The use of an "internal standard" for control of the recovery in microdialysis

Microdialysis of intravenously injected theophylline in blood and in lung tissue was performed in two rats during anaesthesia. The recovery (dialysate extraction fraction) in blood was greater than the recovery in lung tissue and there was a change in recovery with time both in blood and in lung. The concentrations of theophylline in the dialysates were corrected for the recovery using caffeine as an "internal standard" in the perfusate as well as tritiated water injected into the rats. There was excellent agreement between the two different methods. Furthermore, the corrected concentration of unbound theophylline in the blood was in accordance with the simultaneously measured total concentration of theophylline in plasma when binding to plasma proteins was taken into account. The conclusion is that an "internal standard" for correction of the recovery is a useful method to approach the true concentrations of compounds in the extracellular water. The "internal standard" must be as equal as possible to the substance of interest.     

Plasmodium berghei: a mouse model for the "sudden death" and "malarial lung" syndromes

A mouse model for the "sudden death" and "malarial lung" syndromes is described. Mice of the C3H/z strain succumb suddenly approximately 7 days after an infection with Plasmodium berghei becomes patent, at a time when parasitemia is still moderate (6 to 8%). Death could be shown to be due to anaphylactoid shock, probably induced by soluble immune complexes. Increased vascular permeability caused transudation and leakage of serum proteins into the interstitium and the alveoli. The lungs were found to be edematous, with a fine granular precipitate in the alveoli and adherent to the vascular walls. The precipitates reacted with antiglobulins G and M, and could be shown to also contain malaria antigens and C3/4. A dramatic drop in hematocrit was recorded several hours before death, indicating the sudden release of malaria antigens. The myocardium of animals that had died very suddenly showed a patchy loss of phosphorylase activity. This loss of activity was much more extensive, and sometimes almost total, when there had been an agonal period of several (1 to 3) hours before death. In these cases the irreversibility of the myocardial damage was also indicated by the loss of activity of the dehydrogenases, as well as by typical inflammatory reactions of granulocytic and histiocytic infiltrations. The hearts thus presented a typical picture of the acute and peracute shock syndromes. In acute shock cardiac insufficiency develops so suddenly that death ensues before irreversible damage has occurred, and cardiac insufficiency can only be demonstrated by the most sensitive of enzyme histochemical means. In the present case shock was induced by the anaphylactoid activity of immune complexes with the lung as target organ. The described syndrome appears analogous to human "malarial lung."     

Diagnostic significance of "severe dysplasia" in sputum cytology

The diagnostic significance of a cytologic diagnosis of "severe dysplasia" on sputum samples was assessed. In a group of 46 patients with diagnoses of severe dysplasia, follow-up showed no malignancy of the lung in 25 patients (54%) and a malignant process in 21 patients (46%). These groups were compared to 52 patients with correct negative and 202 patients with correct positive sputum diagnoses. Of the patient characteristics investigated, age, previous sputum production, vital capacity and low forced expiratory volume were not significantly related to a sputum cytodiagnosis of severe dysplasia. In contrast, severe dyspnea showed a significantly higher frequency in patients with a sputum cytodiagnosis of severe dysplasia, but without an underlying malignant lung process. Follow-up disclosed a malignant tumor in 10 of 13 patients with disease; the presence of severely dysplastic cells in sputum specimens from such patients should be considered a warning signal for an underlying malignant lung process. Since severe dysplasia should be considered a premalignant epithelial lesion, patients with sputum cytodiagnoses of severe dysplasia should undergo bronchoscopy, with multiple bronchial brushings of all areas showing suspicious mucosal changes, together with segmental bronchial washings. In case a malignant process cannot be located, sputum examinations should be repeated at three-month intervals.     

论“风邪犯肺”的肺微生态失调与中医药干预

肺为"娇脏",易受风邪侵袭而出现咳嗽喘息等症状。研究发现,微生态的平衡对人体健康的保持意义重大。在本文中我们解释了中医病机"风邪犯肺",并从微生态失衡的角度来思考"风邪犯肺"的科学内涵,探讨风邪犯肺与微生态失衡的联系。认为中医药主要通过直接作用于微生物、改变机体内部环境以及肺—肠轴这三种途径来调整风邪犯肺导致的微生态失衡。旨在将现代研究理论与中医理论相结合,挖掘中医药在调整微生态失衡方面的可能作用机制和潜力,深入探讨中医认识疾病、治疗疾病的本质和优势,以期为微生态学的研究和中医药的现代化开拓思路。     

Hochachka's "Hypoxia Defense Strategies" and the development of the pathway for oxygen

Hochachka's "Hypoxia Defense Strategies" identify oxygen signalling, metabolic arrest, channel arrest and coordinated suppression of ATP turnover rates as key factors that determine the ability of organisms to survive exposure to chronic hypoxia. In this review, I assess the developmental role played by these phenomena in the morphogenesis of the gas exchange tissues that define the pathway for oxygen transport to cytochrome c oxidase. Key areas of regulation lie in: (I) the suppression of fetal mitochondrial oxidative function in hand with mitochondrial biogenesis (metabolic arrest), (II) the role of hypoxia-driven oxygen signalling pathways in directing the scope of non-differentiated stem cell proliferation in placenta and lung development and (III) the regulation of epithelial fluid secretion/absorption in the lung through the oxygen-dependent modulation of Na+ conductance pathways. The identification of developmental roles for Hochachka's "Hypoxia Defense Strategies" in directing the morphogenesis of gas exchange structures bears with it the implication that these strategies are fundamental to establishing the scope for aerobic metabolic performance throughout life.     

Spatial-temporal targeting of lung-specific mesenchyme by a <Emphasis Type="Italic">Tbx4</Emphasis>enhancer

Background

Reciprocal interactions between lung mesenchymal and epithelial cells play essential roles in lung organogenesis and homeostasis. Although the molecular markers and related animal models that target lung epithelial cells are relatively well studied, molecular markers of lung mesenchymal cells and the genetic tools to target and/or manipulate gene expression in a lung mesenchyme-specific manner are not available, which becomes a critical barrier to the study of lung mesenchymal biology and the related pulmonary diseases.

Results

We have identified a mouse Tbx4 gene enhancer that contains conserved DNA sequences across many vertebrate species with lung or lung-like gas exchange organ. We then generate a mouse line to express rtTA/LacZ under the control of the Tbx4 lung enhancer, and therefore a Tet-On inducible transgenic system to target lung mesenchymal cells at different developmental stages. By combining a Tbx4-rtTA driven Tet-On inducible Cre expression mouse line with a Cre reporter mouse line, the spatial-temporal patterns of Tbx4 lung enhancer targeted lung mesenchymal cells were defined. Pulmonary endothelial cells and vascular smooth muscle cells were targeted by the Tbx4-rtTA driver line prior to E11.5 and E15.5, respectively, while other subtypes of lung mesenchymal cells including airway smooth muscle cells, fibroblasts, pericytes could be targeted during the entire developmental stage.

Conclusions

Developmental lung mesenchymal cells can be specifically marked by Tbx4 lung enhancer activity. With our newly created Tbx4 lung enhancer-driven Tet-On inducible system, lung mesenchymal cells can be specifically and differentially targeted in vivo for the first time by controlling the doxycycline induction time window. This novel system provides a unique tool to study lung mesenchymal cell lineages and gene functions in lung mesenchymal development, injury repair, and regeneration in mice.

     

False "false-positive" results in diagnostic cytology

With the introduction of transbronchial brushings and fine needle aspiration biopsy, which enable us to obtain samples directly from lesions, the diagnostic potential of cytology for the detection of malignancy, including early cancer, has been greatly enhanced. From 1976 to 1982, five positive cytology reports were initially considered to be "false positives" on the basis of negative gross findings, benign operative biopsies or negative histologic findings in the resected surgical specimens. However, these proved to be false "false positives," based upon the clinical follow-up or further examination of the surgical specimens. Presentation is made of three of these cases with positive cytologic findings and initially negative histologic diagnoses, with an analysis of the causes of the latter. From our experience, four types of cancerous lesions seem prone to being missed during gross examination, namely: any small cancer with a consistency similar to that of the parenchyma of the organ in which the tumor is located, superficially invasive carcinoma, scar cancer and a radiologically occult lung cancer in the presence of a coexisting radiologically demonstrable lesion. With more clinical application of these cytologic methods, false "false positives" are expected to occur more often.     

Role of the biological activity of serotonin in the production of the "shock lung" syndrome]

The influence of the serotin biological activity on forming the "shock" lung syndrome was revealed in experiments on rats. Tachyhyperpnea with predominance of functional emphysema and a small number of atelectic tissue areas were observed in the animals with traumatic "shock" during the serotonin hypersecretion. Tachyhypopnea with a significant predominance of atelectiv areas was seen during the serotonin hypoproduction.     

The state of the "glycocalyx" of rat lung cells following left-sided pneumonectomy]

Edema in the tissue of the right lung developed 24 hours after the leftsided pneumonectomy. It was found that: 1) the layer of acid mucopolysaccharide on the surface of the alveolar and endothelial cells became thicker; 2) accumulation of the product of reaction with the RR on the surface of the alveolar cells of type 1 and of the endothelial cells took place; 3) "blisters" coated with the product of reaction with the RR (Red Ruthenium) appeared. These "blisters" were connected with the plasmolemma of the alveolar and endothelial cells. All these findings suggest that acid mucopolysaccharides of the lung surfactant system participated in the accumulation and elimination of the water from the tissues of the air-blood barrier.     

Association of <Emphasis Type="Italic">XPA</Emphasis> Polymorphisms Towards Lung Cancer Susceptibility and its Predictive Role in Overall Survival of North Indians

The present study investigated the role of Xeroderma pigmentosum group A (XPA) polymorphism (A23G and G709A) with lung cancer risk and its association with overall survival in North Indians. 370 cases and 370 controls were investigated to evaluate association between XPA polymorphism (A23G and G709A) with lung cancer risk using logistic regression analysis. A follow-up study was also conducted for 291 lung cancer cases illustrating correlation between overall survival in lung cancer patients and XPA variants. GG genotype showed an increased lung cancer risk (p = 0.0007) for A23G polymorphism whereas G709A polymorphism was associated with significant protective effect in heterozygous (AG) subjects (p = 0.001). When stratified according to smoking status an increased risk for lung cancer was observed for GG genotype in A23G polymorphism (p = 0.0002). A poor survival in females carrying variant genotype (GG) was observed (p = 0.001; MST = 4.16 months) for A23G polymorphism. Adenocarcinoma patients with heterozygous genotype showed an increased hazard ratio (p = 0.02) for A23G polymorphism. G709A was associated with a reduced hazard ratio marking a better survival among mutant females (HR 0.17; p = 0.05; MST = 18.63 months). It can be concluded that A23G polymorphism might contribute to increased lung cancer risk in North Indian population emphasizing on poor survival among females. G709A polymorphism might result in protective effect in lung cancer subjects. The present study had a low sample size but it could act as reference for the large sample studies in future.     

The significance of the "lung phase" in host-helminth relations.

Many helminth infections have a "lung phase" whose significance considering the host-parasite relations has not yet been clarified. In some nematode infections larvae must pass through the lungs, in others adult worms live in the respiratory tract, and some others cause tropical pulmonary eosinophilia. Some examples of these infections (Nippostrongylus brasiliensis, Schistosoma mansoni, Trichinella spiralis and Toxocara canis) are considered to clarify whether this phase of infection is a "pro-host" or a "pro-parasite" mechanism. Whereas in primary infections--in some cases--transit through the lungs may render the parasite more resistant to host defence mechanisms (e.g., Schistosoma and perhaps Trichinella infections) or enables completion of the cycle (Nippostrongylus and Toxocara infections), in secondary infections the lungs might be the site of parasite killing.     

Double primary lung cancers: with special reference to their exfoliative cytology and to the rare, malignant "mixed" tumor of the salivary-gland type

Two autopsy cases are reported in which double primary cancers of the lung had been strongly or definitely suspected before death by demonstration of two different types of malignant cells in the sputum as well as in smears of aspirates from pleural fluid and/or mediastinal tumor. By exfoliative cytology, one case was characterized by carcinoma cells of the small-cell type plus the large-cell and/or adenocarcinoma type; the other displayed small-cell-type and squamous-cell-type malignant cells. The autopsies definitely revealed in the first case an anaplastic carcinoma of the small-cell type in the left bronchus and a salivary-gland-type malignant "mixed" tumor in the right lower lobe and in the second case an anaplastic carcinoma of the small-cell type in the right upper lobe and a squamous-cell carcinoma in the left upper lobe. The frequence of occurrence and pathologic diagnosis of double primary lung cancers are reviewed and discussed. A rare type of lung cancer, salivary-gland-type malignant "mixed" tumor, is given special reference.     

The influence of multiple types of occupational exposure to radon, gamma rays and long-lived radionuclides on mortality risk in the French "post-55" sub-cohort of uranium miners: 1956-1999

The adverse health effects of radon on uranium miners, especially on their lungs, are well documented, but few studies have considered the effects of other radiation exposures. This study examined the mortality risks associated with exposure to radon, external γ rays and long-lived radionuclides (LLR) in the French "post-55" sub-cohort, which includes uranium miners first employed between 1956 and 1990 for whom all three types of exposure were assessed individually. Exposure-risk relationships were estimated with linear excess relative risk models and a 5-year lag time. The post-55 sub-cohort includes 3377 miners, contributing 89,405 person-years, followed up through the end of 1999 with a mean follow-up of 26.5 years. Mean cumulative exposure was 17.8 WLM for radon, 54.7 mSv for γ rays, and 1,632 Bq.m(-3).h for LLR. Among the 611 deaths observed, 66 were due to lung cancer. Annual individual exposures were significantly correlated. Increased mortality was observed for lung cancer (SMR = 1.30; 95% CI: 1.01, 1.65) and for brain and central nervous system (CNS) cancer (SMR = 2.00; 95% CI: 1.09, 3.35). Cumulative exposure to radon, γ rays and LLR was associated only with a significant risk of lung cancer. These new results could suggest an association between lung cancer and exposure to γ rays and LLR. They must nonetheless be interpreted with caution because of the correlation between the types of exposure. The calculation of organ doses received by each of these exposures would reduce the collinearity.     

PI-specific phospholipase C "alpha" from sheep seminal vesicles is a proteolytic fragment of PI-PLC delta.

Phosphatidylinositide-specific phospholipase C enzymes (PLCs) catalyze the conversion of the phosphoinositides to biologically important signal transducing molecules. These enzymes may be grouped into "families" which share similar structures and modes of regulation. The existence of a structurally distinct family of PLC termed "alpha" has been recently called into question. In the current paper we show by immunoblotting experiments that PLC "alpha" from sheep seminal vesicles is recognized by monoclonal antibodies raised against the delta 1 isoform of bovine brain PLC, and appears to be derived from a higher molecular weight band at 85 kDa. We also show that antibodies raised against PLC alpha efficiently immunoprecipitate the 85-kDa PLC delta 1 isoform from bovine brain and Chinese hamster lung fibroblasts. These data provide strong evidence that the PLC alpha from sheep seminal vesicles is a proteolytic fragment of PLC delta 1. Thus, there is still no conclusive evidence for a separate "alpha" class of PLC.     

Association of <Emphasis Type="Italic">p</Emphasis>53 codon 72 polymorphism and survival of North Indian lung cancer patients treated with platinum-based chemotherapy

p53 helps in maintaining genomic stability by undergoing cellular arrest, DNA repair or cellular apoptosis during DNA damage. So, as to find the association of p53Arg ⁷² Pro towards lung carcinogenesis and overall survival of North Indian lung cancer patients, single nucleotide polymorphic variant (rs1042522) was analyzed. 840 subjects including 420 cases and 420 controls were recruited and genotyped using PCR-RFLP technique for p53Arg ⁷² Pro polymorphic site. Association was analyzed using adjusted odds ratio along with its confidence intervals (95?% CI) and p value predicted from logistic regression whereas overall survival for lung cancer patients was obtained using Kaplan–Meir and Cox regression model for different parameters to obtain hazard ratio and survival time with statistical significance (log-rank p value). None of the variant genotypes for p53Arg ⁷² Pro showed any association towards lung cancer risk or any specific histological subtype. Lung cancer subjects with Pro/Pro genotype had better median survival time as compared to Arg/Pro genotype (10 months; HR?=?0.65; 95?% CI?=?0.45–0.95; p?=?0.03). Furthermore, female lung cancer patients with Arg/Pro (HR?=?0.08; 95?% CI?=?0.02–0.34; p?=?0.0005) and Pro/Pro (HR?=?0.21; 95?% CI?=?0.06–0.67; p?=?0.008) genotypes showed a better overall survival and hence a better prognosis as compared to males. Our data also reveals that lung cancer patients with ECOG scores between 0 and 1 and carrying the Pro/Pro had better chances of survival. p53 codon 72 polymorphism could play a role as a prognostic marker in lung cancer patients.     

Richard Doll and Alice Stewart: reputation and the shaping of scientific "truth"

As the world watched the Fukushima reactors release radionuclides into the ocean and atmosphere, the warnings of Dr. Alice Stewart about radiation risk and the reassurances of Sir Richard Doll assumed renewed relevance. Doll and Stewart, pioneer cancer epidemiologists who made major contributions in the 1950s-he by demonstrating the link between lung cancer and smoking, she by discovering that fetal X-rays double the chance of a childhood cancer-were locked into opposition about low-dose radiation risk. When she went public with the discovery that radiation at a fraction of the dose "known" to be dangerous could kill a child, her reputation plummeted, whereas Doll, foremost among her detractors, was knighted and lauded as "the world's most distinguished medical epidemiologist" for his work. Their lives and careers, so closely intertwined, took contrary courses, he becoming "more of the establishment" (as he said), while she became more oppositional. When it was discovered, after his death, that he'd been taking large sums of money from industries whose chemicals he was clearing of cancer risk, his reputation remained unscathed; it is now enshrined in the "Authorized Biography" (2009) commissioned by the Wellcome Institute, along with Doll's denigration of Stewart as an "embittered" woman and biased scientist. Stewart lived long enough to see radiation science move her way, to see international committees affirm, in the 1990s, that there is no threshold beneath which radiation ceases to be dangerous; recent evidence from Chernobyl is bearing out her warnings. But a look at the making and breaking of these reputations reveals the power of status, position, and image to shape scientific "knowledge" and social policy.     

Potent inhibition of angiotensin-converting enzyme by [des-Pro3]-bradykinin or "converstatin" in comparison with Captopril

The mechanism of bradykinin-potentiating activity of [des-Proline3]-bradykinin, a kinin originally generated from human plasma protein by trypsin, was studied in terms of its inhibitory actions on angiotensin-converting enzyme and kininase II prepared from rat lung. The results were compared with those obtained with Captopril. [Des-Pro3]-bradykinin was found to have a potent inhibitory action against angiotensin-converting enzyme with a K1 of 4.5 X 10(-12) M, which is approximately 7 times more potent than Captopril. It was also inhibitory to kininase II with a Ki of 4 X 10(-11) M, which is approximately 2,300-fold more potent than Captopril. The pattern of inhibition was purely competitive with increased apparent Km but no change in apparent Vmax for both angiotensin-converting enzyme and kininase II. This is in contrast to Captopril, which showed a mixed competitive and non-competitive type of inhibition with increased apparent Km and decreased Vmax for both enzymes. Such a potent inhibitory activity of [des-Pro3]-bradykinin or Arg-Pro-Gly-Phe-Ser-Pro-Phe-Arg is noteworthy, and accordingly we propose the name "converstatin" for this peptide.