is a relatively common fungal infection in individuals who are immunocompromised or have intrinsic lung disease. Clinical, radiological, and pathologic manifestations are quite varied and depend to a large extent on the type and severity of local or systemic host defense abnormalities. In individuals with only structural lung damage, saprophytic growth alone is the rule. Patients with atopy or other hypersensitivity state typically develop allergic disease, most often allergic bronchopulmonary aspergillosis. Individuals with other immunologic abnormalities, particularly immunodeficiency, and with granulocytopenia characteristically develop invasive disease, which may take several morphological forms. Identification of Aspergillus as the cause of all these disease variants is usually not a problem. However, recognition of the different patterns of disease is useful in understanding the pathogenesis of disease and in interpreting premortem clinical and radiographic abnormalities.

Primary pulmonary adenocarcinoma with enteric differentiation.

A pulmonary neoplasm with cytologic characteristics typical of differentiated small intestinal epithelium is reported. Individual cells showed features suggesting columnar absorptive, goblet, Paneth, and neuroendocrine cell differentiation. Thorough investigation and follow-up for 4 years did not identify a primary tumor other than in the lung. The occurrence of such a neoplasm at this site is evidence for the existence of a common stem cell in the lower respiratory and gastrointestinal tract mucosa.

Alpha-1 antitrypsin deficiency and systemic necrotizing vasculitis.

We describe a 42-year-old woman with polyarteritis nodosa characterized by polyarthritis, purpuric rash, mononeuritis multiplex, focal segmental glomerulonephritis and necrotizing arteritis. alpha-1 antitrypsin deficiency was diagnosed incidentally on a liver biopsy. This is the third reported case of systemic necrotizing vasculitis in association with alpha-1 antitrypsin deficiency of the PI ZZ type, and the first to show significant response to cyclophosphamide and steroids.

Transthoracic needle aspiration. The benign diagnosis.

Transthoracic needle aspiration is a relatively innocuous procedure used extensively in the diagnosis of pulmonary disease. Although its sensitivity for malignancy is high, a negative (benign) diagnosis is obtained in 5% to 25% of all cases. Some of these aspirates represent the result of inadequate sampling of a malignant tumor; others, however, are derived from a truly benign process. This review briefly describes and illustrates the cytologic features of these latter aspirates in order to exemplify the wide range of benign diseases that can be identified or suspected by transthoracic needle aspiration. Familiarity with such features should help the interpreting pathologist to prevent needless respiration or thoracotomy in many patients.

Fungal tracheobronchitis. Report of 9 cases and review of the literature.

Clinical, roentgenographic and pathologic findings are described in 9 patients with fungal tracheobronchitis and comparison is made with 25 additional cases in the literature. Two morphologic patterns were identified: the first appears as a pseudomembrane of necrotic tissue, exudate, and fungal hyphae involving more-or-less the entire circumference of the bronchial wall or as mucus/fungus plugs completely occluding the airway lumen; the second consists of single or multiple discrete plaques on the airway wall, sometimes associated with invasion of the adjacent lung parenchyma or pulmonary artery. As with more invasive forms of fungal infection, a compromise in host defenses is probably the most important factor leading to fungal colonization and subsequent local invasion. Malignancies of the hematologic and lymphoreticular systems, solid neoplasms, granulocytopenia, and a history of a protracted course of broad-spectrum antibiotics, corticosteroids, and chemotherapy were present in most of our patients and in those reported in the literature. Despite this, there is some evidence that tracheobronchitis may occur in individuals with a relatively lesser degree of host defense impairment. Local damage to the airway wall such as occurs with prolonged mechanical ventilatory support, neoplastic infiltration, or nonfungal infection may also be a factor predisposing to fungal colonization and invasion. In 4 of our patients, the fungal infection of the tracheobronchial tree probably contributed significantly to the development of terminal respiratory failure. Although recognition of the infection may not have altered the course of the underlying disease in some of our patients, in others identification and early treatment might have been life-saving. Thus, culture and histologic examination of bronchoscopically identified tracheobronchial mucus plugs and necrotic material should be performed in all immunocompromised individuals.

The use of biomarkers in the prediction of survival in patients with pulmonary carcinoma.

Data on ten variables and 16 biomarkers were obtained on 119 patients with newly diagnosed pulmonary cancer. The prognostic value of 16 biomarkers (alpha-1-antitrypsin [AAT], adrenocorticotropic hormone [ACTH], alpha-fetoprotein [AFP], carcinoembryonic antigen [CEA], human chorionic gonadotropin [HCG], immune complexes, immunoglobulins, N-terminal peptide of proopiomelanocortin [NTERM], and tumor-associated antibody [TAA]) was tested by adding these to the model of age, gender, stage, morphology, Feinstein's classification of symptoms, Karnofsky scale, leukocyte count, recent weight loss, and liver enzymes. Using Cox's regression method and a forward stepwise procedure, seven biomarkers (ACTH, AAT, AFP, calcitonin, HCG, TAA, and prolactin) entered the model. Elevated levels of cortisol and TAA were associated with longer survival. The selection of biomarkers by stepwise regression needs to be interpreted with caution, especially since the Z scores were found to be dependent on the particular variables included in the model. Furthermore, when dichotomized on maximum of the normal laboratory values, HCG and AFP were infrequently (2%) elevated. The lack of correlation among the biomarkers supports the hypothesis of random derepression of the genome of cancer cells. Further studies in improved modeling and the formulation of a biomarker index could enhance our understanding of the biology of cancer.

Long-term follow-up of drug abusers with intravenous talcosis.

Six patients who injected talc containing drugs intended for oral use were assessed over a period of ten or more years from the time of initiation of this habit. Despite discontinuation of the drug abuse, all developed severe respiratory disability and three died from their disease. An evolving spectrum of roentgenographic and functional patterns is considered to be virtually diagnostic of this disorder. Roentgenographically, an initial diffuse, pin-point micronodularity subsequently becomes associated with conglomerates, usually in the upper lobes, closely resembling the progressive massive fibrosis (PMF) of the pneumoconioses. The lower lobes, on the other hand, become relatively translucent, in some instances with bulla formation and the development of pneumothorax. Pulmonary function, initially with both restrictive and obstructive features, eventually becomes markedly obstructive with hyperinflation and air trapping. At this late stage, pathologic examination reveals emphysema in addition to the granulomatous inflammation and fibrosis surrounding the talc particles in the pulmonary interstitium.

A beneficial effect of trypsin on the purification of turnip mosaic virus (TuMV) and other potyviruses.

The effects of treatment with trypsin during the purification of turnip mosaic virus (TuMV), on virus yield, infectivity and integrity of virus coat protein were examined. Trypsin increased yield markedly, and at a low concentration, increased infectivity. These effects were probably due to reduced aggregation of virus particles. At higher concentrations of trypsin, there was some degradation of virus coat protein, and infectivity was reduced. Treatment with trypsin at the optimum concentration can significantly improve purification of TuMV; more limited experiments suggest that it can also be applied to other potyviruses.

Lung perforation complicating tube thoracostomy: pathologic description of three cases.

Insertion of a chest tube into the pleural space is standard therapy for a variety of pleural abnormalities. Three cases are described of lung perforation secondary to this procedure. In all three cases the tube had been inserted with the use of a trocar, and in two there were pleural adhesions in the vicinity of the puncture; in none was the perforation suspected clinically or considered to contribute to patient death. Pathologic features included one or two pleural holes continuous with a parenchymal tract of variable length. In one case, there was early epithelialization of the inner surface of the tract, suggesting that some of these may remain patent and be seen as incidental findings long after their formation. Two of the cases were identified among 18 patients who had had chest tubes inserted and came to autopsy over a similar period, implying that the incidence of the complication is greater than is generally appreciated. Reasons for this under appreciation are the lack or nonspecificity of clinical and radiographic findings and the ease with which perforation can be overlooked at autopsy.

Pulmonary involvement in giant cell arteritis.

While clinically suspected in some cases, pulmonary lesions in giant cell arteritis have rarely been described pathologically. We report the findings at autopsy in an elderly woman with typical giant cell arteritis. In addition to inflammation of temporal and other major systemic vessels, large- and medium-sized pulmonary arteries showed focal necrosis as well as medial granulomatous inflammation. These findings, as well as a review of previous clinical and pathologic reports, emphasize that the disease can affect the lungs and may rarely be a significant cause of morbidity.

Catheter-induced pulmonary artery perforation: pathologic and pathogenic features.

Perforation of the pulmonary artery due to insertion of a balloon-tipped, flow-directed (Swan-Ganz) catheter is described in four cases. These cases were found in a consecutive series of 270 autopsies done over a 1.5-year period and suggest that the incidence of this complication may be greater than the number of clinically reported cases implies. In three instances, a focal parenchymal hematoma or thrombotic nodule identified the site of rupture. Other pathologic features and the pathogenesis of the perforation are discussed. Difficulties in postmortem diagnosis include distinguishing perforation from hemorrhage due to trauma, thromboembolism, and coagulation abnormalities.